Diabetic Book

Diabetes Care in India
Today and by 2025?
Editor-in-chief:
Dr B M Jayaram
MD (AIIMS)., FICA., FICP., FIMSA., FICC

Formerly,
Head of the Department of Medicine,
Bangalore Medical College
Superintendent, Bowring and Lady Curzon Hospital
Senior Physician, Government of Karnataka.
MICRO LABS LIMITED

No. 27, Race Course Road, Bangalore- 560 001. INDIA
e-mail: dtfmicro@microlabs.in
Diabetes Care in India Today... and by 2025?
No. of Copies Printed -25,000

Editor-in-chief:
Dr Prof B M Jayaram
Editorial Board:

Dr
Dr
Dr
Dr
Coordination Committee:

Mr B R Srinath
Mr G Jayaraj
Dr Harsha
Dr Gurudutt Nayak U
Mr G Seshagiri
Mr V Gokulananda
Mr B J Reddy
Mr T L Daksha Kumar
Prof Ashok Kumar Das

Prof N R Rau
Samar Banerjee
Kashinath Dixit
First edition 2011 (For private circulation only).

All rights reserved.
ii
No part of this publication may be reproduced, stored in a retrieval system or

transmitted, in any form or by any means electronic, mechanical, photocopying,
recording or otherwise without the prior permission of the copyright owner.
This publication contains views or opinions of experts in the field of
Diabetes Care and do not represent the decisions or stated policies of Micro Labs
Limited.
Published by Dr. Prof. B. M. Jayaram on behalf of Micro Labs Limited, Bangalore.
Designed by: Art Studio, Micro Labs - DTF, Micro Labs Limited.
Dear Doctor,
Micro Labs Limited wishes you a very happy and prosperous New Year. I am very
confident that you are in the midst of very highly knowledgeable educative program during APICON at Ahmedabad. I am sure you will carry sweet memories of
the conference.
As a part of the educative program of MICRO LABS DTF Division, we have so far
published nine books on Type 2. Diabetes Mellitus. The success of these books has
made us to venture out on the latest book titled Diabetes Care in India Today
... and by 2025?.
It is expected that India will suffer from a major epidemic of diabetes by 2025.
Possibly in addition to genetic factors, consumption of junk food, over eating, lack
of physical exercise, obesity including childhood obesity, over indulgence of alcohol, chronic smoking and stress and strain of modern life are leading to increased
incidence of type 2 diabetes. It is expected that this epidemic will cross more than
87 millions by 2025. Although we are aware of the focus of knowledge today, we
need to know how we should combat this escalating epidemic by 2025?. Thus MICRO
LABS - DTF division has ventured out to bring out a publication on Diabetes Care
in India Today ... and by 2025?.
A good number of Diabetologists of reputation have contributed to this book. We
should get prepared for proper diagnosis, management and accuracy of treatment so
that the working capacity of the individual is not lost in the interest of the nation.
I sincerely thank Dr. A K Das, Dr. N R Rau, Dr. Samar Banerjee, Dr. Kashinath
Dixit, as members of the editorial board and I also sincerely thank the coordination committee members Mr. B R Srinath, Mr. G. Jayaraj, Dr. Harsha Dr. Nayak,
Mr. G Seshagiri, Mr. V Gokulananda, Mr. B J Reddy & Mr. T L Daksha Kumar, for
helping me in bring out the volume.
An Unsearching Mind is as Good as Dead - Socrates
Duty is What One Expects from Others - Oscar Wilde
With Regards,
Dr. B M Jayaram, MD (AIIMS)., FICA., FICP., FIMSA., FICC

Formerly,
Head of the Department of Medicine,
Bangalore Medical College
Superintendent, Bowring and Lady Curzon Hospital
iii
Dr Abhijit Deshpande, MD.,

Nagpur, Maharashtra
Dr Ajish TP MD.,
Cochin, Kerala
Dr Anil Bhansali, MD., DM.,
Chandigarh, Punjab
Dr Prof. Apurba Kumar Mukherjee, MD
Kolkata, West Bengal
Dr A J Asirvatham, M.D., D.Diab,
Madurai, Tamil Nadu
Dr Asish Kumar Basu, MD., DM
Dr Ashok Kumar Das, MD., PhD., FICP., FIMS.,
Puducherry
Dr Banshi Saboo, MD
Ahmedabad, Gujarat
Dr Binod K Sahay MD, FICP, FICN, FAIID, FACP, FAMS
Hyderabad, Andhra Pradesh
iv
Dr M Chenniappan, MD., DM., FACC., FRCP.,

Trichy, Tamil Nadu
Dr D Maji, MD., DM.,
Ms M Divya
Chennai, Tamil Nadu
Dr R S Hariharan, MD.,
Chennai, Tamil Nadu
Dr Harish Ranjani, CDE., Ph.D
Chennai, Tamil Nadu
Dr Indira Maisnam, MD., DM., Resident
Dr Jay Deshmukh, MD., FCPS., MNAMS
Nagpur, Maharashtra
Dr R V Jayakumar, MD., DM, MNAMS., FRCP.,
Cochin, Kerala
Dr B M Jayaram, MD., FICA., FICP., FIMSA., FICC
Bangalore, Karnataka
Mrs Kamlesh Sethi,

New Delhi
Dr Kashinath Dixit, MD
Dr R H Lakshmi, MD.,
Chennai, Tamil Nadu
Dr Loganathan Geetha, BDS., MPH
Chennai, Tamil Nadu
Dr K D Modi, MD., DM., DNB.,
Dr M V Muraleedharan, MD., DM., MRCP
Trichur, Kerala
Dr Navneet Agrawal, MD.,
Gwalior, Madhya Pradesh
Dr A Nanditha, MD.,
Chennai, Tamil Nadu
Dr Pankaj Singhania, MBBS., MD., Resident
Dr Pradeep G Talwalkar, MD.,
Mumbai, Maharashtra
Dr Pradip Mukhopadhyay, MD, DM
Dr Pramila Kalra, MD., DM
Dr K M Prasanna Kumar, MD., DM.,
Dr Praveen Jeyapathy, MBBS.,
Cochin, Kerala
Dr Rakesh K Avasthi, MD
New Delhi
Dr Rakesh Sahay, MD, DNB, DM(Endo), FICP, FIACM, FACE, MAMS
Dr A Ramachandran, MD., PhD., Dsc., FRCP(Lon)., FRCP(Edin)., FICP., MNAMS
Chennai, Tamil Nadu
Dr T K Ramesh, MS., DNB., FRCS.,
Dr N R Rau, MD., FICP.,
Manipala, Karnataka
Dr Samith A Shetty, MBBS., MDRC

Chennai, Tamil Nadu
Dr Sanjay Kalra, MD., DM.,
Karnal, Hariyana
Dr Sarita Bajaj, MD., DM
Allahabad, Uttar Pradesh
Dr Semanti Chakrabarty, MBBS., MD., Resident
Dr Shaliesh Lodha, MD., DM., FACE.,
Jaipur, Rajasthan
Dr Shashank R Joshi, MD., DM., FICP., FACE
Mumbai, Maharashtra
Dr Shivashankara KN, MD
Manipala, Karnataka
Dr M Shunmugavelu, MD
Trichy, Tamil Nadu
Dr C Snehalatha, MSc., D.Sc., D.Phil
Chennai, Tamil Nadu
Dr Subhankar Chowdhury, DTM&H., MD., DM., MRCP.,
vi
Dr Sunil Gupta, MD., FIAMS., FIACM., FICP.,

Nagpur, Maharashtra
Dr Swati Agrawal, MD.,
Gwalior, Madhya Pradesh
Dr R Uday Sankar, MD
Trichy, Tamil Nadu
Dr A G Unnikrishnan, MD., DM.,
Cochin, Kerala
Dr Viral Shah, FCCP., DM., Resident
Chandigarh, Punjab
Dr V Mohan, MD., FRCP., (Lon, Edin, Glasgow, Ireland) Ph.D., D.Sc., FNASc.,
Chennai, Tamil Nadu
Dr Vijay Viswanathan, M.D., Ph.D., FRCP(Lon)., FRCP(Glasgow).,
Chennai, Tamil Nadu
EPIDEOMIOLOGY
Burden of Type 2 Diabetes in India:
Prevalence and Projections
Dr
Dr
Dr
Dr
01-11
A Ramachandran, Chennai
A Nanditha, Chennai
Samith A Shetty, Chennai
C Snehalatha, Chennai
Translational Research in India: Today

And By 2025?
12-22
Type 2 Diabetes: The Present International Classification
23-28
Dr Viswanathan Mohan, Chennai

Dr Loganathan Geetha, Chennai
Dr Harish Ranjani, Chennai
Dr R V Jayakumar, Cochin
Dr Praveen Jeyapathy, Cochin
vii
PATHOPHYSIOLOGY
Genetics of Type 2 Diabetes Mellitus:
Is there any Protective Approach?
29-34
Problems Of Obesity In Type 2 Diabetes
35-46
Dr Anil Bhansali, Chandigarh

Dr Viral Sharma, Chandigarh
Dr K D Modi, Hyderabad
DIAGNOSIS AND MONITORING

HbA1c: Present Status and Predictions for 2025
47-54
Self Monitoring of Blood Glucose:

A Window to Better Management & Patient Education
55-63
Dr A G Unnikrishnan, Cochin
Dr Ajish TP, Cochin
Dr Jay Deshmukh, Nagpur

Dr Abhijit Deshpande, Nagpur
COMPLICATIONS
Screening & Management of Diabetic Dyslipidemia
64-72
Burden of CV Disease in T2DM
73-76
Management of Hypertension in Diabetes:

The Role of ACEIs and ARBs
77-81
Antiplatelet Agents in T2DM
82-91
Diabetes and Angiogenesis
92-98
Recent Trends & Future Perspectives

in the Management of Peripheral Neuropathy
99-110
Diabetic Retinopathy: With Special Reference

to Fundus Photography
111-120
Diabetic Kidney Disease: Clinical Manifestation,

Diagnosis & Treatment
121-127
Neuropsychiatric Screening In T2DM
128-131
Gestational Diabetes: Screening and Treatment
132-136
Management of Women with Pre-existing

Type 2 Diabetes During Pregnancy
137-159
Dr Banshi Saboo, Ahmedabad

Dr Chenniappan, Trichy
Dr Uday Shankar, Trichy
Dr M V Muraleedharan, Trichur
Dr Subhankar Chowdhury, Kolkata

Dr Pradip Mukhopadhyay, Kolkata
Dr Navneet Agrawal, Gwalior
Dr Sanjay Kalra, Gwalior
Dr Swati Agrawal, Gwalior
viii
Dr Vijay Viswanathan, Chennai

Mrs Divya, Chennai
Dr T K Ramesh, Bangalore
Dr D Maji, Kolkata
Dr Semanti Chakrabarty, Kolkata
Dr Shailesh Lodha, Jaipur
Dr R S Hariharan, Chennai
Dr R H Lakshmi, Chennai
Dr Sunil Gupta, Nagpur
LIFE STYLE MODIFICATION & PHARMACOTHERAPY

Nutritional Recommendations in T2DM
160-173
Yoga & Meditation in The Prevention of Type 2 Diabetes
174-182
Management of Prediabetes
183-188
Metformin: A Reappraisal
189-203
Diabetes Care in a Hospital Setup
204-215
Mrs Kamlesh Sethi, New Delhi

Dr R K Avasthi, New Delhi
Dr B K Sahay, Hyderabad
Dr R K Sahay, Hyderabad
Dr P G Talwalkar, Mumbai
Dr A J Asirvatham, Madurai
Dr N R Rau, Manipala
Dr K N Shivashankara, Manipala
EDUCATION & COUNSELLING

Education of T2DM for School Children
in their Curriculum
216-225
Dr K M Prasanna Kumar, Bangalore

Dr Pramila Kalra, Bangalore
ix
T2DM Education for the Urban and

Rural Population
226-234
Education In Diabetic Foot Care
235-245
Dr Apurba Kumar Mukherjee, Kolkata

Dr Indira Maisnam, Kolkata
Dr Asish Kumar Basu, Kolkata
Dr Pankaj Singhania, Kolkata
FUTURE DIRECTIONS
Future Strategies for Improving
246-268
Information Technology and Diabetes:

How can Clinicians use it?
269-278
Dr Ashok Kumar Das, Puducherry
Dr Shashank R Joshi, Mumbai
Immunization In T2DM
279-283
Current and Future Strategies for

Preservation of Beta Cells
284-290
Therapeutic Approaches In T2DM: Whats in the Offing?
291-301
Dr B M Jayaram, Bangalore
Dr Kashinath Dixit
Dr Sarita Bajaj, Allahabad
Dr M Shunmugavelu, Trichy

Dr A Ramachandran
President India Diabetes Research Foundation &

Chairman & Managing Director
Dr. A. Ramachandrans Diabetes Hospitals
28, Marshalls Road,
Egmore, Chennai 600 008, India.
Phone : +91 44 28982003 005, Fax: + 91 44 42146652
e-mail: ramachandran@vsnl.com
&
Dr A Nanditha
Dr Samith A Shetty
C Snehalatha

Abstract
Diabetes has reached an epidemic proportion in many developing countries. As per the
estimates made by the International Diabetes Federation, of the 285 millions adult diabetic
subjects in the world, 70% live in low and middle income countries. Unfortunately, India
tops the list with the largest number of diabetic persons (57 millions in 2010) which is
expected to rise to 90 millions in another 20 years. The high prevalence is due to a strong
genetic predisposition, and also by the presence of low threshold levels for age and environmental risk factors for diabetes. Indians develop diabetes at a young age and develop
the vascular complications in the productive years of their lives. Presence of complications
increases the economic burden of diabetes care by many folds, for the affected families
and the society. Poor glycaemic control, which is associated with lack of awareness, low
education and poor patient education facilities as well as the high cost of treatment,
increases the risk of complications. The large population of India with varied cultural and
socio economic background poses a great challenge in diabetes care in India. Improving
the national capacity for early diagnosis and management, distribution of medicines at
affordable cost and above all, steps towards primary prevention of the disease are urgent
needs to combat the epidemic of the disease.
The global prevalence of diabetes in 2010 is 6.6% and it is expected to increase to 7.8%
in 2030.1 The corresponding numbers of people with diabetes are 285 millions and 438
millions respectively. In addition, there are 344 million people with IGT in 2010 which is
predicted to rise to 472 millions by 2030.
The International Diabetes Federation (IDF)1 has highlighted that The diabetes epidemic
is here and threatens to overwhelm health systems if left unchecked. It is also stated
Diabetes is a development issue-the epicenters of the epidemic are in low-and middleincome countries and it is a threat to the health and economic prosperity of nations.
India unfortunately tops the list of countries with the largest number of people with
diabetes (50.8 millions) in 2010 and is likely to remain so in 2030 (87.0 millions), if no
drastic steps are taken to curb the epidemic.
Although many communicable diseases have been successfully wiped out, the prevalence
of non-communicable diseases like diabetes and Cardio Vascular Diseases (CVD) are increasing rapidly, chiefly due to increasing risks associated with modern life style. Several
epidemiological studies in migrant Indians2 and in India3, 4 itself show that the population has a high genetic predisposition for diabetes, which is precipitated by the adverse
environmental factors due to urbanization. In 1970s reports of migrant Asian Indians
living in different parts of the world showed that they had higher prevalence of diabetes
than other ethnic groups living in the same countries.2 This was attributed to change in
the environmental factors, such as increased affluence, which unmask a genetic or racial
tendency for diabetes.
Risk Factors for Diabetes

The important risk factors for th e high prevalence of diabetes include: (1) High familial
aggregation (2) Age (3) Adiposity (4) Body fat percentage (5) Insulin resistance (6) Life style
changes due to urbanization and (7) High prevalence of prediabetic conditions.
Familial Aggregation
Studies in India and abroad have shown that Indians have a genetic predisposition to
diabetes, which gets unmasked when the environmental conditions are adverse. The facts
that nearly 75% of the type 2 diabetic patients have first degree family history of diabetes
indicate a strong familial aggregation in the Indian diabetic patients5.
Age
Indians develop diabetes at a younger age and at a lower weight, suffer longer from chronic
hyperglycaemia, develop multiple complications and mortality occurs at a younger age than
in developed countries.4,6 In the developed Western countries, behavioural changes occurred
at a slower pace due to gradual economic developments. In Asia and other developing
countries, the changes are occurring at a rapid pace. This has affected the lifestyle of the
youth adversely, overweight and obesity are increasing and concomitantly, a rising prevalence of associated metabolic risk factors also occur.7 A study by the authors in Chennai,
among school children of 12 to 19 years showed that overall 67.7% of the apparently
healthy children (64.8% of normal weight and 85% of overweight children) had at least
one cardiometabolic abnormality i.e. low HDL-cholesterol, increased triglycerides, fasting
plasma glucose or blood pressure.8
People in Asia develop diabetes at a younger age than the white populations. An analysis
of 11 studies of 4 Asian countries comprising of 24,335 adults subjects of 30-79 years
of age showed that Indians had the highest prevalence among Asian countries. The peak
prevalence of diabetes was reached approximately 10 years younger in Indians compared
with Chinese and Japanese subjects. Indians also had higher prevalence of impaired glucose
regulation at a younger age of 30-49 years.9
In the national Indian study, onset of diabetes occurred before the age of 50 years in 54.1%
of cases, implying that these subjects developed diabetes in the most productive years of
their life and had a greater chance of developing the chronic complications of diabetes.10
Figure 1 shows the shift in the mean age at diagnosis of type 2 diabetes among the urban
and rural populations in Tamil Nadu. The figure also shows that the proportion of young
people with diabetes has increased significantly 16.
40
Diabetic
< 44(y
Diabetes
< 44 years
Mean
age
(
Mean
age

53.2
49.6
Table 1: Prevalence of Diabetes in Rural and Urban India Since 2000
Diabetes Prevalence (%)

Urban
Rural
Reference (Year)
National
Ramachandran et al (2000)10
Reddy et al (2006)24
Sadikot et al (2004)25
Northern India
Delhi (2000)10
Delhi (2001)19
Delhi (2005)26
Kashmir (2000)27
Jaipur (2003)28
Rajasthan (2004)29
Maharastra (2006)30
Southern India
Chennai (2000)10
Kerala (2000)31
Chennai (2003)32
Chennai (2004)33
Kerala (2005)34
Mysore (2005)35
Andhra Pradesh(2006)36
Chennai (2006)16
12.1
8.4
5.9
2.7
11.6
10.3
15
8.6
-
4
1.8
9.3
13.9
12.4
14.3
19.5
18.6
2.5
6.4
3.8
13.2
9.2
Study in industrial workers (men only)
Prevalence of type 2 diabetes in children is increasing, especially in Asian children in both

native lands and in migrant population.11 Population based and community based studies
of type 2 diabetes in children are few, but clinic based studies have been reported. A clinic
based report of the characteristics of type 2 diabetes in children in Tamil Nadu has been
reported.12 The rising trend in young onset of diabetes and type 2 diabetes in children are
probably linked to epigenetic factors such as maternal imprinting and unhealthy lifestyle
changes resulting in overweight and obesity. Evidences show that both the thrifty genotype
and thrifty phenotype might be operative in the Indian population.13, 14
Adiposity
Body Mass Index (BMI)
Indians show several distinct characteristics related to adiposity. In Indian population, BMI
has been strongly associated with glucose intolerance although the mean BMI is much
below the obesity level.10 Insulin resistance gets adversely affected by even small increments in the BMI.
The existence of high insulin resistance despite a lower BMI could be explained by the
upper body adiposity in Asian Indians. Studies in migrant Asians comparing body fat topography with Caucasians have confirmed these findings.15
Prevalence of obesity increases with the rate of urbanization.16 Figure-2 shows the rate of
obesity in a city, a town and an urbanizing village in Tamil Nadu, in 2006. The prevalence
of obesity was similar in the town and the city 16.
Picture 2: Prevalence of Obesity
1989
2
0
4
Total
Men
Women
BMI > 25 (kg/m2)%

Year of Study
2003
17.1
14.3
19.1
2006
19.5
18.6
20.4
Table-2: Temporal Changes in Prevalence of Obesity in Southern Rural Indian Populations
Abdominal Adiposity
Rural populations
45 have significantly lower BMI compared with the urban population, but
both groups have a similar Waist to Hip Ratio (WHR).17
40.8
It was also observed that despite having a lower BMI, the low income group in the city
had a WHR comparable
to the high income group.18 This probably was an indication that
40
there was a preferential abdominal adiposity in Indians irrespective of the degree of general
adiposity. In a study of the socially deprived urban slum dwellers, in New Delhi, Misra et
al.19 also observed appreciable prevalence of obesity, dyslipidemia, diabetes (10.3%) and
increased body35
fat in the population. High WHR was observed, especially in women (51.1
vs 9.4% in men) in the study.
35.7
Abdominal adiposity is an important risk factor for diabetes and insulin resistance. The
normal cut-off30
values for waist circumference (WC) in male and female Indians are 85 and
80 cm, respectively, whereas the cut-off values for WHR are 0.89 and 0.81, respectively.20
Visceral fat increases the risk of diabetes and hyperlipidemia by favoring insulin resistance.
25

We noted that insulin resistance was also associated with subcutaneous fat in Indians.21
Body Fat Percentage

It has also been noted that for a given BMI, Asian Indians have higher fat percentage
compared with Caucasians.15 Higher insulin resistance and an increased risk of diabetes
may be attributed, in part to this feature.
Insulin Resistance
Insulin resistance has been demonstrated to be a characteristic feature of Asian Indians.22
Comparison of Asian Indians, Europeans and other ethnic groups has shown that the
former have higher insulin response than others.15,23 Insulin resistance is prevalent even
among non obese Indians and it becomes worse in presence of overweight or obesity.
The peculiar features of having higher percentage of body fat even among the lean subjects and also the increased percentage of visceral fat probably explain the higher insulin
resistance in Indians. Insulin resistance is a key etiological factor for several metabolic
diseases like cardiovascular diseases, diabetes, hypertension and also for the clustering
of the risk factors which are common in Indians.23 Physical inactivity, unhealthy diet and
the resulting obesity promote insulin resistance. With increasing rate of urbanization the
pathophysiological components associated with diabetes and other metabolic diseases are
bound to increase many folds.
An alarming increase in prevalence of type 2 diabetes is occurring in urban areas.4, 6 Epidemiological studies in Chennai showed that the total physical activity level including the
activity at work and during leisure time was very low, especially in women.16,17 Physical
activity levels decreased with affluence and this in turn was also associated with a higher
prevalence of diabetes.
Even within the urban areas, prevalence of diabetes was found to be lower in the lowincome group than among wealthier group.10 This could be attributed to the higher level
of physical activity and lower consumption of refined foods by poor people.
Urban-Rural Difference
The urban-rural difference in the prevalence rate observed till a decade ago indicated that
the environmental factors related to urbanization had a significant role in increasing the
prevalence of diabetes.4,6 The prevalence of diabetes in the urbanizing rural population was
found to be midway between the rural and urban populations.4,6 The rate of urbanization
and changes in lifestyle observed in rural areas in different states of India demonstrate
the impact of environmental factors on the already existing genetic predisposition for
diabetes among Indians. The recent trends seen in urban and rural prevalence of diabetes
is shown in table-1.10, 16, 19, 24-36
Until 2000, the prevalence of diabetes in rural areas had been reported to range from 1.5%
to 4.0%.6 Recent studies have shown a rapid conversion of impaired glucose tolerance to
diabetes in the southern states of India.16 The prevalence of diabetes among adults has
reached approximately 20% in urban populations as in Chennai16 and in Kerala.34
In rural Andhra Pradesh, Chow et al.36 reported a high crude prevalence of diabetes (13.2%;
6.4% known) and impaired fasting glucose (15.9%) in 2006. These are probably the highest
prevalence rates reported for a rural area. In 2006, Deo et al. reported a rural prevalence
of diabetes of 9.3% in western India.30
An increasing trend in obesity has been observed in the rural population of Tamil Nadu
as shown in (table-2.)
Presently, India is largely a rural nation, but according to WHO estimates, by 2030 urbanization is expected to reach 46%.37 Therefore, in the future, urbanizing rural areas will
contribute largely to the rising prevalence of diabetes. Improved socioeconomic conditions
in rural India have resulted in an explosion of metabolic disorders, such as diabetes, CVD,
and hypertension.
High prevalence of prediabetes- Impaired Glucose Tolerance (IGT) and Impaired Fasting
Glucose (IFG)
India has a large pool of prediabetic subjects who have a high potential to develop type
2 diabetes and also CVD. It is estimated that in 2010 India has 39.5 million adults with
IGT.1 In the National Urban Diabetes Survey conducted in 2000, we noted that IGT occurred
at a very young age and its prevalence was significantly more than that of diabetes in
the young population.10 In a more recent study in Chennai, we found that the prevalence
of IGT decreased rapidly which could be an indicator of a rapid conversion of the susceptible subjects to diabetes.16 The need for an early screening for glucose intolerance in
the population and also a need for implementation of preventive measures at an early
age are highlighted by these observations. Prevalence of IFG is also high in Indians. The
prediabetic conditions have several metabolic aberrations which include insulin resistance,
presence of hypertension and obesity. Clustering of these risk factors is also common in
these conditions.
Socio-Economic Influences
Socioeconomic environment influences occupation, lifestyle, and nutrition of social classes
which in turn would influence the prevalence and profile of glucose intolerance and diabetic
complications. In urban India, there are wide social and economic disparities. Prevalence of
diabetes was found to be lower in the low socio-economic group (LIG) living in urban areas
compared with the high-income group (HIG) (12.6 vs 24.6% in subjects >40 years).18 This was
probably related to the physical activity of the LIG as most of them were involved in moderate to strenuous physical activity at work. Mohan et al38 also found a lower prevalence of
diabetes in the LIG compared with middle income group in southern India. The finding of lower
prevalence of diabetes in the socially deprived urban Indians was in contrast to the positive
association of diabetes and social deprivation in western countries.39 Lack of formal education,
poor awareness about chronic diseases and high cost of treatment result in late diagnosis and
poor control of diabetes. Hence the long-term complications of diabetes were more prevalent
among low-socio economic people. Although free health care facilities are available for the
economically backward classes, due to the low level of education and occupational problems,
the facilities are not always used. This was to some extent related to the high rates of other
risk factors such as, high cholesterol, hypertension, smoking and alcohol consumption.18
Complications
Ample evidences have accumulated to show that developments of complications are determined by uncontrolled hyperglycaemia.40, 41 Control of both hyperglycaemia and hypertenBurden of Type 2 Diabetes in India:
sion reduces the occurrence significantly. Unfortunately, both in high income countries as
well as in countries of low or middle income, hyperglycemic control among the diabetic
patients is far from the ideal.42 Occurrence of complications may be determined by genetic
predisposition to a great extent.
Data from Chennai show that the prevalence of complications in type 2 diabetes are as
follows: retinopathy 23.7%; nephropathy 5.5%; peripheral neuropathy 27.5%; CVD 11.4%;
peripheral vascular disease 4.0%; and stroke 0.9%. The prevalence of hypertension is also
high (38.0%).45
Prevalence of retinopathy is high among the Indian type 2 diabetic subjects. A study by
Mohan et al in South India showed a prevalence of 34.1% of retinopathy.44 Studies in India
show that the prevalence of CVD in Indians may be as high as in the migrant Indians,
ranging from 11.4% to 21.4%.6
Diabetic foot infections are a major problem and a common cause for hospital admission
of diabetic patients in India. Although the prevalence of PVD is low, neuropathy is very
common and is an associated risk factor for foot infections, which often tend to recur.4
Cost of Treating Diabetes
The costs involved in diabetes care are considerable both for the patients and the health
care system. Cost of diabetes treatment involves a direct cost borne by the patients, their
families, and healthcare authorities. Indirect and intangible costs are larger. The indirect
costs result from lost production as a result of frequent absence from work, an inability
to work because of disability, premature retirement, and even premature mortality as a
result of complications. Intangible costs are those that reduce the quality of life, because
of pain, anxiety and stress.45
India lacks a comprehensive health care system and no uniform norms exist for management of diabetes. A chronic care model is lacking except in a few private centres. Both
diabetic subjects and many medical practitioners are not aware of the need for constant
disease monitoring and consistent glycaemic control.45, 46 It is also noted that the economic
burden of diabetes care is increasing even after accounting for the inflation.47
A recent study showed that total the annual expenditure by patients on diabetes care was,
on average, ` 10 000 in urban areas and ` 6260 in rural areas.47 A secular increase of 113%
was observed in the total expenditure between 1998 and 2005 in the urban population. The
cost of treatment increases several fold with development of complications. Low-income
groups spent a higher proportion of their income on diabetes care (34% and 27% for
urban poor versus rural poor, respectively).47 The medical costs incurred by a person with
diabetes are two to five fold higher than those incurred by people without diabetes. The
estimated annual cost of diabetes care would be approximately 180 000 million rupees.
Prevention of Diabetes
India is facing a big challenge posed by the rising prevalence of diabetes and its complications. There is an urgent need to implement primary and secondary prevention in diabetes.
Primary prevention of diabetes is possible by modifying the environmental factors influencing diabetogenesis such as obesity, diet and physical activity. Long-term studies have shown the beneficial effects of life-style modiDiabetes Care in India Today... and by 2025?
fications on reducing the risk of diabetes in different ethnic groups.48

A genetic-environmental interaction leads to the final expression of the disease.
Although the genetic component cannot be corrected, many of the environmental factors are modifiable. Obesity, diet, and physical activity are the modifiable risk factors.
The interaction between diet and exercise influences the body fat pattern, which has a
significant role in determining insulin sensitivity. Traditional lifestyles, characterized by a
diet including low saturated fat and more complex carbohydrates, and greater physical
activity may protect against the development of cardiovascular risk factors and diabetes,
even in the presence of a potential genetic predisposition.
Two prospective, randomized primary prevention studies conducted by the authors and their
team have conclusively shown the effectiveness of lifestyle modification.49, 50 Consistent
moderate physical activity and healthy diet habits are shown to be effective in preventing
type 2 diabetes in Indians with IGT.
Conclusion
The rising burden of diabetes and its complications need urgent attention of the health
care system and the policy makers. Early diagnosis of diabetes and prediabetes, appropriate management of these conditions by increasing awareness among the populations and
ensuring availability of medical care will help to reduce the development of complications.
Primary prevention of diabetes at population level is of paramount importance. Translation
of research findings at population level can be done only by joint endeavors promoted by
the government by formulating polices and planning to implement satisfactory management of diabetes and also to prevent the disease.
Acknowledgement: We thank Ms. Pricilla S and Ms. Mary Simon for preparing the manuscript and Ms. L. Vijaya
for secretarial support.
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11
Translational Research in India:

Today and by 2025?
Dr V Mohan
Director & Chief Diabetologist,
12
Madras Diabetes Research Foundation &

Dr. Mohans Diabetes Specialities Centre,
4, Conran Smith Road, Gopalapuram,
Chennai - 600 086. Tamil Nadu
Tel: 9144 - 4396 8888. Fax No: 9144 - 2835 0935
e-mail: drmohans@vsnl.net. Website: www.drmohansdiabetes.com
Dr Loganathan Geetha
&
Dr Harish Ranjani
Abstract
Translational research is a rapidly evolving field that seeks to bring findings from a laboratory setting to a practical setting, such as in a hospital, or in a community. Given that
this is a relatively new science, many issues co-exist, including inefficiency, lack of cultural
competency, socioeconomic and cultural differences. Currently, translational research is
a tool used by scientists to extrapolate the findings of a study to a broader population
by conducting the study in the community under natural conditions. The end goal of
translational research is to facilitate the efficient practice of medicine and public health
initiatives on a global scale. By understanding current successes and difficulties, scientists
and physicians can look to translational research for answers in the form of prevention
and management of chronic disorders like diabetes.
This article illustrates with examples our experience with translational research at the
Madras Diabetes Research Foundation (MDRF), Chennai.
Outline
1. What is translational research?
2. Phases of Translational Research
3. Why is it important in the field of diabetes?

Prevention of Diabetes
Global scenario
4. MDRF experience
5. Current issues in translational research
6. Gaps and pitfalls in translational research
7. Future directions - Translational research in 2025
1. What is Translational Research?

Translational research transforms currently available knowledge into useful measures for
everyday clinical and public health practice. Translational research aims to assess implementation of standards of care, understand the barriers to their implementation, and intervene
throughout all levels of health care delivery and public health to improve quality of care
and health outcomes, including quality of life 1. The ability to study effectiveness, rather
than efficacy alone, comes as a result of translational research. Any translational study
that centers on management and treatment of chronic diseases like diabetes or its preventive mechanisms, if it is to succeed must be culturally appropriate, must pass regulations,
and must be easy to translate from the realm of science to the art of applying it to the
community 2.
2. Phases of Translational Research

The primary goal of translational research is to integrate advancements in molecular
biology with clinical trials, taking research from the bench-to-bedside-to-community 3, 4
so that it ultimately benefits mankind.
Translational Research In India: Today and by 2025?
13
Bench to bed side: This involves molecular level research in a controlled laboratory setting to clinical research applications in a select number of patients afflicted with the
disease. This represents the bench to bedside definition of translational research. It is the
transfer of basic knowledge gained in the laboratory into development of new methods
for diagnosis, treatment and prevention and their first testing in humans. Preclinical trials
and Phases I-III of clinical trials come under this approach. This stage includes the T1 &
T2 translational blocks (Figure 1).
Bedside to practice: This examines how the efficient and safe treatment findings from
laboratory research function when applied to real patients in real life situations. This
represents the bedside to clinical practice definition of translational research. It is the
translation of results from the early clinical studies to everyday clinical practice and health
decision making. Phase IV clinical trials and post marketing surveillance come under this
approach. For example, hypoglycemic treatments such as insulin and frontline antidiabetic
drugs like sulfonylureas and big uanides were discovered in the laboratory and then tested
in huge clinical trials such as the Diabetes Control and Complications Trial (DCCT) and
United Kingdom Prospective Diabetes Study (UKPDS). This stage includes the T3 translational block (Figure 1).
14
Clinical practice to community, public health and health policy: This involves translating evidence based research from a clinical research setting to the real world practice.
It helps to translate the treatment and the prevention strategies developed in T2 &T3
translation blocks into sustainable solutions. This represents the practice to community
definition of translational research. This phase of translational research refers to the dissemination and implementation of established research preventive strategies or treatment
into the community. This stage includes the T4 translational block and is associated with
the challenge of moving scientific knowledge into the public sector and thereby changing
everyday lives of the people (Figure 1). 3, 4.
Figure 1: Different Phases of Translational Research
3. Why is it Important in the Field of Diabetes?

Diabetes is a growing public health problem in India leading to significant increase in
morbidity and mortality. According to the Diabetes Atlas published by the International
Diabetes Federation in 2009, at present 285 million people worldwide live with diabetes
and it is expected to increase to 438 million by 2030 and India has 50.8 million people
living with diabetes. It is predicted that by 2030 India would have 87.0 million people
with diabetes 5. Controlling this epidemic of Type 2 Diabetes Mellitus (T2DM), should be
a priority for both public health officials and physicians. This can be done by preventing
new cases of diabetes through translational research 6.
4. Prevention of Diabetes
Diabetes usually progresses from a prediabetes stage which includes Impaired Fasting
Glucose (IFG) and / or Impaired Glucose Tolerance (IGT) to the onset of clinical diabetes
and gradually progresses to the complication stage. Prevention of diabetes can happen
at every stage.
Primordial prevention: a new concept receiving special attention especially in prevention
of chronic diseases. In purest sense it is primary prevention that is prevention of development of risk factors in a population. For example many adult health problems start in
their childhood [e.g.: obesity] 7. In primordial prevention efforts are aimed at encouraging
children to adopt healthy lifestyle though mass communication.
Primary prevention: refers to action taken prior to the onset of the disease, which decreases the possibility of the disease occurring 7. This prevention generally focuses on the
high risk individuals from a population, i.e.: people who have greater chance of getting
the disease. Thus, in case of diabetes people having prediabetes will be the targeted group
for any intervention strategy to be implemented.
Secondary prevention: refers to action which stops progression of disease at initial stage
and prevents complication 7. It refers prevention of complications in people diagnosed
with diabetes.
Tertiary prevention: refers to phase which reduce or limit complications, disability and
impairment 7. It refers to limitation of disability and impairment in people with diabetic
complications.
a. The Global Scenario

Evidence based intervention program for the prevention of diabetes have been largely successful when high risk groups were targeted. In the past decade many trials have shown
the effect of lifestyle modification which includes a combination of healthy eating, behavior changes and increased physical activity and/or a frontline anti-diabetes agent like
Metformin in the prevention and delaying of diabetes 8 -13.
One of the earliest lifestyle intervention studies for prevention of diabetes was done among
men aged 47-49 in Malmo, Sweden 8. All the Normal Glucose Tolerant (NGT) and some
of the Impaired Glucose Tolerance (IGT) subgroups were given standard care and all the
men with type 2 diabetes and remaining IGT men were given lifestyle intervention. Men
who participated in the lifestyle intervention had a lower incidence of type 2 diabetes, and
had a greater reversal of glucose intolerance compared to men who received standard care.
15
The Da-Qing study 9 compared a diet group separate from an exercise group and included
a third group which did diet and exercise and a control group without any treatment. In
this clinical trial 577 IGT subjects were randomized to either the control group or one of
the three intervention groups. 6 years follow up evaluation showed all the three intervention reduced the risk of diabetes by 31-46%.
The Finnish Diabetes Prevention Study (DPS) 10-11 another randomized controlled trial that
specifically examined the effect of a lifestyle intervention in preventing type 2 diabetes.
522 overweight/obese subjects with IGT were randomized to either a lifestyle intervention
or a control group. Follow up of 3.2 years showed a 58% reduction in the risk of diabetes
in the intervention group.
The Diabetes Prevention Program (DPP) 12 one of the largest randomized controlled clinical
trials to date was conducted in 3234 American adults with glucose intolerance (IGT). The
DPP demonstrated that a 3 years risk of developing T2DM was reduced by 58% in the
lifestyle intervention group compared to the 31 % risk reduction in the Metformin group
and the life style changes.
The Indian Diabetes Prevention Programme (IDPP) 13, a community based prospective
study, studied the influence of lifestyle intervention on the progression of diabetes among
the Asian Indians with IGT who are leaner, younger, more insulin resistant compared to
population studied in the above studies (Chinese, Americans). The IDPP reported that by
lifestyle modification diabetes risk reduced by 28.5%.
16
All these major trials proved that by lifestyle modification diabetes can either be prevented or delayed in different ethnic populations in high risk groups. To be precise the
interventions were targeted on subjects with Impaired Glucose Tolerance (IGT) which is
the fist stage in the natural history of diabetes. More over these studies were all done in
a clinical or research setting where high risk individuals are invited to hospital or clinic or
research centre and were advised to undergo lifestyle modification under the supervision of
a multidisciplinary research team. Thus, translating these research studies into community
action becomes a big challenge.
b. The Madras Diabetes Research Foundation (MDRF) Experience: Community Based Intervention
MDRF has been at the forefront of positive experiences in translational research, with
studies such as Chennai Urban Population study (CUPS) empowering a community to
start exercising in Chennai, Prevention Awareness Counseling Evaluation (PACE) spreading awareness about diabetes and its complications and Diabetes Community Lifestyle
Improvement Program (D-CLIP) looking at whether culturally appropriate interventions
can not only lower risk of diabetes, but also remains cost effective.
Given below are a few successful examples of feasible community based interventions done
by MDRF; for the people by the people.
(i) Asiad colony experience: The Chennai Urban Population Study (CUPS) 14 was carried
out in two urban residential colonies, one representing the middle income group (Asiad
colony in Tirumangalam) and the other representing the low income group (Bharathi Nagar
in T.Nagar) in Chennai city, in southern India. The study was conducted from 1996 to 1998
and all individuals aged 20 years and above residing in these two colonies were invited to
participate in the study. This study showed a significantly higher prevalence of diabetes in
a middle income group12.4% as compared to a lower income group 6.5% 15. The results
of the study were discussed with the residents of both colonies. As the prevalence rates
of diabetes were low in the low income group, only standard lifestyle advice was given to
this group. As the middle income group had a two fold higher prevalence of diabetes, the
need for prevention of diabetes and the importance of lifestyle modification was strongly
stressed to this group.
The corporation of Chennai subsequently built many new parks and upgraded many of the
[existing parks with bushes, trees, play area for children and walking and jogging tracks]
leading to more than 230 parks being constructed and maintained by the corporation
of Chennai. This is a true example of T4 research that is scalable to other parts of the
country and sustainable.
ii) Prevention Awareness Counseling Evaluation (PACE): One of our earlier studies
Chennai Urban Rural Epidemiology Study conducted in Chennai showed that there was a
lack of awareness about diabetes in the community 17. It showed that only 75% of the
population knew about a condition called diabetes. Only 22.2% of the whole population
and 41.0% of the known diabetic subjects were aware that diabetes could be prevented.
Only 19.0% of whole population and 40.6% of the known diabetic subjects knew that
diabetes could cause complications. The findings of the study strongly indicated that a
large scale diabetes awareness and prevention programme is urgently needed. Consequently
a large scale diabetes awareness and prevention programme was undertaken in Chennai
called the PACE (Prevention Awareness Counseling Evaluation) diabetes project 18.
The main objective of the programme was:
1. To conduct massive free public awareness campaigns reaching out at least one million people.
2. To do free blood sugar screening at a large scale in at least two million people
3. Implementation of community based diabetes primary prevention program by lifestyle
changes.
Free public awareness campaign: A) A large scale public awareness programme on diabetes was held in many places like residential sites, workplaces [banks, factories], worship
places [temples, mosques, church], public places [shopping complexes, exhibitions, and park]
and educational institutions [schools, colleges] through lectures and interactive programs.
B) Education has always been an important tool in promoting health. PACE educational
counters was opened in many places in Chennai with diabetes education materials in
English and Tamil. Free diabetes educational materials like brochures, booklets, flash card,
posters in both English and Tamil was also distributed to the public. The materials were
also made available at bookshops, shopping complexes, food chain stores, and family
physician clinics.
C) Mass Media has always been successful tool in promoting health to a larger audience.
A documentary film prepared on diabetes was telecasted in the local television and radio.
The messages on diabetes and its prevention were also conveyed using various other media
like newspaper, cinema theaters, and mobile phones [SMS (short message service)].
17
D) General practitioners training programme was conducted in which the GPs were trained
on clinical diabetology and prevention. The aim of the training was to improve the overall
diabetes health care management.
Through the PACE project two million people in Chennai were educated about diabetes
and its complications, close to 77, 000 individuals were screened for diabetes, around 235
general practitioners were trained in diabetes prevention and treatment.
iii) Diabetes Community Lifestyle Improvement Programme (D-CLIP): D-CLIP is the
Diabetes Community Lifestyle Improvement Program, a culturally specific lifestyle intervention program in the lines of the DPP to prevent diabetes in Chennai. D-CLIP is an
ongoing study at MDRF where prediabetes individuals are randomized into an intervention
arm (aggressive lifestyle intervention through 16 weekly once classes followed by 8 maintenance classes) or control arm (standard care). Even though DPP was hugely successful,
no other study tried to replicate this model in their respective community. DCLIP is one
of the first initiatives to culturally modify the very structured DPP lesson plans and test
it in a real world setting. The unique feature of DCLIP is its effort to involve members
from the community (calling them Dia-ambassadors) into the program along with peer
support groups; all of which will help the sustainability of the program and prove it to
be an effective translational research project.
5. Current Issues in Translational Research
18
One of the biggest challenges in health promotion and prevention of chronic diseases like
diabetes is translating the research findings from an ideal setting to a less than optimal
real world environment 4. Research has shown that the time taken for a discovery (basic
science) to reach the public and actually improve health (community) can be around 17
years 19. Key criticisms of this integral aspect of science include the perceived inefficiency
in the very translation process, which is bringing these processes from the laboratory to
the healthcare arena, the cultural barriers, and the variability between humans 20. Whether
a study centers on diabetes, cancer, or other co morbidities, in order to succeed it must
be culturally appropriate, it must pass regulations, and it must be easy to translate from
scientific process to medical habit. In order for translational research to perpetuate its
burgeoning presence, it must address these criticisms, in addition to improving the lengthy
nature of the development process from recommendation to policy.
6. Gaps and Pitfalls in Translational Research

The well known author, Mark Twain, commented on human habit saying habit is habit, and
not to be flung out of the window by any man, but coaxed downstairs a step at a time.
Applying this axiom to a public health or a medical setting is laborious to say the least.
Attempting to change a habit, especially deep-rooted habits such as eating and exercising behaviors and medication regimen, requires strong incentives, as well as overwhelming
support from researchers and study staff. Translational research in many ways addresses to
change this very habit. Listed below are a few gaps in translational research 2, 4.
a). Many researchers would argue that recruitment is the worst part of a study, simply
because participants who are both eligible and compliant with any program are few.
People are often wary of change, and feel uncomfortable with revising behaviors that
have been engrained. In some ways, recruitment issues can be seen to result from habit;
therefore, emphasizing peer support groups and buddy systems can foster a sense of
belonging, and retain participants over the course of the study 21.
b) An important indirect cost of participating in any translational research study is time.
Individuals are often apprehensive to take off time from work or household duties to
participate in research studies unless they feel that they either stand to gain a significant
amount from the study or if they feel that they stand to lose a significant amount by
failing to join the study. In order to entice populations, studies must offer incentives
for time lost, but also for indirect spending as a result of the study.
c) As globalization continues to make the world seem smaller, applying research across
cultural boundaries becomes increasingly important and challenging. What may be
acceptable in one culture may be considered inappropriate in another. Cultural appropriateness is a key struggle in translational research and advance preparation and
significant measures should be taken to ensure that the study is tailored towards the
traditions of the individuals being studied. Taking data from one community to create
global policies is especially difficult in countries such as India, where culture can vary
dramatically from state to state. In these instances, careful consideration must be given
to subtle variations, such as those in eating and exercise behaviors.
d) Findings from translational research can be used to shape policies in general practice, preventive guidelines, and generalized notions of how treatments can be handled.
Skeptics of translational research often note the use of statistical significance over
clinical significance to generalize specific results to a population. Hence, specific individual recommendations should be left to the physicians, who understand patients
at a deeper level.
e) Overcoming variation should not be a goal of translational research. In fact, translational
research should appreciate the dissimilarity of the human race. The process of examining
these perceived dissimilarities can provide interesting research opportunities by not only
revealing novel mechanisms of preventing and treating disease, but more importantly, of
creating unity within the field of translational research. The fact that recommendations
made based on a small group may not necessarily turn into global recommendations
enable scientists to look further at what it is that makes these recommendations differ
within groups, thereby expanding the scope of translational research.
7. Future Directions Translational Research in 2025

The heightened enthusiasm for translational research have witnessed the birth of journals
such as the American Journal of Translational Research devoted solely to the pursuit of
knowledge in this ever-expanding and thrilling field 22. The National Institute of Health
(NIH) notes that its program, the NIH-RAID pilot program, seeks to offer public funding
for translational research pursuits, thereby helping bridge the funding gap that can often
hamper the progress of such studies. BRiDGES (Bringing Research in Diabetes to Global
Environments and Systems) is a pioneering program initiated by the International Diabetes
Federation (IDF) that aims to fund translational research projects in diabetes prevention and
treatment to provide the opportunity to translate lessons learned from clinical research
to those who can benefit most: people affected by diabetes 23. Thus NIH and IDF have
19
taken up the mantle of prevention by funding translational projects.

In looking at the current state of translational research, the future of this science looks
bright. Translational research can demonstrate the role of lifestyle in improving chronic
conditions, such as diabetes, can be used to compare various treatment and prevention
strategies and their overall value for patients and public together, while looking at the
effectiveness of medication, rather than just the efficacy. Thus, by making evidence part
of clinical and public health practice, translation research can help tackle the epidemic of
diabetes by 2025. Somewhere down the road, society can look to translational research
to reduce the incidence of chronic non-communicable conditions such as diabetes and
cardiovascular disease.
20
Prevention of diabetes should take a multisectoral approach involving the government,

corporates, urban planners and the public 24. Priority should be given to build roads with
footpath for pedestrians, bicycle lanes, parks with walking, jogging tracks and play ground.
Efforts need to be made to reintroduce stairs rather than easy access to elevators and
escalators in all government buildings, shopping malls, cinema halls, offices and residential
buidings. The availability, accessibility and affordability of healthy food options in the
market should also be emphasized 25. By altering the environment and changing the attitude and behavior of the people it is possible prevent diabetes. Over the past century,
our health care system has evolved for the management of communicable diseases but
is not optimally suited for managing non communicable diseases. Newer systems of care
and newer ways of thinking are needed to tackle non communicable disease like diabetes.
In essence, the possibilities for translational research are limitless, provided that time and
effort is dedicated towards making the process efficient and respectful. As scientists, we
can hope to use translational research to bring healthcare to those less fortunate, and to
those who may not have access to the same level of care considered desirable. The ability
to improve the quality of life worldwide should be the reason why translational research
should be conducted on a much larger scale than it is being currently done.
Table 1: Lifestyle Intervention & Prevention of Diabetes
Evidence from Major Trials
Study
Year
DA QING8 19861992
FINNISH
DIABETES
PREVENTION
STUDY
(DPS) 9-10
19931998
Study
Subjects
Intervention
FollowUp
Results - Cumulative Incidence

of T2DM
Risk Reduction
577 Subjects With

IGT
33 Clinics
Diet Only
6 Years
Controls - 68%
Diet - 46%
Exercise 32%
Exercise Only
Diet - 44%
Diet & Exercise

Control
Exercise -41%
523
Diet & Exercise
Overweight Control
subjects
with IGT
Diet & Exercise 46%

4 Years
Controls - 22%
Intervention 10%
Diet & Exercise - 46%

58%
DIABETES
PREVENTION
PROGRAM
(DPP) 11
1996
1999
INDIAN
DIABETES
PREVENTION
PROGRAM
(IDPP) 12
2006
3234
overweight
subjects
with IGT
27 centers
Placebo,
Lifestyle (Diet &
Exercise)
2-8
Years
(Terminated
one year
earlier than
planned)
531
Control
2.5 Years Control- 55%
Subjects
with IGT
Lifestyle
Lifestyle- 39.3%
Metformin
Metformin- 40.5%
Lifestyle &
Metformin
Lifestyle +
Metformin
Placebo - 11%
MetforminMetformin - 7.8% 31%
Lifestyle 4.8%
Lifestyle58%
Lifestyle28.5%
Metformin26.4%
Lifestyle +
Metformin- 39.5% Metformin28.2%
References
1.
Narayan et al. Diabetes Translation Research: Where Are We and Where Do We Want To Be? in Ann
Intern Med, 2004; 140:958-963
2.
Levin, Leonard, and Helen Danesh-Meyer. Lost in Translation: Bumps in the Road Between Bench and
Bedside. JAMA V. 303 No. 15 (April 21 2010) P. 1533-4, 303.15 (2010): 1533-1534.
3.
Woolf SH. The Meaning of Translational Research and Why It Matters. JAMA 2008;299;211-213.
4.
Garfield S, Malozowski S, Chin M, Narayan V et al. The Diabetes Mellitus Interagency Coordinating Committee (DMICC). Translation Conference Working Group. Considerations for Diabetes Translational Research
in Real-World Settings. Diabetes Care 2003; 26 (9): 2670-74.
5.
International Diabetes Federation Diabetes Atlas. Unwin N, Whiting D, Gan D, Jacqmain O, and Ghyoot G
(eds). IDF Diabetes Atlas. Fourth Edition. International Diabetes Federation, Belgium, 2009.
6.
Weber MB and Narayan V. Preventing type 2 diabetes: Genes or lifestyle? Primary Care Diabetes 2008; 2:
6566
7.
Park K . Concept of health and disease. In: Parks text book of preventive and social medicine. M/s Bnarsidas
Bhanot publishers. 2005;p.12-47
8.
Eriksson K-F, Lidgarde F. Prevention of type 2 (non-insulin dependent) diabetes mellitus by diet and physical
exercise. The 6 year Malmo feasibility study. Diabetologia 1991; 34: 891-898.
9.
Pan X, Li g, Hu Y, Wang J, Yang W, An Z. Effects of diet and exercise in preventing NIDMM in people
with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20: 537-544.
10. Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson J, Hemio K. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study.
Lancet 2006; 368: 1673-1679.
11. Lindstrom J, Louheranta A, Mannelin M, Rastas M, Salminen V, Eriksoon J. The Finnish Diabetes Prevention
Study (DPS): Lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003;
26: 3230-3236.
12. Knowler W, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM. Reduction in the incidence of type 2 with
lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.
13. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar A, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects
with impaired glucose tolerance (IDPP-1). Diabetolgia 2006; 49: 289-297.
21
14. Shanthi Rani CS, Rema M, Deepa R, Deepa R, Premalatha G, Ravikumar R, et al (1999). The Chennai Urban
Population Study (CUPS) - Methodological details - (CUPS Paper No.1). International Journal of Diabetes
in Developing Countries 19: 149-157
15. Mohan V, Shanthi Rani S, Deepa R, Premalatha G, Sastry NG, Saroja R (2001). Intra urban differences in
the prevalence of the metabolic syndrome in southern India - the Chennai Urban Population Study (CUPS
No.4). Diabetic Medicine 18: 1-8
16. Mohan V, Shanthirani CS, Deepa M, Manjula Datta, Williams OD, Deepa R (2006). Community Empowerment A successful model for prevention of non-communicable diseases in India The Chennai Urban
Population Study (CUPS-17). Journal of Association of Physicians of India 54: 858-865
17. Deepa M, Deepa R, Shanthirani CS, et al. Awareness and knowledge of diabetes in Chennai-The Chennai
Urban Rural Epidemiology Study (CURES-9). J Assoc Physicians of India 2005;53:283-7
18. Somannavar S, Lanthorn H, Pradeep R, Narayanan V, Rema M, Mohan V. Prevention Awareness Counselling and Evaluation (PACE) Diabetes Project: A Mega Multi-pronged Program for DiabetesAwareness and
Prevention in South India (PACE-5). J Assoc Physicians of India 2008;56:429-435.
19. Peter G. Szilagyi. Crossing the Abyss: From Research to Dissemination/Implementation to Better Health Presentation. School of medicine and Dentistry, University of Rochester Medical Centre. February 2010.
20. Levin, Leonard, and Helen Danesh-Meyer. Lost in Translation: Bumps in the Road Between Bench and
Bedside. JAMA V. 303 No. 15 (April 21 2010) P. 1533-4, 303.15 (2010): 1533-1534.
21. West R, Edwards M, Hajek P. A randomized controlled trial of buddy systems to improve success at giving
up smoking in general practice. Addiction. 1998; 93(7):1007-1011.
22. Lee, Wen-Hwa. Translational Research: Present and Future.American Journal ofTranslational Research1.2
(2009): 99-100. Print.
23. http://www.idfbridges.org/ accessed on September 2010.
24. Mohan V and Pradeepa R. Redesigning the urban environment to promote physical activity in Southern
India. 2007; 52 (1):33-35
22
25. Deepa M, Suresh Somanavar, Mohan V. Community based strategy for prevention of diabetes in Indians.
In: Type 2 Diabetes in South Asians: Epidemiology, Risk Factors and Prevention. Mohan V, Gundu HR Rao
(Eds), Under the Aegis of SASAT. Jaypee Brothers Medical Publishers. 2006;p.344-359.
Type 2 Diabetes: The Present

International Classification
Dr R V Jayakumar
Professor of Endocrinology
Amrita Institute of Medical Sciences, Kochi
e-mail: rvjaykumar@aims.amrita.edu
Ph: 94472 88159
&
Dr Praveen Jeyapathy
Diabetology PG
Department of Endocrinology
Amrita Institute of Medical Sciences, Kochi
23
Introduction
Diabetes mellitus is defined as a syndrome characterized by chronic hyperglycemia due to
defects in insulin secretion, insulin action or both which leads to disturbance in the protein,
carbohydrate and fat metabolism of the individual. Type 2 diabetes affects many people
from all types of ethnicity, social and economic levels of the society. Diabetes is among
the 5 leading causes of death in most countries 1. The prevalence of diabetes has reached
epidemic proportions in India and large number of patients belongs to the younger age
group. Better and early disease detection, changing lifestyle and changes in the diagnostic
criteria have led to this increase. Death and disability associated with diabetes poses a
serious challenge to physicians and the health system at large.
History
Araetus of Cappadocia and Sushruta were the first to give descriptions of what we know
today as Type 1 and Type 2 diabetes 2. It was Sir Harold Himsworth in 1936 who proposed
that there were 2 clinical types of diabetes the insulin sensitive and insulin insensitive
types 3. This was further confirmed when the assays for insulin measurement was made
available for use. The differences in the age for onset led to the terms Juvenile-onset
and Maturity onset diabetes.
24
The diagnostic criterion of insulin-dependent diabetes was quite obvious because of its
presentation. The non-insulin dependent variety didnt have a very clear distinction between what was normal and what was a state of disease and that created the need for a
diagnostic criteria. The WHO in 1964 began discussions on an uniform classification system
but it took almost 16 years and it was in 1980 an accepted classification was established
4
. In 1985 the revised NDDG (National Diabetes Data Group) - WHO classification agreed
upon the Insulin-Dependent Diabetes Mellitus (IDDM) and Non-Insulin Dependent Diabetes
Mellitus (NIDDM) 5. The other types of diabetes, gestation diabetes mellitus and Impaired
Glucose Tolerance (IGT) based on the oral glucose tolerance test were retained from the
1980 classification system.
The understanding about the etio-pathogenesis of diabetes has increased over the past 20
years. Changes that have happened include the identification of auto-immune markers and
the recognition that diabetes has a dynamic phase 6. Thus, the classification of diabetes
into IDDM an NIDDM would not be satisfactory. Auto-immune mechanisms causing diabetes
were seen in the elderly and diabetes of the young which didnt require insulin for treatment is seen in clinical practice. A patient diagnosed to have NIDDM may require insulin
for survival years after the diagnosis. The development of immune markers has shed much
more light on the Type 2 diabetic patients who after a brief duration of treatment with
OHAs require insulin for survival and have positive immune markers, who we now know
to belong to the class LADA (Latent Auto-immune Diabetes of the Adult).
A Brief History to todays Classification System

The U.S. National Diabetes Data Group and WHO dealt with the task of classification and
criteria of diabetes 7, 8. It has been endorsed by many bodies like the ADA. The terms
juvenile-onset diabetes and maturity-onset diabetes were replaced by insulin-dependent
diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) which has
not been replaced by type 1 diabetes and type 2 diabetes respectively. The category
Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG) was also created.
The advantage of the latest ADA / WHO classification is that it combines both clinical stages
of hyperglycemia and the etiological types (Figure 1). The actual staging reflects that any
etiological type can pass or progress through several clinical phases (both normoglycemic
and hyperglycemic) during its natural history. Moreover, individuals may move in either
direction, from stage to stage. The type of diabetes, however, is now determined by the
etiological process rather than the treatment modality.
Figure 1: Clinical Staging of Hyperglycemia
Current Criteria for Diagnosis of Diabetes Mellitus

Diabetes is clinically diagnosed by the classical signs of polyuria, polydipsia, unexplained
weight loss and fatigue. The diagnostic thresholds are based on long-term diabetes complications. Microvascular changes in the kidney and retina have been used to define the
diagnostic cut-points. In 1997, the ADA confirmed the 2-hr PG criterion at 199.8 mg / dl
based on the data from the Pima Indians, Egypt, and unpublished NHANES III analyses 9.
They also found that both FPG and 2h PG were similarly associated with retinopathy, indicating that both could be used equally well for the diagnosis of diabetes. Although the
prevalence defined by these two measures may be similar, its been found that the two
tests clearly identify different individuals 10, 11. Thus, the fasting plasma glucose cut-off
was lowered in 1997 to enable the FPG to identify the same percentage of population
identified by the 2-hr cut-off 9.
Diabetes Mellitus is Diagnosed when12

Fasting plasma glucose > 126 mg / dL
(or)
2 hr 75g OGTT >200 mg / dL
(or)
Symptoms associated with hyperglycemia (polyuria, polydipsia, unexplained weight loss)
with a random plasma glucose > 200 mg / dL
25
Table 1: Categories of Glucose Tolerance
12
FPG
2-hr 75 gm OGTT
Normal: <100 mg / dl
Normal: <140 mg / dl
IFG (Impaired fasting glucose): >100 mg / IGT (Impaired glucose tolerance): >140 mg
dl and <126 mg / dl
/ dl and <200 mg / dl
Diabetes: >126 mg / dl
Diabetes: >200 mg / dl
Table 2. Etiological Classification of Diabetes
1. Type 1 Diabetes Mellitus

2. Type 2 Diabetes Mellitus
3. Other specific types
26
12
a. Immune mediated
b. Idiopathic
a. Genetic defects of beta-cell function
1. MODY 1 - 6
2. Mitochondrial DNA
3. Mutant insulins
4. Hyperproinsulinemia
5. Others
b. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipoatrophic diabetes
5. Others
c. Diseases of the exocrine pancreas
1. Pancreatitis
2. Trauma/pancreatectomy
3. Neoplasia
4. Cystic fibrosis
5. Hemochromatosis
6. Fibrocalculous pancreatopathy
7. Others
d. Endocrinopathies
1. Acromegaly
2. Cushings syndrome
3. Glucagonoma
4. Pheochromocytoma
5. Hyperthyroidism
6. Somatostatinoma
7. Aldosteronoma
8. Others
e. Drug- or chemical-induced
1. Vacor
2. Pentamidine
3. Nicotinic acid
4. Glucocorticoids
5.
6.
7.
8.
9.
10.
11.
Thyroid hormone
Diazoxide
Beta-Adrenergic agonists
Thiazides
Phenytoin
Alpha-Interferon
Protease inhibitors (e.g., indinavir,
Saquinavir, Ritonavir,
Nelfinavir)
12. Atypical antipsychotics
(e.g., Clozapine, Olanzapine,
Quetiapine, Risperidone)
f. Infections
1. Congenital rubella
2. Cytomegalovirus
3. Others
g. Uncommon forms of immune-mediated diabetes
1. Stiff-man syndrome
2. Anti-insulin receptor antibodies
3. Others
h. Other genetic syndromes sometimes associated with diabetes
1. Downs syndrome
2. Klinefelters syndrome
3. Wolframs syndrome
4. Friedreichs ataxia
5. Huntingtons chorea
6. Laurence-Moon-Biedl syndrome
7. Myotonic dystrophy
8. Porphyria
9. Prader-Willi syndrome
10. Others
4. Gestational diabetes mellitus
Type 2 Diabetes and the Present International Classification

Today the classification of diabetes is into 4 major types based on the etiology. Todays
system seems more logical but a precise classification is yet to be reached given our fast
changing knowledge about the mechanisms of diabetes. Screening patients in advance as
per guidelines to detect them either early in the disease or in the stage of pre-diabetes
puts us and our patient at an advantage from the therapeutic point of view. Either a
FPG or a 2hr GTT can be employed understanding well that they detect different patient
populations though the overall prevalence doesnt seem to change.
In clinical practice, we see more and more of our patients diagnosed to have diabetes at
an increasingly younger age which has been attributed to a variety of reasons. Our understanding on the etio-pathogeny of diabetes is making us re-think and re-consider the
diagnosis of diabetes in many patients. In a variety of studies, the world over its been
shown that a good number of patients who have been tagged as Type 2 Diabetes have
27
auto-immune mechanisms behind their diabetes. This would mean that in the future more
patients with type 2 diabetes would move into the other types of diabetes category which
may have a bearing on the way we treat them as well.
References
1.
Finch CF, Zimmet PZ: Mortality from diabetes. In The Diabetes Annual/4. Alberti KGMM, Krall LP, Eds.
Amsterdam, Elsevier, 1988, p. 116
2.
Dwivedi G, Dwivedi S. Sushruta The clinical teacher par excellence. Indian J Chest Dis Allied Scie 2007;
49:243-244.
3.
Himsworth H. Diabetes mellitus: its differentiation into insulin sensitive and insulin insensitive types. Lancet
1936;i:117-120
4.
World Health Organization. World health organization expert committee on diabetes mellitus: First report.
WHO, Geneva, 1965
5.
World Health organization. Diabetes Mellitus: Report of a WHO study group. Who, Geneva, 1985.
6.
Abourizk N, Dunn J. Types of diabetes according to National Diabetes Data Group classification. Limited
applicability and need to revisit. Diabetes Care 1990; 13(11):1120-1123.
7.
National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of
glucose intolerance. Diabetes 28:10391057, 1979
8.
World Health Organization: WHO Expert Committee on Diabetes Mellitus. Second Report. Geneva, World
Health Org., 1980 (Tech. Rep. Ser., no. 646)
9.
Expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee
on the diagnosis and classification of diabetes mellitus. Diabetes care 1997; 20(7):1183-1197.
10. McCance DR et al. Comparison of tests for glycated hemoglobin and fasting and two hour plasma glucose
concentrations as diagnostic methods for diabetes. BMJ 1994;308(6940):1323-1328
28
11. Engelgau MM et al. Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes.
Diagnostic criteria and performance revisited. Diabetes care 1997; 20(5):785-791.
12. Diabetes Care January 2010 vol. 33 no. Supplement 1 S11-S61
Genetics of Type 2 Diabetes Mellitus:

Is there any Protective Approach ?
Dr Anil Bhansali
Senior Professor and Head Department of Endocrinology,

Post Graduate Institute of Medical Education and Research
(PGIMER), Chandigarh.
Tel: 91-172-747585-600, Ext. 6583
Fax: 91-172-744401, 745078
e-mail: anilbhansali_endocrine@rediffmail.com
&
Dr Viral Shah
Senior Resident, Department of Endocrinology,

Postgraduate Institute of Medical Education & Research,
Chandigarh. e-mail: drshahviral@gmail.com
Genetics of type 2 diabetes mellitus: Is there any

protective approach ?
29
Introduction
Diabetes mellitus refers to group of common metabolic disorders that share the phenotype
of hyperglycemia. There are several distinct types of diabetes exist, but two most common types are type 1 diabetes and type 2 diabetes (T2DM) out of which type 2 diabetes
constitutes more than 90% of cases of diabetes. The world wide prevalence of diabetes
has risen dramatically particularly in developing countries like India 1 and is now referred
as capital of diabetes. We have very clear understanding for the role of genetic factors in
development of type 1 diabetes however; it is not the case with T2DM. T2DM is caused
by complex interactions between the adverse environmental factors and certain genetic
factors.
There are number of epidemiological, observational and experimental evidences
suggest the role of genes in development of T2DM including
2,3,4,5
to
1. Ethnic variation in prevalence of diabetes.

2. Variation in concordance rate of type 2 DM in identical twins (60-90%).
3. Familial aggregation of T2DM
4. Whole genome scan have implicated numerous regions on many different chromosomes, which are linked to diabetes.
5. Association of certain gene polymorphism & susceptibility for diabetes.
30
Genetics of type 2 diabetes mellitus can be classified as 1) genetics of monogenic forms of

diabetes and 2) genetics of polygenic form. The major difference in genetics of these two
types is gene involvement in monogenic form of diabetes is causal while genes involved
in polygenic forms are not causal but predispose for future development of diabetes.
Genetics of Monogenic Form of Diabetes

Maturity Onset Diabetes of Young (MODY) is one of the monogenic form of diabetes
first reported by Tattersall and Fajans in 1975 6. First gene for MODY, was discovered in
1993 by Froguel and colleagues 6. This discovery received attention by numerous scientists and opened the path for future genetic research in diabetes. Until date, six distinct
MODY subtypes have been identified based on characteristic gene defect. All these genes
are expressed in pancreatic beta cell. Table 1 shows these MODY subtypes and their gene
defects. Genetic studies, have been carried out on MODY in India 7 and showed few differences in genotypes as compared to west. For example; MODY 3 is most common type
worldwide but this type is responsible for only 6-8% of MODY in one of large south
Indian study. Further generally MODY is caused by defect in insulin secretion but Indian
study showed that patients with MODY despite being young have more insulin resistance
than even type 2 DM.
Why Genetic Studies for MODY are Important?

The MODY constitutes around 3% of total diabetic population and that makes a huge
number in a country with higher prevalence of diabetes. Furthermore, as said previously
not all young diabetes are T1DM, therefore, patients are treated with insulin due to lack
of suspicion and genetic analysis. In this era, mutation screening is easy therefore; one
can predict the future development of diabetes if any of the mutations are found to be
positive. One can screen the family member and can diagnose and treat at the earliest.
knowing the carrier status helps the person to be motivated for lifestyle modification
as active life style may help not in prevention but at least delaying the development of
diabetes in known carriers, this hold true with Indian scenario where MODY have accompanying component of insulin resistance.
Table-1: Genetic defects in MODY.
MODY Type
MODY 1
MODY 2
MODY 3
MODY 4
MODY 5
MODY 6
Affected Gene
HNF-4
Glucokinase
HNF-1
IPF-1
HNF-1
Neuro D1
Chromosomal Location
20q13
7p15
12q24
13q12
17q21
2q32
Genetic Studies in Type 2 DM in Indians

Aforementioned, the T2DM is characterized by defect in insulin secretion as well as insulin
action and hence, it is better to segregate the genetic studies on Indians, which has shown
the role of genes in these two types of defects. Mohan et al, have reviewed the genetic
studies in Indians, recently 8.
Studies on Gene Associated with Insulin Secretion in Indians
Sanjeevi et al have shown increased occurrence of the class 3, allele of the hypervariable
region in 5 region of insulin gene and this was more pronounced in south Indians than
in Punjabi Sikhs. Rani et al and others failed to show any abnormalities in Islet Amyloid
Polypeptide (IAPP) gene in south Indians. The most promising gene associated with T2DM
is TCF7L2 gene. There are numerous studies from west linking TCF7L2 gene polymorphism
with T2DM. Similarly, two Indian studies from Pune and Hyderabad also replicated the
same results that of west.
Studies on Genes Associated with Insulin Resistance in Indians
Insulin resistance at two major organ namely skeletal and adipose tissue are of prime
importance in pathophysiology of T2DM. Hence, they are the major target for the genetic
studies. One of the main genes implicated in adipogenesis and development of insulin resistance is PPAR-v gene. In a recent study by Radha et al showed that Ala allele offered
no protection against diabetes in south Indians, this is in contradiction to that found in
Europeans. However, the gene polymorphism in Plasma cell glycoprotein (PC-1) and IRS-1
predicted the genetic susceptibility of T2DM in south Indian. Other gene studied in south
Indians are GLUT-1, GLUT-4, PGC-1A, Calpain-10 and glucokinase with variable results.
Role of Pharmacogenetics in Treatment of T2DM

Pharmacogenetics refers to the use of genetic information to select, from various treatment options, those most likely to benefit a particular disease.

31
MODY have already afforded tantalizing proof of concept as they respond better with
sulfonylureas than Metformin. Similar story for neonatal diabetes caused by either mutation in KCNJ11 or its associated SUR1 channel can be safely transitioned from insulin to
sulfonylureas.
The application of pharmacogenetics in treatment of T2DM is not that rewarding as in
MODY. However, number of studies has been carried to address this issue and many have
answered some of the intriguing questions like who will respond and who wont with
particular drug.
32
For unknown reasons, not all type 2 DM patients respond to the antidiabetic action of
sulfonylureas and this is known as primary sulfonylurea failure and those who respond
well initially may have a loss of effective antidiabetic response after years of treatment is
called secondary sulfonylurea failure. In the United Kingdom Prospective Diabetes Study
(UKPDS), treatment with sulfonylureas achieved an HbA1c less than 7% in 50% of patients at three years, 34% at six years and 24% at nine years. This fact suggests the role
of gene in drug response and hence numbers of studies have been carried out. Study by
Sesti G and colleague showed that carriers of the Lys23 variant of the KCNJ11 Glu23Lys
polymorphism are more susceptible to secondary failure when treated with a sulfonylurea
and Metformin combination. Carriers of the lysine allele had a relative risk of secondary
failure of 1.45 compared with Glu23Glu homozygotes9. Similarly, the Diabetes Prevention
Program cohort suggested KCJN11 Lys23 carriers progressed to diabetes at a higher rate
when treated with Metformin for 1 year than the Glu/Glu homozygotes10. Until date, the
strongest gene candidate associated with risk of diabetes is TCF7L2. Homozygous carriers
of the risk T allele at rs7903146 showed an 80% increase in risk of developing diabetes
and one study also showed that 53% of such individuals failed to reach target A1c (<7%)
on sulfonylurea compared to CC allele carrier 11.
Metformin decrease the hepatic gluconeogenesis and hence reduces the fasting plasma
glucose. This drug is being, taken up by hepatocyte by organic cation transporter (OCT1).
This fact has been, explored for OCT 1 gene polymorphism and effects of drug in patients
with T2DM. In a study by Shu et al, Metformin lowered the glycemic excursion by 7.5%, in
response to oral glucose challenge test in subjects with intact OCT1 function 12. However,
further studies are required to substantiate this observation.
Thiazolidinediones are Peroxisome Proliferator-Activated Receptor gamma (PPAR-y) activator. These drugs enhance the insulin sensitivity in peripheral tissues like muscle and
adipocytes. A nonsynonymous SNP in PPAR-y (Proline 12 alanine) was one of the first
common genetic variant associated with a predisposition to T2DM. Kang et al studied
the response of Rosiglitazone with this polymorphism and they showed significant higher
response rate to 4 mg Rosiglitazone once daily for 12 weeks in patients with the Pro/Ala
genotype compared with the Pro/Pro genotype 13.
In summary, number of candidate genes has been linked to the development of diabetes
but they are not stronger than environmental factor and replication studies have been in
way to strengthen the association between the two. Furthermore, the studies have been,
carried out to predict, prevent and treat type 2 diabetes with modest success. In future,
the application of this knowledge may have significant impact on individualizing the
medical treatment.
Present Status and Future of Stem Cell Transplantation:

Research in the field of stem cells for their use in management of diabetes is recent
phenomenon. Stem cells are the cells, which are capable of both self-renewal and differentiation into at least one mature cell type. These cells colonize to injured tissues due
to prevailing cytokine milieu (homing in). The sources of stem cells include embryonic
stem cells, cord blood stem cells and adult stem cells. However, the embryonic as well
as cord blood stem cells are presently facing ethnic, ethical and legal issues. Therefore,
autologous adult stem cells are preferred. The adult stem cells can be obtained from liver,
bone marrow and neural tissues. However, the bone marrow is most commonly and easily
available source for the same. Though, they are easily available, but they do have a limited
proliferative capacity and their lineage is restricted. There are few animal data showing the
use of Autologous bone marrow derived stem cell therapy (ABMSCT) in mice with reversal
of diabetes. However, there are limited data of the use of ABMSCT in patients with Type
1 diabetes from Brazil with some success and there is only one work in our centre in
patients with some success either in reduction of insulin doses or elimination of insulin
requirement in patients with T2DM.
Our data on use of adult bone marrow derived stem cells in patients with T2DM showed
either reduction in insulin doses or stoppage of insulin in two third of the subjects and
it worked for a period of 15 months till last follow-up. There were no adverse events
reported during this whole study period. However, we had limitations including lack of
control group and a very small number of patients. However, the results were encouraging,
but needs more data to substantiate these observations.
References
1.
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for year 2000 and
projections for 2030. Diabetes Care 2004; 27: 1047-1053.
2.
Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetes mellitus in the Pima Indians: Incidence, risk factors
and pathogenesis. Diabetes Metab Rev 1990; 6: 1-27.
3.
Pyke D A, Theophanides C G, Tattersall R B. Genetic origin of diabetes: Re-evaluation of twin data. Lancet
1976; 2: 464.
4.
Newman B, Selby JV et al. Concordance for type 2 diabetes mellitus in male twins. Diabetologia 1987;
30: 763-768.
5.
Viswanathan M, Mohan V, Snehalatha C, Ramachandran A. High prevalence of type 2 diabetes among

offspring of conjugal diabetic parents in India. Diabetlogia 1985; 28: 907-910.
6.
Tattersall R. Maturity onset diabetes of the young: a clinical history. Diabet Med 1998; 15: 11-14.
7.
Radha V, Jakob EK, Pederson O, Mohan V, Torben H. Identification of novel mutations in south Indian
patients with maturity onset diabetes of the young. Diabetes 2003; 52: 515.
8.
Radha V, Mohan V. Genetic predisposition to type 2 diabetes among Asian Indians. Indian J Med Res 2007;
125: 259-274.
9.
Sesti G, Laratta E, Cardellini M, et al. The E23K variant of KCNJ11 encoding the pancreatic -cell adenosine
5-triphosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary
failure to sulfonylurea in patients with Type 2 diabetes. J. Clin. Endocrinol. Metab 2006; 91:23342339.
10. Florez JC, Jablonski KA, Kahn SE, et al. Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and
ABCC8 A1369S influence progression to diabetes and response to interventions in the Diabetes Prevention
Program. Diabetes 2007; 56:531536.

33
11. Pearson ER, Donnelly LA, Kimber C, et al. Genetic susceptibility to Type 2 diabetes andimplications for
antidiabetic therapy. Diabetes 2007;56:21782182. Discusses the potential effect of TCF7L2 on diabetes
and response to sulfonylureas.
12. Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter1 (OCT1)
on Metformin action. J. Clin. Invest 2007; 117:14221431. Discusses the potential effect of common genetic
variation in OCT1 on Metformin response.
13. Kang ES, Park SY, Kim HJ, et al. Effects of Pro12Ala polymorphism of peroxisome proliferator activated
receptor 2 gene on rosiglitazone response in Type 2 diabetes. Clin. Pharmacol. Ther 2005; 78:202208.
34
Problems of Obesity in Type 2 Diabetes

Dr K D Modi
Medwin Hospital, Hyderabad.
E-mail: drkdmodi@yahoo.co.in
35
Introduction
Diabetes is a chronic disease which is reaching epidemic proportions in many parts of the
world. Type 2 diabetes accounts for more than 90% of the diabetic population worldwide.
Both genetic & environmental factors are going to contribute in the development of the
disease. The International Diabetes Federation estimates showed that 194 million people
had diabetes in 2003 & is expected to reach 333 million by the year 2025. The rising
prevalence of type 2 diabetes appears to be greatly related to the increasing prevalence
of overweight & obesity globally.
Obesity is one of the most important risk factor for the present epidemic of non communicable diseases diabetes, hypertension and coronary heart disease. Obesity is known
to contribute 55-90% of cases of type 2 diabetes. The prevalence of obesity has tripled
in last 20 yrs in developing countries. Even though in India non obese type 2 diabetes
is more common than in the western world, obesity still remains an important risk factor.
The two conditions are so much interlinked that the new terminology combining both
the condition has come as Diabesity (International Herald Tribune, 17 Mar. 2003). As per
family health survey in India, diabesity prevalence in urban area ranges from 12 20%,
more in adult females (15-20 %) in comparison to males (12-15%). In spite of some draw
backs best defining tool for obesity is Body Mass Index (BMI). It is calculated as weight
in kg divided by square of height in meter.
BMI
Body weight (kg)

Height (meter)
As per standard WHO definition obesity is classified as following:
36
Obesity classification
Under weight
Normal weight
Over weight
Class I obesity
Class II obesity
Class III obesity
BMI (kg/m2)
< 18.5
18.5 24.9
25 29.9
30 34.9
35 39.9
> 40
The impact of obesity to cause metabolic derangement seems to be more in Asians and
hence cut off value of body mass index (BMI) to define obesity is different in Asian countries (India & Japan BMI > 25, China , BMI > 28) in comparison to standard WHO definition
of obesity (BMI > 30 kg/m2). However, the distribution of body fat is a more important
determinant than the degree of obesity. Asian Indians generally have lower BMI than any
other population. They show a tendency for fat deposition in the abdominal area which is
known as central adiposity. Measurement of waist girth is a simple index of central adiposity than with BMI. Indians have a high proportion of body fat and abdominal obesity
despite having lower BMI. Central obesity (waist circumference > 80 cm in females and >
90 cms in males) reflects visceral obesity and it correlates more with the risk of diabetes
than generalized obesity. The presence of central adiposity in Asian Indians predisposes
them to insulin resistance even at a lower degree of obesity compared to the European
population. Moreover, in Indians type 2 diabetes develops at a younger age.
The important risk factors for becoming obese are dietary factors, physical inactivity &
family history. Diets high in fats & sugars influence weight gain because they increase the
energy density in foods. Urbanization leads to life style changes especially in diet with
most of the populations preferring refined food. In addition, decreased physical activity
burns fewer calories, thus increasing the risk of obesity. Insulin resistance worsens with
small increments in weight and also with lack of physical activity.
It is proved that roots of metabolic syndrome in form of hyperinsulinemia starts right from
early childhood. Childhood obesity should be defined only by plotting BMI against BMI
for age charts. Eighty five to 95th percentile weight in children is considered over weight
while > 95th percentile of weight falls in obese category. This childhood obesity is caused
by unhealthy eating patterns and lack of physical activity. The escalating prevalence of
type 2 diabetes in children poses a serious public health problem. A study in urban South
Indians showed that 17.8% of boys & 15.8% of girls in the age group of 14-19 years were
overweight. Similar reports have appeared from other parts of India.
Epidemiology
Diabetes
Over all prevalence of type 2 diabetes in India ranges from 12-20% in urban area and
6-10% in rural area. In western world 64% cases in males and 77% of female type 2
diabetes are related to obesity 2. The problem is global and increasingly extends into the
developing world; for example, in Thailand the prevalence of obesity in 5 to 12 year olds
children rose from 12.2% to 15-6% in just two years. WHO further projects (WHO 2005)
that by 2015, approximately 2.3 billion adults will be overweight and more than 700 million will be obese.
Obesity in the Indian Scenario
There has been an increase in the standard of living, as a consequence of industrialization &
urbanization, leading to a nutritional transition with consumption of diets that are energy
dense and high in fat and sugar component. Moreover, with changes in occupation from
predominantly agriculture based manual labour jobs to sedentary office type jobs; there is
a perceptible decrease in physical activity. This is the basis for the rapid weight gain and
obesity seen in several parts of the sub-continent. There is paucity on nationwide data on
the prevalence of obesity. However, studies in different states of India provide some data
on the magnitude of the health threat due to this problem. Published data from different studies shows that the prevalence of obesity ranges from 10% to 50%. According to
the Nutritional Foundation of India, the prevalence of obesity is 1% for males & 4% for
females in the slums while corresponding figures for the middle socio-economic class was
32.2% and 50%, respectively. In the Chennai Urban Population Study (CUPS), over 35% of
the males in the middle-income group were obese compared to 13% in the low-income
group. The corresponding figures for females were 33% and 24% respectively. Abdominal
obesity among middle income group 47.4% compared to 19.2% in the low income group.
(In India as per various studies the prevalence of overweight (BMI 25-29.9 Kg/m2) ranges
from 14-20% while obesity from 1-4%)
Recent data, shows that in India the trend is alarming. (Overweight population, including
obesity from 9% in 1999 to 24% by 2025.)
37
Figure 1: Prevalence of Obesity from 1995 to 2025
Diabetes & Obesity
38
The prevalence of type 2 diabetes increases with age and increasing obesity (particularly
visceral or abdominal). It is well known that type 2 diabetic subjects are often obese
and alternatively, obese subjects are likely to have insulin resistance. The link between
obesity and diabetes may be accelerated due to the transition from an active rural to
sedentary urban socio-economic milieu. In the Chennai Urban Population Study (CUPS),
the prevalence of diabetes increased with increase in quartiles of body mass index (BMI),
the prevalence being 2.9%, 8.1%, 17.6%, & 19.5% in the first, second, third, & fourth
quartiles of BMI respectively. Prevalence of diabetes in subjects with abdominal obesity
was significantly higher compared to those without abdominal obesity (27.8% vs. 9.0%).
In addition to prevalence of Impaired Glucose Tolerance [IGT] also increased with increase
in quartiles of body mass index being 2.2%, 3.2%, 5.9%, & 12.1% in the first, second,
third, & fourth quartiles of BMI respectively & this increase was statistically significant.
Prevalence of IGT in subjects with abdominal obesity (15.0%) was also significantly higher
compared to subjects without abdominal obesity (2.6%).
Though studies have shown both total & visceral fat to be associated with diabetes,
visceral fat is considered to be more important as it has been shown to have a strong
correlation with glucose intolerance and insulin resistance. The visceral fat stored beneath
the muscles and wrapped around the internal organs is considered to be the most atherogenic, diabetogenic and hypertensiogenic fat depot of the human body. However,
this is still a debated issue with some authors suggesting that subcutaneous fat is more
strongly associated with diabetes while others report that visceral fat is a stronger risk
factor for diabetes.
Diabetes & Obesity in Children

There has been a disturbing trend, over the last two decades of increasing cases of type 2
diabetes, in children in parallel with increasing rates of obesity. Several studies from India
have predicted that the epidemic of diabetes in urban India would become worse due to
the rising trend in obesity in children. In urban south India, the prevalence of overweight
among school children is above 16% and showed a strong association with lack of physical
activity & high social stratum. Type 2 diabetes is more prevalent among obese children.
Sinha et al have reported that impaired glucose tolerance is highly prevalent among children and adolescents with severe obesity, irrespective of ethnic group and overt type 2
diabetes was linked to beta-cell failure.
Pathogenesis
Obesity is the main risk factor for type 2 diabetes apart from other environmental and
genetic factors. However all obese people are not diabetic. An adipocyte-hormone called
Resistin is known to provide link between obesity and diabetes5. Central obesity is more
important than generalized obesity to make someone prone for type 2 diabetes. Central
obesity correlates well with insulin resistant state. Lipotoxicity, inflammation of fat depots
and availability of excess free fatty acid play important role to cause type 2 diabetes at
hypothalamus level 8. Leptin binds to neuropeptide y (NPY), a feeding hormone at arcuate
nucleus and reduces satiety. It also promotes synthesis of Alpha-MSH, an appetite suppressant. Just like insulin resistance, obese people have desensitization of Leptin.
Management
Anti
Metfor- SulfoGlidiabetic min
nylureas tazones
agents
Wt
+
++
gaining
property
Insulins*
+
DPP4
inhibitors
0
GLP1
analogues
--
SGLT2
inhibitors
-
Acarbose
0
Table 1: Anti-Diabetic Drugs and Obesity
Weight Gaining Properties of Various Anti Diabetic Agents

*Insulin therapy in generally is known to cause weight gain due to correction of uncontrolled diabetes and anabolic effect of the hormone, however insulin Detemir is known
to cause less weight gain. Glargine insulin causes lesser weight gain than NPH insulin.
Overall Sulfonylureas, Glitazones and insulin cause weight gain on long run. Metformin
can cause weight reduction up to 2-4%. Newer agents like SGLT2 inhibitors are known
to cause weight loss due to their main mechanism of action to cause glycosuria. DPP4
inhibitors are considered weight neutral.
Managing Obesity in Diabetic Patients

Life style measures like regular exercise at least hour per day; 5 days a week and
weight reduction of 5-10% in a year can prevent diabetes by 50-55% 1. Most patients
with type 2 diabetes are significantly overweight and obese. They play a major role in the
pathophysiology of the disease essentially by increasing insulin resistance. Moreover, it is
well established that weight loss provides for rapid and marked improvement of glycemic
control in obese diabetic patients and should thus represent a major target in the treatment of the obese patient with type 2 diabetes.
39
Various beneficial effects of weight loss have been demonstrated in numerous studies
focusing on the prevention, treatment, prognosis of diabetes in obese individuals. As far
as prevention is concerned, it has been shown that weight loss markedly reduces the risk
of developing type 2 diabetes: women with a BMI>35kg/m2 had about 100-fold increased
risk of diabetes as compared to those with a BMI<22kg/ m2 and women who lost >5kg
reduced their risk of diabetes by >50%. With respect to treatment, weight loss has been
shown to reverse secondary failure to oral hypoglycemic agents in obese diabetic patients.
Finally as far as prognosis is concerned weight loss has been shown to reduce the risk of
death from co-morbid diabetes: in overweight women with moderate weight loss (<10kg)
mortality from comorbid diabetes was reduced by 44%. Furthermore, weight loss increases
life expectancy in patients with diabetes and each loss of 1 kg has been estimated to
add 3-4 months.
Dietary Therapy
Individuals with diabetes should be counseled by their healthcare providers especially physicians and dieticians to achieve non-obese body weights (i.e. BMI<25kg/ m2). For persons
with BMI values of 25-30 kg/ m2 dietetic counseling and a structured Low Energy Diet
(LED) may be the most cost effective approach. For persons with BMI values >30kg/ m2
medically supervised LEDs may be the most effective approach. Higher carbohydrate, higher
fiber diets, lower fat diets provide glycemic, lipidemic and weight management advantage
for long term management of obese individuals with type 2 diabetes.
Yoga Therapy
40
Yoga is an ancient art time tested since ages and has proved in providing solution for many
chronic conditions. The best prevention method against developing type 2 diabetes is by
maintaining weight. In a recent epidemiological survey in a south Indian city, nearly 79%
of the doctors say that regular and continuous practice of yoga can help prevent diabetes
& 55% conform to the fact that glycemic control is better in those who practice yoga.
Pharmacotherapy
Anti-obesity drugs should be considered only if glycemic control is good. The potential sites
of therapeutic intervention for obesity include the brain to alter neural signals regulating
appetite, the gut to alter nutrient adsorption and adipose tissue to alter fat storage and
promote fat oxidation.
Out of the 2 drugs which were approved by the FDA, for the treatment of obesity; the
neurotransmitter reuptake inhibitor Sibutramine was recently withdrawn from the market
on the basis of on new data from the Sibutramine Cardiovascular Outcomes (SCOUT)
trial. Sibutramine acts in the brain to suppress appetite, while the 2nd drug Orlistat acts
by inhibiting the enzyme pancreatic lipase. Orlistat works in the gut to limit free fatty
acid formation & inhibit their adsorption.
SCOUT Trial
The SCOUT trial was a randomized, double-blind, placebo-controlled multicenter trial conducted between January 2003 and March 2009 in Europe, Latin America, and Australia.
The study population consisted of approximately 10,000 men and women aged 55 with
a BMI between 27 kg/m2 and 45 kg/m2, or between 25 kg/m2 and 27 kg/m2 with an
increased waist circumference. Patients were also required to have a history of cardiovascular disease (coronary artery disease, stroke, occlusive peripheral arterial disease) and/or
type 2 diabetes mellitus with at least one other cardiovascular risk factor (hypertension,
dyslipidemia, current smoking, or diabetic nephropathy). All patients underwent a 6-week
lead-in period on Sibutramine 10 mg. Eligible patients were then randomized to either
placebo or Sibutramine 10 mg daily. Titration to Sibutramine 15 mg daily was allowed for
individuals with inadequate weight loss on 10 mg daily. The mean duration of exposure
to Sibutramine and placebo was approximately 3.5 years.
There was a 16% increase in the relative risk of the primary outcome event (a composite
of non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, and
cardiovascular death) in the Sibutramine group compared to the placebo group. FDA has
therefore concluded that the risk for an adverse cardiovascular event from Sibutramine
in the population studied outweighed any benefit from the modest weight loss observed
with the drug.
Orlistat
Orlistat is a lipase inhibitor developed for the long-term management of obesity and its
associated co-morbidities. A dose-dependent reduction in dietary fat absorption is produced
by Orlistat, with a maximum 30% inhibition of fat absorption with a dosage of 120 mg
t.i.d. By selectively inhibiting the absorption of dietary fat, Orlistat is directed toward one
of the putative causes of obesity, namely, excess dietary fat intake. Several short-term
studies have shown that Orlistat plus diet is more effective in reducing weight compared
with diet alone.
A multicenter double-blind randomized placebo-controlled trial was conducted on obese
patients of either sex (aged 18 years) with a BMI of 2840 kg/m2, who were on an oral
hypoglycemic drug therapy for at least 6 months before the study, and had a stable plasma
glucose level on a second generation sulfonylurea agent (Glyburide or Glipizide) as the
only hypoglycemic agent at entry into the trial.
Orlistat plus diet therapy produced an average weight loss of 6 kg (6% of body weight)
in patients with type 2 diabetes. Moreover, this loss was significantly greater than that
seen with diet therapy alone and was maintained for 1 year. Orlistat plus diet not only
improved glycemic control more than diet alone, but it also lowered the dose requirement
for sulfonylurea therapy and had favorable effects on total cholesterol, LDL cholesterol,
the LDL to HDL cholesterol ratio, and apolipoprotein B levels.
Gastrointestinal side effects of Orlistat, including loose stools, increased defecation, fecal
urgency, and oily discharge, are significantly more common than observed with placebo
and may lead to discontinuation of the drug. One study found that concomitant use of
natural fiber (psyllium mucilloid) may reduce the incidence of these gastrointestinal side
effects.Future of Obesity Drugs Is It Bleak or Bright?
Future of Obesity Drugs Is it Bleak or Bright?

The maximal weight loss achievable with any current dietary or pharmacological strategy
for treating obesity varies with the individual but appears to be no more than 10% of
initial weight. As this threshold is approached, or perhaps as the time spent below initial
weight increases, physiological mechanisms acting to preserve body fat mass cause a proProblems of Obesity in Type 2 Diabetes
41
gressive increase in appetite and decrease in energy expenditure. These regulatory responses
prevent further weight loss and make maintenance of achieved weight loss difficult. It is
now appreciated that the long-term regulation of adiposity involves both peripheral signals
that relay information about adipose tissue mass to the CNS and opposing circuits in the
hypothalamus that regulate appetite and energy expenditure. To improve the pharmacological options for treating obesity, it will be necessary to intervene at key points within
this regulatory network.
Melanocortin Receptor Agonists and Melanocortin

Mutations in the melanocortin receptor (MC4R) have been identified in extremely obese
individuals and human patients and mutant mice with deficiencies in the synthesis of
melanocortins are typically obese. Administration of MC4R agonists has been demonstrated
to lead to a decrease in food intake and/or body weight in rodents, and decreased body
fat and body weight in lean but not obese humans.
Melanin-Concentrating Hormone (MCH) Antagonists

MCH is a cyclic, highly conserved, 19-amino-acid polypeptide implicated in the control
of feeding behaviour and energy homeostasis. Central administration of MCH stimulates
food intake in rats and mice. MCH mediates its effects through G-protein-coupled receptors located in the central nervous system, of which two receptor subtypes, MCH1R
and MCH2R, have been identified. MCH1 receptor antagonists have been demonstrated to
suppress food intake and reduce body-weight gain following continuous infusion in lean
rats and completely suppress body-weight gain and significantly decrease cumulative food
intake in diet-induced obese mice.
42
Antiepileptics
Zonisamide is an antiepileptic drug which demonstrated weight loss as an adverse effect during treatment in epilepsy clinical trials, and as such is now being studied for its
potential use for the treatment of obesity and binge-eating disorders. Administration of
zonisamide to obese patients on a hypocaloric diet resulted in a 6% weight loss after 16
weeks, in comparison to a 1% weight loss for dietary intervention alone.
Low doses of the amphetamine-derived compound phentermine and the anticonvulsant
agent topiramate, is being developed for the treatment of obesity. Topiramate is an antiepileptic/antimigraine agent and which has multifactorial effects on the CNS, involving
blockade of voltage-dependent sodium channels and action on the GABA (-amino butyric
acid) and glutamate systems. Phase II data for the combination demonstrated a placeboadjusted non-plateaued weight loss of 9.2 kg after 24 weeks, and the proportion of patients
achieving 10% or more total body weight loss was greater than the sum of phentermine
and topiramate comparator agents administered alone.
Ghrelin
Ghrelin is an acylated peptide produced in response to decreased food intake that stimulates the release of growth hormone from the pituitary gland. Ghrelin decreases the production of leptin and neuropeptide Y, and has an orexigenic effect when administered
to humans or rodents that promotes weight gain and adiposity, and decreases energy
expenditure and fat catabolism. Intervention targeted at antagonism or inverse agonism

of the ghrelin receptor provides additional therapeutic strategies; however, most recently
vaccination of rats on low-energy diets with ghrelin immunoconjugates decreased feed
efficiency and body-weight gain due to the subsequent immune response elicited against
endogenous ghrelin.
3-Adrenoceptor Agonists
Stimulation of the seven-transmembrane G-protein-coupled 3-adrenoceptor induces

cAMP-dependent lipoprotein lipases (responsible for triglyceride lipolysis), and uncoupling
protein 1, which has been shown to be associated with increased thermogenesis, activities
that will lead to diminished adipocity. Polymorphisms in the 3-adrenoceptor gene have
been associated with obesity and diabetes. To date agonists of the 3-adrenoceptor have
proved disappointing in the clinic, and efficacy in rodent models has not translated into
beneficial effects in humans.
Contrave is a combination of the centrally acting medications bupropion, a dopamine
and noradrenaline-reuptake inhibitor that has demonstrated dose-related weight loss, and
naltrexone, an opioid-receptor antagonist used to treat narcotic and alcohol dependency.
Bupropion and naltrexone have been reported to synergistically stimulate the pro-opiomelanocortin (POMC) system that is associated with reducing food intake by blocking a
-endorphin mediated inhibition of POMC neurons. Phase II data for Contrave demonstrated
a 6.6% non-plateaued weight loss after 24 weeks in subjects with a BMI of 3040, in
comparison with 3.8% (bupropion alone), 2.2% (naltrexone alone) and 0.9% (placebo),
respectively.
Peripheral Mechanisms
Lipid Metabolism Modulators
Human growth hormone (hGH) has lipolytic/antilipogenic properties. As an inhibitor of
lipoprotein lipase, it can increase circulating free fatty acids and ultimately reduce fat
cell mass. GH-deficient patients display a strong correlation between excess abdominal
adiposity and reduced circulating GH levels that can be normalized after GH-replacement
therapy. GH levels decrease as a normal part of ageing, and an hGH-deficient state precedes age-onset obesity.
The lipolytic domain of the hGH molecule has been identified as being the carboxyl terminus of the intact hormone (residues 177191). hGH(177191) inhibits the activity of acetyl
co-enzyme A carboxylase in adipocytes and hepatocytes, which reduces glucose incorporation into lipid in both isolated cells and tissues, and thereby enhances the breakdown
of stored fats and inhibiting the synthesis of new fat without the diabetogenic effects
associated with the amino-terminal region of the molecule. Results of a Phase IIb clinical
trial showed that once-daily administration of 1 mg hGH(177191) led to weight loss of
2.0 kg more than placebo over the course of 12 weeks.
Gut Hormones
Gut Hormones and Obesity
Many peptides are synthesized and released from the gastrointestinal tract, several of which
43
are known to modulate eating behaviour, such as cholecystokinin, glucagon-like-peptide-1

(GLP-1), ghrelin, oxyntomodulin and peptide YY (PYY), all of which respond to nutrients
within the gut by interacting with specific receptors to regulate appetite. Food ingestion
causes the release of anorexigenic peptides as well as vagal stimulation by mechanical
and chemical receptors in the gut.
Peptide YY (PYY)
PYY is a 36-amino-acid peptide synthesized and secreted from endocrine L cells of the distal
gut in response to food ingestion. Obese individuals have lower endogenous increases in
PYY(336) levels in response to calorie intake in comparison with normal-weight subjects.
In contrast to leptin, obese individuals are characterized by lower levels of PYY(336), and
its anorexigenic effect is preserved, making PYY(336) an attractive therapeutic target.
PYY(336) is currently in a dose-ranging Phase 1 clinic trial as a nasally administered obesity therapeutic. Previous Phase I data indicated that PYY(336) is safe and well tolerated,
and showed evidence of reducing caloric intake, moderating appetite and a tendency to
produce weight loss in human subjects.
Leptin
Leptin is a 16-kDa adipocyte-derived catabolic hormone that has an important role in
energy regulation. In the majority of humans, obesity is characterized by raised plasma
leptin, suggesting resistance to the actions of leptin. The effects of recombinant leptin have
been studied in both lean and obese genetically uncharacterized human subjects. Daily sc
injection of leptin in obese volunteers for 24 wk produced a variable degree of weight
loss, with a mean change of 7.1 kg at a dose of 0.3 mg/kg, the highest dose studied.
44
Pramlintide
Pramlintide is Pro25, Pro28, Pro29-amylin, a soluble synthetic analogue of amylin, approved in the United States as an adjunct to insulin for subcutaneous use in patients
with either type 1 or type 2 diabetes who have failed to achieve desired glucose control
through optimal insulin therapy. A 16-week Phase II dose-ranging study in which obese
subjects received either placebo or pramlintide at one of six dosage regimens (120, 240
or 360 g, given either two or three times a day before meals) yielded an average weight
loss across the pramlintide-treatment groups of 3.86.1 kg from baseline, compared with
2.8 kg for the placebo group.
GLP-1 and EXENDIN-4

GLP-1 mediates its anorectic effects via the GLP-1 receptor in the CNS. The combination
of anorectic and incretin effects of GLP-1 and analogues thereof have attracted much
attention as potential treatments for type 2 diabetes. Chronic subcutaneous administration
of GLP-1 to obese patients with type 2 diabetes for 6 weeks led to an average 1.9-kg
decrease in body weight. Twice-daily subcutaneous administration of Exenatide in patients
with type 2 diabetes led to a dose-dependent weight loss of 1.8 0.3 kg over 28 days,
2.8 0.5 kg over 30 weeks, and 4.7 0.3 kg over 2 years.
Oxyntomodulin
Oxyntomodulin is secreted postprandially from the L cells of the small intestine in proportion to calorie intake, and has effects on gastric acid and pancreatic secretion. A 4-week
study investigated the effect of the administration of subcutaneous preprandial oxyntomodulin three times daily to volunteers with mean BMI 33.7 0.9 kg/pm2. Volunteers
were asked to maintain their regular diet and level of physical exercise during the study
period. Administration of oxyntomodulin resulted in a body-weight reduction of 2.4 0.4%
compared with 0.5 0.6% in the control group (p = 0.01), corresponding to a weight loss
of 2.3 0.4 kg in the treatment group, compared with 0.5 0.5 kg in the control group.
Surgical Treatment for Obesity and Diabetes

Laparoscopic bariatric surgeries are becoming increasingly popular to manage severe obesity (BMI > 40) with or without co morbidities like type 2 diabetes. Trend is for surgical
treatment for less severe obesity with BMI >35 with or without co morbidities. This is
because of significant long lasting weight loss (20-40%), improvement in co morbidities like
hypertension, hyperlipidemia and diabetes. Diabetes cure rate is reported in tune of 50-90
% after gastro jejuna bypass surgery. Restrictive surgery like gastric band offers lesser cure
rate or improvement in hyperglycemia in comparison to malabsorptive bariatric surgeries.
Figure 2: Gastric sleeve with Ileal transposition
45
Newer modality like gastric sleeve with ileal transposition (figure 2) offers remarkable glycemic and metabolic improvement 3 without causing malabsorption. Glycemic improvement
with this surgery is disproportionately more than weight reduction. Hence it is also tried
in normal weight people only for glycemic improvement 6.
Conclusion
Diabetes is a chronic disorder reaching epidemic proportions worldwide. Obesity is one of
the most important primary risk factor for development of type 2 diabetes accounting for
55-90% of the cases of type 2 diabetes. Recent rates of increase indicate that in India, the
proportion of overweight people will increase from 9% to 24% between 1995 and 2025.
There has also been a disturbing trend over the last two decades of increasing cases of
type 2 diabetes in children, in parallel with increasing rates of obesity, & the corresponding increase in type 2 diabetes in obese children. The current management of obesity in
diabetes includes a combination of diet therapy, physical exercise & pharmacotherapy.
Currently, orlistat is the only drug widely used along with diet therapy to induce weight
loss in obese & overweight diabetic patients. Many drugs in the pipeline hold promise in
the future management of obesity which includes melanocortin receptor agonists, antiepileptics, 3 agonists, human growth hormone, gut hormone modulators such as peptide
YY, leptin, pramlinitide & oxyntomodulin.
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46
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10. PRISCILLA A. HOLLANDER. Role of Orlistat in the Treatment of Obese Patients With Type 2 Diabetes. DIABETES CARE 1998;21(8)1288-1294.
11. Dunstan Cooke, Steve Bloom. The obesity pipeline: current strategies in the development of anti-obesity
drugs. Nature Reviews Drug Discovery 2006;5:919-931.
12. David S. Weigle. Pharmacological Therapy of Obesity: Past, Present, and Future. J. Clin. Endocrinol. Metab.
2003 88: 2462-2469.
HbA1c: Present Status and

Predictions for 2025
Dr A G Unnikrishnan
Professor, Department of Endocrinology,

Amrita Institute of Medical Sciences, Cochin.
Phone: 98460 05343
e-mail: unnikrishnanag@aims.amrita.edu
&
Dr T P Ajish
Trainee
Dept. of Endocrinology
Amrita Institute of Medical Sciences, Cochin.
47
Summary
The HbA1c is currently considered to be the benchmark test in the management of hyperglycemia in diabetes. Large multicenter studies have repeatedly used HbA1c as an important marker of glucose control, as the HbA1c has shown a strong association with the
microvascular complications of diabetes. Broadly, there is general agreement that the target
HbA1c levels must be kept below 7% in subjects with diabetes. However, it is interesting
to note that the HbA1c has been recently recommended as a diagnostic test for diabetes.
An HbA1c level that is > 6.5% suggests the diagnosis of diabetes. However, the HbA1c
cannot be considered perfect. HbA1c measurement can be confounded by various illnesses,
medications and clinical conditions, which must be considered when using HbA1c values
for a clinical decision. In addition the HbA1c, while being very sensitive to hyperglycemia,
is quite unreliable when it comes to detecting hypoglycemia. Finally, the HbA1c, while
being a weighted measure of hyperglycemia across the last 3 months, is generally biased
towards glucose control for the immediately previous month. Recently there has been a
good interest in the use of the estimated average glucose (calculated from the HbA1c) as
a more practical and understandable value that the patient can comprehend. Crystal gazing
into the future, what are the likely changes in the clinical use of glycemic measurement?
For one, glucose sensors that last for long periods are possible, as they are currently being used in animal studies already. The future might also see the use of an HbA1c that
specifically reflects postprandial hyperglycemia. However, these predictions may be a little
too futuristic and further studies, are required before these predictions are to be fulfilled.
HbA1c: The Basics

48
The adult human red blood cells contain hemoglobin A as the major hemoglobin along with
several minor hemoglobins like hemoglobin A2, hemoglobin F, hemoglobin A1a, hemoglobin
A1b and hemoglobin A1c. Hemoglobin A1a-c is glycohemoglobins. In the normal 3 to
4-month (120 days) life span of red blood cells glucose molecules react with hemoglobin
to form glycated hemoglobin. Glucose reacts with the N terminal Valine of the beta chain
of Hb A to form HbA1c. Once hemoglobin molecule is glycated it remains glycated interminably. Measurement of glycated hemoglobin within the red cells therefore reflects the
average level of glucose the red cell has been exposed during its life cycle of 120 days.
Thus HbA1c allows the estimation of an integrated value of the glucose excursions over a
period of weeks to months.1, 2 HbA1a and HbA1b react with other carbohydrates and are
not important in diabetes monitoring.
Glucose undergoes non-enzymatic chemical reaction with various proteins in the blood including hemoglobin leading to formation of glycated hemoglobin, glycated serum proteins
(albumin) and advanced glycated end products (AGE). Formation of glycated hemoglobin
is a two step process resulting in covalent attachment of aldehyde group of an acyclic
glucose molecule to protein amino group of the beta chain N-terminal Valine in hemoglobin A. The first step of this reaction results in formation of an aldimine linkage or Schiff
base (pre A1c). This reaction can be transient and reversible. The second step involves a
slower Amadori rearrangement to yield a stable ketoamine linkage HbA1c. The rate of
formation of the Schiff base depends on mainly the ambient glucose concentration while
the formation of ketoamine depends on the glucose concentration and the duration of
exposure of protein to glucose. Accumulation of this protein glycated product is significantly increased in patients with chronic hyperglycemia. Total glycated hemoglobin (GHb)
includes glycation at the N terminal of Valine of beta-globulin of HbA (HbA1c) as well as

additional derivatives with glycation at the Valine and lysines in the hemoglobin molecule.
Glucose linkage to N-terminal Valine of hemoglobin serves as a recognition target for
clinical biochemical assay methods.3 In contrast to other glycated products, glycation of
hemoglobin is an intracellular process in red blood cells, thus red cell turn over and intracellular glucose concentrations affect its blood level. The degree of glycation of hemoglobin
depends upon the level of free glucose molecules inside the red blood cells4 and the activity of enzymes involved in intracellular metabolism of glucose, which declines with the
lifespan of red blood cells. In normoglycemic individuals HbA1c content increases linearly
during the lifespan of the erythrocytes.
Currently available assays for glycated hemoglobin estimation are of three types. The first
is based on charge difference between glycated and non glycated hemoglobin. This includes
ion exchange chromatography, High Performance Liquid Chromatography17 (HPLC), isoelectric focusing and agar gel electrophoresis. The second method assesses the glucose within
glycated species representing total glycated hemoglobin (GHb). Weak acid hydrolysis
and affinity chromatography employ this technique. A third method includes immunoassays using monoclonal antibodies. This wide array of methods adds to the confusion of
interpreting the results.19, 20
It is generally not recommended to perform interconversion of results obtained by different methods. The HPLC method adopted by DCCT7 is considered as gold standard
against which other methods are standardized. National Glycohemoglobin Standardization
Program (NGSP) was initiated in 1996 in United States for the purpose of standardizing
Hemoglobin A1c test results to those of the Diabetes Control and Complications Trial
(DCCT)7 and United Kingdom Prospective Diabetes Study (UKPDS)8 which established the
direct relationships between HbA1c levels and outcome risks in patients with diabetes.
HbA1c in the Diagnosis of Diabetes

The range of glycated hemoglobin varies significantly in normal population.5 Most significant factors associated with HbA1c levels are age, followed by fasting plasma glucose,
body mass index, impaired glucose tolerance, pregnancy, after menopause and family history of diabetes. The levels can be variable in presence of hemoglobinopathies28 due to
decreased erythrocyte lifespan. In view of ethnic and biological variations in HbA1c, it
has been difficult to recommend this test as a tool for screening for diabetes mellitus. In
populations with high incidence of diabetes the correlation between glycemia and glycated hemoglobin appears to be good6 but it is not considered superior to fasting blood
glucose measurements.
The usefulness of HbA1c in the diagnosis and screening of diabetes is not well established. It
is further complicated by the wide variability in measurement using different assays.13,14,15,16
Large epidemiological studies have suggested that HbA1c testing is less sensitive than fasting plasma glucose measurement in terms of its diagnostic capabilities. A combination of
both these parameters is a better predictor of diabetes. A cut off value for diagnosis of
diabetes was assessed in several studies along with fasting plasma glucose. Davidson etal9
suggested an HbA1c level above 7.1% (1% above the normal upper limit of normal) as
the diagnostic threshold for diabetes. Little etal12 suggested an HbA1c value 2 SDs above
the mean as highly specific for the diagnosis of diabetes. The choice of the HbA1c was
49
based on current treatment goal and not for diagnosis purposes. This approach has got a
high specificity than sensitivity. Weiner suggested that an HbA1c value more than 6.2%
is highly specific for the diagnosis of diabetes. The Third National Health and Nutrition
Examination Survey have also indicated that HbA1c measurements are 97% specific for
diagnosis of diabetes. So, patients with elevated HbA1c levels are likely to be diabetic even
when fasting plasma glucose is non diagnostic.
The American Diabetes Association23 (ADA) recommends an HbA1c level > 6.5% done in
laboratory using an NGSP certified assay as the cut off for diagnosing diabetes.
Target Levels of HbA1c for Diabetes Control

In diabetic patients, the level of HbA1c can be used as a valuable tool for monitoring
the control of hyperglycemia. It is particularly useful in type 1 diabetes as the day to day
variation of blood sugars is high, making it difficult to assess glycemic control by blood
glucose monitoring alone.
Several studies have assessed the relative contribution of fasting and post prandial sugars
with HbA1c. Data from Diabetes Control and Complication Trial7 (DCCT) showed bedtime
and post lunch plasma glucose correlated most strongly with HbA1c while there was
less correlation with fasting and post breakfast plasma glucose values. The DCCT study
confirmed the direct relationship between the degree of glycemic control as estimated by
glycohemoglobin determination and the development of long term complications in type
1 diabetes.
50
Lowering HbA1c to below or around 7% has been shown to reduce the microvascular
complications of type 1 and type 2 diabetes. For microvascular disease prevention A1c
goal for non-pegnant adults in general is <7%. Long term follow up of the DCCT (EDIC
study29) and United Kingdom Prospective Diabetes Study8 (UKPDS) cohorts suggests that
the treatment to HbA1c targets below or around 7% is associated with long term reduction in risk for macrovascular disease. Until more evidence becomes available a goal of
<7% appears reasonable for prevention of microvascular risk reduction.
Subgroup analyses of clinical trials such as the DCCT and UKPDS, and evidence for reduced
proteinuria in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation30 (ADVANCE) trial suggest a small but incremental benefit
in microvascular outcomes with A1C values closer to normal. So in selected patients with
short duration of diabetes, long life expectancy and no significant cardiovascular disease a
lower HbA1c target may be attained. Conversely, less-stringent A1C goals than the general
goal of <7% may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, and extensive
comorbid conditions and those with longstanding diabetes.
In 2008, results of three large trials (ACCORD32, ADVANCE30, and VADT31) suggested no
significant reduction in CVD outcomes with intensive glycemic control in these populations.
The ADA guidelines for glycemic goals23 include HbA1c as the primary target for glycemic
control. Goals should be individualized based on duration of diabetes, age, life expectancy,
comorbid conditions, known CVD or advanced microvascular complications and hypoglycaemia unawareness. ADA recommends HbA1c measurement at least two times a year
in patients who are meeting treatment goals (and who have stable glycemic control). In
patients whose therapy has been changed or who are not meeting glycemic goals HbA1c
has to be tested quarterly. Point of care testing of HbA1c for timely decisions on therapy
changes when needed is recommended.
American Association of Clinical Endocrinologists11 (AACE) recommends an HbA1c target
of <6.5% for optimal glycemic control for prevention of microvascular and macrovascular
complications of diabetes. The American Diabetes Association23 (ADA) recommends a target
HbA1c level <7% in diabetes.
Limitations of HbA1c as a Marker of Hyperglycemia

The interpretation of HbA1c is complex and requires complete consideration of the clinical
status of the patient as well as the methodologies involved. 23-33 HbA1c help to identify
patients with poorly controlled diabetes mellitus, but a high level by itself cannot guide a
physician toward specific adjustment in insulin dosage. There are many pitfalls in the use
of HbA1c in the presence of hemoglobinopathies28 or other complicating illness affecting
erythrocyte life span like hemolytic anemia. Glycated hemoglobin will be falsely elevated in
the presence of negatively charged hemoglobin variants, uremia, alcoholism, lead poisoning, hyper triglyceridemia, iron deficiency anemia, post splenectomy, hyperbilirubinemia,
opiate addiction and chronic aspirin therapy. GHb levels will be falsely low in the presence
of positively charged hemoglobin variants, hemolytic anemia, acute or chronic blood loss
and pregnancy. These co morbidities should be considered while interpreting the glycemic
control of patients using HbA1c. Though HbA1c is indicative of glycemic control over 3
months, it is more biased towards the glycaemic control for last one month. The rate of
decline of HbA1c starts after 2 weeks in newly detected type 1 diabetes after insulin initiation and level off after 7 weeks. A half life of 28 days for HbA1c was shown in patients
with type 1 diabetes who achieved rapid normalization of glycemic control after insulin
initiation. Though HbA1c is a very good tool for assessing hyperglycemia, it is not useful
when the patient is having recurrent hypoglycemias. Hemoglobin A1c is not influenced by
daily fluctuations in blood sugars.
The future: Non- Invasive Testing, Long-Term Sensors and More

Recent interest in the follow up of patients with diabetes is the measurement of estimated average glucose (calculated from the HbA1c) as meaningful tool of glucose control.
It has gained much interest after the ADAG Study (A1c-derived Average Glucose Study).
Glycosylation gap21 (calculated from the difference between measured HbA1c and calculated HbA1c from fructosamine estimation) is an additional tool may be a useful clinical
research tool for evaluating physiologic sources of variation in diabetic complications
beyond glycemic control.
Continuous glucose monitoring provides information about the direction, magnitude, duration, frequency, and causes of fluctuations in blood glucose levels. Compared with conventional intensified glucose monitoring, defined as three to four blood glucose measurements
per day, continuous monitoring provides much greater insight into glucose levels throughout the day. Continuous glucose readings that supply trend information can help identify
and prevent unwanted periods of hypo- and hyperglycemia. Recent research and development largely focused on needle-type glucose sensors (enzyme electrodes) implanted in the
subcutaneous tissue. Non-invasive glucose sensing will maximize acceptance by patients
51
and overcome biocompatibility problems of implants. Non invasive glucose monitoring

techniques33 involves infrared spectroscopy, fluorescence, light scattering, photo-acoustic
spectroscopy or reverse iontophoresis. Infrared spectroscopy has been most investigated
but the precision needs to be improved for eventual clinical application.
1,5 Anhydroglucitol(1,5AG) excretion in urine can rapidly detect a slight change in glycemia24 and is therefore suitable for monitoring the control of glycemia25 in patients with near
normoglycemia. Hyperglycemia cause a reduction in 1, 5 AG levels in urine and its levels
in urine is an indicator of glycemic control in patients without advanced renal glomerular
disease. Urinary excretion of N-Acetyl Glucosaminidase (NAG) shows a negative correlation with serum concentrations of 1,5AG. Severini et al, 26 reported that an isoenzyme of
NAG was significantly correlated with the status of glycemia. In UKPDS 27, the decrease in
urinary albumin and NAG excretion was associated with a reduction in the fasting plasma
glucose level in response to dietary treatment. 1,5AG is a sensitive index of renal damage
induced by diabetes as well as of hyperglycemia.
Search for newer advanced glycated products (AGE) are ongoing. AGE protein adducts
like carboxy methyl lysine (CML) and pentosidine are relatively stable in the body. AGE
modifications of proteins are potentially involved in the micro and macrovascular complications of diabetes. The discovery of specific AGE receptor (RAGE) on a variety of cell types
led to the development of whole cell radioreceptor assay for AGEs. At present monitoring
AGEs remains a research tool that is not widely available.
Conclusion
52
HbA1c continues to remain as important marker of glucose control; it shows strong association with the microvascular complications of diabetes. Recently, (Hba1c > 6.5%) also
being recommended for diagnosis of diabetes. HbA1c may be biased towards glycemic
control for last one month.
The future of diagnostic for glycemic control may move towards use of continuous glucose
monitoring than conventional methods. Non invasive glucose monitoring techniques like
spectroscopy, light scattering, fluorescence and reverse iontophoresis may also become
available for clinical application.
References
1.
Rohlging CL, Wiedmeyer HM, England JD, Tennill A, Goldstein DE: Defining the relationship between plasma
glucose and HbA1c. Diabetes care 25:275-278,2002
2.
Sacks DB, Bruns DE, Goldstein DE, Maclaren NK, Mc Donald JM, Parrott M: Guidelines and recommendation
for laboratory analysis in the management of diabetes mellitus. Clin Chem 48:436-472,2002
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Bunn HF, Haney DN, Gabbay KH, Gallop PM: Further identification of the nature and linkage of the carbohydrate in haemoglobin A1C. BiochemBiophys Res Commun 67:103-109.1975
4.
Higgins PJ, Garlick RL, Bunn HF: Glycosylated hemoglobin in human and animal red cells, the role of glucose
permeability, Diabetes 31:743-748,1982
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Kilpatrick ES, Maylor PW, Keevil BG: Biological variation of glycated hemoglobin:implications for diabetes
screening and monitoring. Diabetes Care 21:261264,1998
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Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A: Correlation of glucose regulation and
haemoglobin AIc in diabetes mellitus. N Engl J Med 295:417420, 1976
7.
The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes
on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
NEngl J Med 329:977986,1993
8.
UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
Lancet 352:837853,1998
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Davidson MB, Schriger DL, Peters AL,Lober B: Relationship between fasting plasma glucose and glycasylated haemoglobin. Potential for false positive diagnosis of type 2 diabetes using new diagnostic criteria.
JAMA281:1203-1210,1999
10. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive
insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with
non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract
28:103117, 1995
11. The American Association of Clinical Endocrinologists Medical Guidelines for the Management of Diabetes
Mellitus. The AACE System of intensive diabetes self-management2000 update. Endocr Prac 2000;6:4384
12. Little RR, Wiedmeyer HM, England JD, et al. Interlaboratory comparison of glycated hemoglobin results:
College of American Pathologists (CAP) survey data. Clin Chem 1991; 37:1725-29.
13. Bodor G, Little R, and Garrett N, et al. Standardization of glycated hemoglobin determinations in the clinical
laboratory: three years experience. Clin Chem 1992; 38:2414-18.
14. Little RR, Wiedmeyer HM, England JD, et al. Inter laboratory standardization of measurements of glycated
hemoglobin. Clin Chem 1992; 38:2472-78.
15. Feichtner M, Ramp J, England B, et al. Affinity binding assay of glycated hemoglobin by two-dimensional
centrifugation referenced to hemoglobin A1c. Clin Chem 1992; 38:2372-79.
16. Weykamp CW, Penders TJ, Frits AJ, et al. Effect of calibration on dispersion of glycated hemoglobin values
as determined by 111 laboratories using 21 methods. Clin Chem 1994; 40:138-44.
17. Goldstein DE, Little RR, England JD, et al. Methods for quantitating glycosylated hemoglobins: high performance liquid chromatography and thiobarbituric acid colorimetry. In: Clarke WL, Larner J, Pohl SL, eds.
Methods in Diabetes Research, Vol.2. Clinical Methods. New York: John Wiley, 1986:475-504.
18. Colman PG, Goodall GI, Garcia-Webb P, Williams PF, Dunlop ME: Glycohaemoglobin: a crucial measurement
in modern diabetes measurement. Med J Aust 167: 9698, 1997
19. Gillery P, Dumont G, Vassault A: Evaluation of GHb assays in France by National Quality Control Surveys.
Diabetes Care 21:265270, 1998
20. Guerci B, Durain D, Leblanc H, Rouland JC, Passa P, Godeau T, Charbonnel B, Mathieu-Daude JC, Boniface
H, Monnier L, Dauchy F, Slama G, Drouin P: Multicenter evaluation of the DCA 2000 system for measuring
glycated haemoglobin: DCA 2000 study
21. Robert M. Cohen, Yancey R Holmes, Thomas C Chenier, Clinton H Joiner: Discordance between HbA1c and
fructosamine- evidence for a glycosylation gap and its relationship to diabetic nephropathy.
22. Schnedl WJ, Krause R, Halwachs-Baumann G, Trinker M, Lipp RW, Krejs GJ: Evaluation of hemoglobin A1c
determination methods in patients with hemoglobinopathies. Diabetes Care 23:339344, 2000
23. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33
(Suppl. 1):S62S69
24. Yamanouchi T, Akanuma Y: Serum 1,5-anhydroglucitol (1,5AG): new clinical marker for glycemic control
(Review).Diabetes Res Clin Pract24 (Suppl.):S261S268,1994Yamanouchi T, Ogata N, Tagaya T, Kawasaki
25. T, Sekino N, Funato H, Akaoka I, Miyashita H: Clinical usefulness of serum 1,5-anhydroglucitol in monitoring
glycaemic control Lancet 347:15141518,1996
26. Severini G, Aliberti LM, Girolamo MD: N-acetyl-glucosaminidase isoenzymes in serum and urine of patients
with diabetes mellitus. Clin Chem 34:24302432,1988 U.K. Prospective Diabetes Study Group
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27. U.K. Prospective Diabetes Study (UKPDS): X: Relationships of urinary albumin and N-acetyl-glucosaminidase
to glycaemia and hypertension at diagnosis of type 2(non-insulin-dependent) diabetes mellitus and after 3
months diet therapy. Diabetologia 36:835842,1993
28. Roberts WL, MacCraw M, Cook CB: Effects of sickle cell trait and hemoglobin C trait on determinations of
HbA1c by an immunoassay method. Diabetes Care 21:983986,1998
29. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications
Research Group. N Engl J Med 2000;342:381389
30. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M,
Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter
N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and
vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:25602572
31. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward
R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD, VADT Investigators. Glucose
control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129139
32. Cushman WC, Grimm RH Jr, Cutler JA, Evans GW, Capes S, Corson MA, Sadler LS, Alderman MH, Peterson
K, Bertoni A, Basile JN, ACCORD Study Group: Rationale and design for the blood pressure intervention of
the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99:44i55i
33. Klonoff DC: Non-invasive blood glucose monitoring. Diabetes Care 20:433437,1997
54
Self Monitoring of Blood Glucose: A Window to

Better Management & Patient Education
Dr Jay M Deshmukh
Consultant Physician
Director, Dr Jay Deshmukh Hospital

#3, Maya East, High Court Road,
Ramdas Pet, Nagpur.
&
Dr Abhijit Deshpande
Consultant Physician,

55
Introduction
Imagine trying to bake a cake without knowing the temperature of the oven or trying
to judge how much gas is left in the cars tank during a long trip without a gas gauge.
Although it would not be impossible to do these tasks without the proper measurement
tools, it would take much more time and you wouldnt have the information you need to
solve any problems that occur.
Similarly, during previous generations, people with diabetes, working only with urine testing or retrospective laboratory glucose results, had limited information or which to base
day-to-day self care decisions.
The advent of Self Monitoring of Blood Glucose (SMBG) in the late 1970s gave people
with diabetes a valuable tool for self-management. No longer dependent on inconvenient
laboratory diagnostics or inaccurate urine testing, patients now had accurate glucose values
within minutes, using a hand-held meter and a small drop of blood. Having access to blood
glucose values whenever they choose to perform the test enables patients to improve their
glycemic control, preventing acute and chronic complications.
Self-Monitoring of Blood Glucose (SMBG) provides significant benefits to patients with
diabetes and their healthcare providers. SMBG is increasingly recognized as an integral
part of intensive therapy for all forms of diabetes. This article discusses the clinical utility of SMBG in type 1 (T1DM) and type 2 diabetes (T2DM) and looks at the relationship
between SMBG and improved overall glycemic control as measured by A1c1.
Guidelines for SMBG

56
A major obstacle to increased SMBG utilization is the lack of clear guidelines for testing
frequency. A global consensus conference was convened in 2004 to address this issue.
The results of that conference were published as a supplement in the American Journal
of Medicine.3
Table 1: Specific Recommendation of SMBG Frequency.
Treatment Regimen
Insulin Therapy (multiple Daily Injections or
Insulin Pump)
Patients above target on other regimens
(orals and / or QD insulin)
Patient at target on oral agents or QD insulin
Patients at target on orals agents plus QD
insulin
Patients on non-pharmacologic therapy
SMBG Frequency
> 3 4 x / day
> 2 x / day
> 1 x / day + 1 profile* / week
> 1 x / day + frequent profiles
? 1 profile / week
* A collection of pre-and post-meal glucose test results over a 7-day period.
Accuracy of SMBG
Another important issue is patient accuracy. Alto and colleagues conducted a study of 111
patients in two family practice settings to determine the technical skill and accuracy of
SMBG in an outpatient population.4 The patients were observed using a 13-point checklist of critical steps in the calibrat6ion and operation of their glucose monitor. Overall,
53% of patients glucose values were within 10% of the control value, 84% were within
20% of the control value and 16% varied 20% or more from the control value. In short,
the study showed that despite multiple technical errors when using SMBG, most patients
obtained clinically useful values.
A study reported by Bergenstal and colleagues found that 19% of patients had inaccuracy
rates of more than 15% in blood glucose monitoring.5 Some of the most common causes
of inaccurate readings included: lack of periodic meter technique evaluation, difficulty
using wipe meters, incorrect use of control solutions, lack of hand washing9 even when
under clinical observation, and using unclean meters.
These studies demonstrate the need for healthcare providers to monitor patient use of
SMBG to help improve the accuracy of test results.
Utility of SMBG
Many published studies have demonstrated that regular and frequent SMBG improves glycemic control in T1DM and T2DM patients on insulin treatment. There is also very strong
evidence that SMBG improves control in T2DM patients who are not on insulin therapy.
T1DM and Insulin-Treated T2DM Patients

Davidson and colleagues showed that there is an inverse correlation between frequency of
SMBG and A1c values in T1DM patient.6 Patient using SMBG have lower A1c than those
who do not. The authors found that the more times per day that people check their blood
glucose levels, the lower their A1c. However, after reaching a frequency of 6-7 tests per
day, the improvement levels off.
Strowig and colleagues showed similar results, reporting a 0.25% decrease in A1c for each
blood glucose test per day.7 Again, there was a point of diminishing returns; improvements
in A1c leveled off at approximately 8 tests per day. Studies of pediatric T1DM patients
have demonstrate similar findings. 8,9
In a retrospective study of more than 24,000 patients, Karter and colleagues found that
increased frequency of SMBG correlated strongly with improved A1c regardless of the type
of diabetes or therapy used.10
Non-Insulin-Treated T2DM Patients

There has been much debate on the impact of SMBG on A1c in T2DM patients who are not
treated with insulin Skeptics of the benefits of SMBG use in this patient group often cite
small or poorly designed studies that demonstrate no A1c benefit. This perspective often
overlooks the fact that many T2DM patients are not adequately trained to interpret and
respond to their test results. Utilization of SMBG involves more than simply documenting test results in a logbook; patients must understand and be able to make appropriate
changes in therapy or activity based upon those results. SMBG testing in T2DM patients
has also been hampered by a lack of consensus on the timing and frequency with which
testing should be performed. Most patients who do perform blood glucose monitoring
seldom test postprandial glucose. Other factors that inhibit testing frequency include cost,
pain, and inconvenience. All of these factors work against seeing a benefit in T2DM patients.
57
Despite these factors, there is strong evidence that SMBG is in fact, an effective method
for lowering A1c in this patient group. A meta-analysis by Sarol and colleagues found
an overall A1c improvement of 0.4% in non-insulin treated T2DM patient who use SMBG
compared with those who do no monitor.11 To counter potential criticism of their report,
the authors critiqued the studies included in their meta-analysis and found no publication
bias in their selection.
A second meta-analysis conducted by Welschen et al. found similar results: an overall
0.39% improvement in A1c in type 2 patients not on insulin.12 The authors concluded
that SMBG lowers A1C levels. Another review of the literature by Saudek in 2006 yielded
similar findings.13
In a recent epidemiologic, non-randomized retrospective study, Martin and colleagues
looked at disease-related fatal and non-fatal events in approximately 3,200 T2DM patients.14 Unlike the meta-analyses cited above, this study directly assessed clinical outcomes
relatives to SMBG utilization. Fewer patients who used SMBG experienced fatal or nonfatal events than patient who did not monitor their glucose (7.2 versus 10.4%, p = 0.002).
The authors concluded that SMBG may be associated with a healthier lifestyle and/or better
disease management. Significantly, this study did no simply show that SMBG correlates with
improved A1c; it demonstrated that SMBG is actually linked to better clinical outcomes1.
Controversies in SMBG
58
The frequency for performing SMBG varies depending on the needs of each patient. Insulin-using patients (with type 1 or type 2 diabetes) are advised to perform SMBG three
or more times daily.15 Most practitioners agree on the relevance of glucose monitoring in
this group. There has been much controversy about the efficacy of SMBG among patients
who do not use insulin. However, guidelines for these patients with type 2 diabetes are
vague, and no specific frequency is recommended2.
N. Kleefstra et al16 investigated the effects of SMBG in patient with T2DM who were in
persistent moderate glycemic control whilst not using insulin in ZODIAC TRIAL.
Patients were eligible when between 18 and 70 years age, with A1c between 7 and
8.5% using one or two oral blood glucose lowering agents. A fasting glucose value and
three post-prandial glucose values were measured twice weekly (including a Saturday or
a Sunday). The primary efficacy parameter was A1c. Change in A1c between groups was
-0.05% (p = 0.507). Also there was no significant change between groups in Perception
of Health questionnaires. They concluded that on top of absence of a clinical benefit,
tablet-treated T2DM patients experience some worsening of their health perception.
Clinical Utility of SMBG: A Patient Education Tool

When first developed, this innovation in diabetes care held such promise: it would encourage a new level of patient-provider collaboration, empower patient to become more
active participants in their own care, and act as a personal guide for trouble-shooting
glucose control issues related to diet, physical activity, travel, and other lifestyle changes.
Unfortunately, SMBG has fallen far short of achieving its promise. Why? Saudek et al.13
reviewed many SMBG trials and concluded that the trials support the conclusion that
SMBG, if effectively translated into action, improves glycemia. Prescribing SMBG without
an educational link so that patients can effectively use the information they gain had no
affect on A1c values.
Surely, for some patients, seeing their glucose results and associating changes in food
and activity with their glucose levels give them insight into their metabolism. But for
too many others, SMBG is a tattletale that tells when patients cheat on their diet, or
a report card that signifies when they have failed to closely follow their diabetes care
plan. Unfortunately, a tool that was designed to improve and individualize care has, in
many instances, become a barrier, another problem to overcome.
Operating a meter has become easier. Todays meters feature smaller devices with larger
screens and pictorial screen prompts for each step. Performing SMBG involves fewer steps,
offers faster results, requires no calibrations or codes, and needs only tiny blood samples.
There are now easy-to-use lancing devices, sharper and finer lancets, and capillary action
strips. Meters no have large memories, averaging capabilities, markers for various events,
prompts for hyper- and hypoglycemia values, and capabilities for computer downloading
and interacting with insulin pumps.
However, technology is only as useful as the knowledge and motivation of those who
possess it. These innovative features mean little if patient do not use their meter or
understand how their results can be used to make a significant difference in their own
self-management.
Helping Patients to use SMBG:

The American Association of Diabetes Educators (AADE) position statement Self-Monitoring of Blood Glucose: Benefits and Utilization17 offers both the educational components for meter use (the steps for meter care and usage) and a list of the roles and
responsibilities of health care providers in teaching SMBG. One of those responsibilities is
to provide education in making appropriate therapy adjustments utilizing the results.17
The statement also calls on the diabetes health care community to promote and adopt
standardized SMBG education.
The dilemma is that there is no research demonstrating or supporting the best method for
educating patients about SMBG to improve glycemic control and reach targets.
In many instances, once patients learn the technical aspects of meter use and the times
to perform SMBG, the educational process comes to a halt. Although the educational
components of SMBG and meter use as defined by the AADE position statement are integral to the use of this tool, without continuing instruction on the translation of SMBG
results into action the opportunity to improve self-management is limited. If SMBG is to
be a problem-solving tool, it must move beyond the mere reporting of glucose levels to
the application of these data in retrospective and prospective analysis of lifestyle behaviors
and medication usage.
Based on teaching and learning principles that have been applied to other areas of skill
acquisition in diabetes management, it is logical to approach the use of SMBG in a stepwise manner, building on each successive task to achieve greater independence, as discussed
in more detail below.

59
Presenting SMBG as a Tool

Tools allow those who use them to complete a task or achieve an outcome more easily.
It is important to present SMBG as an important tool for achieving glycemic control.
Clinicians need to teach patients that SMBG gives valuable information that allows patient the freedom to make changes that best suit their lifestyle. SMBG not only helps to
individualize care, but also allows patients to assess what works or does not work in their
own self-management. It can also be a safety tool, helping to assess signs and symptoms
of hyper- and hypoglycemia.
Determining Monitoring Times

Patients need to understand the action of their prescribed medications and how specific
times for glucose monitoring can assist in evaluating their medications effects. Knowing
the times frame for increases in post meal glucose levels helps patients see that postprandial
SMBG can provide valuable data about the effects of the size and content of their meals.
Giving guidance to patients about using SMBG to assess the effects of physical activity or
exercise on glucose control demonstrates the importance of exercise in controlling type
2 diabetes and becomes crucial to safe exercise programs for patients who use insulin.
Individualizing Monitoring Times
60
For newly diagnosed people with diabetes, a recommendation to perform SMBG before
each meal and at bedtime can seem daunting. Although such a regimen may be helpful
for providers in adjusting therapy, it is overwhelming for patients and can create anxiety
and confusion when its purpose and results are not fully explained. It is far better to limit
testing times and discuss how those times relate to therapy and affect decision-making.
If more intensive testing is needed, try to limit the time period to the time necessary
to adequately evaluate and treat the problem. The more stable patients physical activity,
medication dosages, and meal schedule are, the fewer testing times are needed. However,
during periods when schedules change or lifestyle transitions occur, it may be necessary
to increase monitoring to guide appropriate therapeutic decisions.
Relating Action to Results

If patients realize early on that the glucose results they obtain from SMBG play a vital part
in making therapeutic changes, the process has validity for them. Outlining appropriate
action based on SMBG results and empowering patients to act accordingly supports the
concepts of patient-provider collaboration and self-care management. Guidelines for data
analysis and related actions should be specific, and directions should be clearly written for
home use, enabling patients to feel confident in proceeding independently. When patients
achieve a successful outcome, it reinforces self-efficacy.
Patients should be taught how to look for patterns in their SMBG data times when the
high or low results tend to cluster, indicating a recurring problem. The urge to impulsively
respond to a high or low result without putting it into the context of the days events
may cause dramatic glycemic shifts and not successfully address the underlying problem. If
patients see results that consistently fall outside their target range during a 3-day period
when no changes in their meal plan, medications, or activity have occurred, then they
should make adjustments according to the agreed upon action plan.
Data management of glucose results can take many forms, including written logbooks
or diaries and periodic meter memory downloads. The best method is the one that an
individual patient feels will be most effective for him or her. Often, the way in which
data are organized is crucial to decision making. Patients may need to experiment with
different methods before deciding on the one that works best for them.
A color-coded system is one method that helps some patients recognize glucose patterns. The first step is to agree on a target glucose range. SMBG results that are
above the range are colored with a pink highlighter pen; those below the range are
highlighted yellow; and those within the range are colored green. The colors relate to
those of a traffic light: Pink means stop Hyperglycemia, Yellow mean use Caution
because results are too low, and green means Go. Youre in the Target Range. The clustering of any one color at a particular time of day is not a judgment of patient efforts,
but rather indicates that they need to review that time frame for possible issues and
action steps to achieve their self-management targets.
Follow up
Whether by telephone, e-mail, or an office visit, providers need to contact patients
shortly after their initial education session on SMBG to offer continuing support. Helping patients make changes based on SMBG supports the formation of new behaviors
essential to self-management. Keep in mind that working to achieve targets can be
frustrating, particularly when patient have endeavored to make positive changes, and
their results do no reflect this.
Reviewing Logs
During subsequent office appointments, providers have many opportunities to educate
patients about how to use their SMBG results to improve glycemic control. Sitting side
by side so that the log is visible to parties, patients and providers can analyze glucose
readings focusing on positive factors (such as target attainment at the fasting time) and
problematic results (such as higher post-supper readings). Start by asking patients what
they see and have learned from SMBG. You might be surprised what you learn from
their insights that will then lead to individualized solutions to problems.
This is also an ideal time to educate patients about the questions they should ask
themselves when reviewing their SMBG results:

Did I eat or drink anything that may have affected the glucose result?
Did I skip or delay a meal, causing a change in my blood glucose?
Did I take my medication or insulin as prescribed?
Did I change my exercise level?
Did I feel ill or stressed or start a new medication?
Was there a change in my schedule that could have altered my glucose?
All of these recommendations seem very simple and direct, but they take time to implement. As with any skill acquisition, learning to use a glucose meter and SMBG results
for self-management requires guidance and support. Providers need to move from seeing
61
SMBG as a report of glucose level that helps in prescribing medication to viewing it as an

integral tool that allows for adaptability and flexibility in self-management.
If SMBG has not fulfilled its early promise as a tool that supports self-management and
patient-provider collaboration, it is the lack of education on its use, rather than the tool
itself, that bears the blame.
Table 2 : A Step-Wise Approach to SMBG Education
1.
2.
3.
4.
5.
62
Discuss the importance of SMBG as a tool that guides care decisions and helps
analyze problems in maintaining glucose control, no as a judgment.
Establish mutually agreed upon glucose goals tailored to individual patients needs
and discuss which testing times will give patients the best information to make
self-care decisions. Collaborate with patients to select one or two times during
the day to regularly monitor glucose, comparing their values to their target glucose
levels and noting possible indicating for self-adjustment. Work with patients to
create an action plan for improving glycemic control based on their glucose meter data. Establish plans for recording data in a format that will be most useful
to patient. Encourage and support patients efforts to problem solve and make
necessary changes.
Follow up with patients within a short time frame to reinforce their self-care
behaviours.
Review glucose logs with patients and focus on both positive changes they have
made and areas of concern indicated by their SMBG results.
Discuss with patient how they will handle glucose results that do no appear to
reflect their efforts at self-management.
Summary
To summarize, though study results vary, the evidence doesnt support a positive effect of
regular SMBG on HbA1c results among type2 diabetic populations.
Exceptions to this rule may be newly diagnosed diabetics, poorly controlled patients, &
patients who can adjust therapy based on SMBG results.
As far as patients with T2DM on Oral glucose lowering agents are concerned, the data is
by far conflicting, & as of now no firm recommendations can be made regarding the use
of SMBG in this subset of patients.
When patients ask their providers, What are you looking at when you see my numbers?,
the windows of opportunity flies open, and the providers then have the chance to make
what patients may see as an onerous task into a meaningful, life changing practice.
SMBG also should be looked upon as an opportunity to reach out to diabetes patients &
teach them about their disease & to involve them more actively in the care of diabetes.
References
1.
David C. Klonoff, J Diabetes Sci Technol 2007;1(1):130-132.
2.
Geralyn R Spollett, Clinical Diabetes; Vol 28, Number 3, 2010.
3.
Bergenstal RM et al, Global Consensus Conference on Glucose Monitoring Panel : The role of SMBG in care
of people with diabetes. Am J Med. 2005; 118(9A): 1S 6S.
4.
Alto WA et al, Assuring the accuracy of home glucose monitoring. J Am Board Fam Pract. 2002;15:1-6.
5.
Bergenstal RM et al, Identifying variables associated with inaccurate SMBG: proposed guidelines to improve
accuracy. Diabetes Educ. 2000;26:981-9.
6.
Davidson P et al, increase frequency of SMBG improves A1c I non-insulin-using patients with diabetes.
Diabetes 2004;53(Suppl.2):A101.
7.
Strowig SM et al, improved glycemic control in intensively treated type 1 diabetic patients, using blood
glucose meters with storage capability and computer-assisted analyses. Diabetes Care 1998;21:1694-8.
8.
Levine BS et al, Predictors of glycemic control and short-term advser outcomes in youth with type 1
diabetes. J Pedtr.2001;139:1972-203.
9.
Haller MJ et al, Predictors of control of diabetes : monitoring may the key, J Pedtr. 2004;144;660-1.
10. Karter AJ et al, SMBG levels and glycemic control : The Northern California Kaiser Permanente Diabetes
registry. Am J. Med. 2001;111:1-9.
11. Sarol JN et al, SMBG as part of multi-component therapy among non-insulin requiring type 2 diabetes
patients : metanalysis (1966-2004): Curr Med Res Opin. 2005;21:173-83.
12. Welschen LM et al, SMBG in patient with type 2 diabetes who are no using insulin: A systemic review.
Diabetes Care 2005;28:1510 7.
13. Saudek CD et al, Assessing glycemia in diabetes using SMBG and haemoglobin A1c. JAMA 2006;295;1688-97.
14. Martin S et al, SMBG in type 2 diabetes and long term outcome : an epidemiological cohort study. Diabetologia. 2006;49:271-8.
15. American Diabetes Association : Standards of Medical Care in Diabetes. Diabetes Care 32(Suppl.1): S13S61, 2009.
16. N Kleefstra et al, The Netherlands Journal of Medicine 2010;68:7, 311-316.
17. Austin MM et al, SMBG benefit and utilization, Diabetes Educ. 32:835-847, 2006.

63
Screening & Management of

DiabeticDyslipidemia
64
Dr Banshi Saboo
Dia Care
No 1 & 2, Gandhi Park, Near Nehrunagar Circle,
Ambawadi, Ahmedabad 380 015.
Ph: +91 79 2630 4104
Introduction
Risk of coronary artery disease in patients with type 2 diabetes is 2-4 times higher than
those without diabetes1. As much as 75 % deaths in diabetes patients is attributed to
cardiovascular disease and deaths due to coronary artery disease are at least three times
higher than general population2. The risk of microvascular complications and poor glycemic control is an established fact. There is no strong relationship between the duration of
diabetes or severity of hyperglycemia and risk of coronary heart disease. Glycemic control
plays a modest role while other associated risk factors like hypertension, dyslipidemia have
significant importance for such high cardiovascular risk.
Mere achievement of tight glycemic control will not be able to completely eliminate this
risk of CHD, but clearly a multifactorial approach with aggressive treatment of dyslipidemia
will be an important approach in this regard. A recent survey by Center for Disease control
and prevention has shown that 70-97% of diabetes patients have associated dyslipidemia3.
In spite of all this, awareness and proper treatment of dyslipidemia is still lacking. One
such large study showed that only 35.5 % of patients attending their diabetes clinic
achieved LDL goal of less than 100mg/dl4.
Epidemiology of Diabetic Dyslipidemia

Most common type of dyslipidemia in patients with diabetes is increased triglycerides and
decreased HDL cholesterol levels. The levels of LDL cholesterol are usually not significantly
different form non diabetic individuals. Type 2 diabetes patients have smaller and denser
LDL particles which increase the risk of atherosclerosis. National Cholesterol Education
Program (NCEP) Adult Treatment Panel (ATP) III identifies small dense LDL particles are
identified as an emerging CHD risk factor5. This also suggests that even if patients with
diabetes have a low LDL level, they may still have an increased risk for atherosclerosis.
These Small dense LDL particles will be much more easily oxidized. Hence patients with
diabetes also have an increased amount of oxidized LDL. Many evidences have shown that
oxidized LDL is more atherogenic than unoxidized LDL. Further because of their small mass,
greater number of LDL particles is contained within the plasma of patients with small dense
LDL, increasing atherogenic risk much further. This triad of low HDL, high triglyceride with
increase in small density LDL is known as diabetic dyslipidemia.
Studies have shown that abnormalities in serum lipids were much higher in diabetic women
compared to men. These findings were also noted in large studies like UKPDS, where
elevated triglyceride and low HDL cholesterol were much higher in female patients with
diabetes than male patients 6, 7. This can also indicate the reason for high relative risk of
developing CHD in women than in men.
Table 1: Lipid Abnormalities in Type 2 Diabetes24
Lipid abnormality
Kinetic abnormality
VLDL (Hypertriglyceridemia)
Production, catabolism
Quality abnormality
Large VLDL, Glycation
HDL
Catabolism
TG rich HDL
Glycation
LDL
Turnover
Small dense LDL

Oxidation
Glycation
Catabolism
Screening & Management of DiabeticDyslipidemia
65
Pathophysiology of Diabetic Dyslipidemia

Insulin resistance plays a pivotal role in the pathogenesis of diabetic dyslipidemia. Insulinresistant fat cells undergo greater breakdown of their stored triglycerides and greater
release of free fatty acids into the circulation. The Increased fatty acids in the plasma
lead to increased fatty acid uptake by the liver. The liver utilizes these fatty acids and
synthesizes them into triglycerides.
The presence of increased triglycerides in liver stimulates the assembly and secretion of
the VLDL. This results in an increased number of VLDL particles and increased level of
triglycerides in the plasma. Each molecule of VLDL particle will give up a molecule of
triglyceride, donating it to the HDL, in return for one of the cholesteryl ester molecules
from HDL with the help of enzyme cholesteryl Ester Transfer Protein (CETP).
This leads to two outcomes

Cholesterol-rich VLDL remnant particle that is atherogenic,
Triglyceride-rich cholesterol-depleted HDL particle.
The triglyceride rich HDL is unstable and easily broken down and excreted causing low
levels of HDL.
66
Image 1: Pathophysiology of Diabetic Dyslipidemia
24
Evidences for Benefits of Treatment

Over the past decade multiple clinical trials (Table 2) have shown significant effects of
drug therapy on CVD outcomes in subjects with CHD and for primary CVD prevention.
Several sub group analysis of large trials and clinical trials specifically done in subjects
with diabetes also showed significant primary and secondary prevention of CVD events
with and without CHD deaths in diabetic populations 9, 10. The overall benefits of Statin
therapy in diabetes patients with risk for CVD are convincing.
Table 2: Clinical Trials of Lipid Lowering Agents in Type 2 Diabetes
Study
(ref)
CVD
Prevention
Statin dose and

comparator
Risk
reduction
Relative risk
Reduction
Absolute
risk
Reduction
LDL Cholesterol Reduction %
4S-DM
20
Simvastatin 20 40 mg Vs placebo
85.7 to
43.2%
50%
42.50%
186 to 119
mg /dl (36%)
ASPEN 20
20
Atorvastatin 10
mg Vs placebo
39.5 to
24.5%
34%
12.70%
112 to 79
mg /dl (29%)
HPS-DM
20
Simvastatin 40 mg
Vs placebo
43.8 to
36.3%
17%
7.50%
123 to 84
mg /dl (31%)
CARE-DM
20
Pravastatin 40 mg
Vs placebo
40.8 to
35.4%
13%
5.40%
136 to 99
mg /dl (27%)
TNT-DM
20
Atorvastatin 80
mg Vs 10 mg
26.3 to
21.6%
18%
4.70%
99 to 77
mg / dl (22%)
HPS-DM
10
Simvastatin 40 mg
Vs placebo
17.5 to
11.5%
34%
6.00%
124 to 86
mg /dl (31%)
CARDS
10
Atorvastatin 10
mg Vs placebo
11.5 to
7.5%
35%
4.00%
118 to 71
mg / dl 40%)
ASPEN10
10
Atorvastatin 10
mg Vs placebo
9.8 to
7.9%
19%
1.90%
114 to 80
mg / dl 30%)
ASCOTDM
10
Atorvastatin 10
mg Vs placebo
11.1 to
10.2%
8%
0.90%
125 to 82
mg / dl 34%)
Treatment Priorities for Management of Dyslipidemia

The initial priority in the management of diabetic dyslipidemia is to achieve a target of <
100mg/dl of LDL. Life style interventions physical exercise and stoppage of smoking may
help in small majority of patients. Dietary modifications should focus on reduction of
saturated fat, cholesterol and Trans unsaturated fat intake. Increased intake of fiber like
whole grains, oats, legumes vegetables are beneficial. Achieving glycemic control will have
beneficial effect on plasma lipid levels especially so for very high triglycerides8.
Current recommendations also suggest that presence of clinical CVD or age over 40 years
with CVD risk factors must receive additional pharmacological treatment along with lifestyle changes irrespective of their baseline lipid levels. Recommendations also suggest
consideration of lipid lowering agents for type1diabetes similar to type 2 diabetes patients,
if other cardiovascular risk factors are present.
Data from recent clinical trials in high risk patients, like those with acute coronary syndrome or previous cardiovascular events have shown that an aggressive therapy with high
dose Statins, targeting LDL of <70mg/dl 11, 12. There is a strong correlation between LDL
cholesterol lowering effect of Statins and reduction of CVD events.
A recent controversy with the use of Statins and risk of insulin resistance has been debated
in medical journals. A recent meta-analysis published in Lancet involving 13 Statin trials with more than 91,000 patients, Statin therapy is associated with a slightly increased
risk of development of diabetes, but the risk is low both in absolute terms and when
compared with the reduction in coronary events. The article concludes no change in the
67
current clinical practice 19. (Table 3) shows order of priority in the treatment of diabetic
dyslipidemia.
Table 3 Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults 16.
68
i. LDL cholesterol lowering

Life style interventions
Preferred
HMG CoA reductase (Statin)
Others
Bile acid binding resin (Resin)
Cholesterol absorption inhibitor
Fenofibrate or Niacin
ii. HDL cholesterol rising
1. Life style interventions
2. Nicotinic acid or Fibrates
iii. Triglyceride lowering
Lifestyle interventions
Glycemic control
Fibric acid derivative (Gemfibrozil, Fenofibrate)
Niacin
High dose Statins (in those who also have high LDL cholesterol)
iv Combined hyperlipidemia
First choice
Improved glycaemic control plus high dose Statin
Second choice
Improved glycaemic control plus Statin plus Fibric acid derivative
Third choice
Improved glycaemic control plus Statin plus Nicotinic acid
Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data
indicating safety as well as efficacy of the available agents. The combination of Statins
with Nicotinic acid, Fenofibrate and especially Gemfibrozil may carry an increased risk of
myositis. See text for recommendations for patients with triglyceride levels > 400 mg /dl.
Role of Combination Therapy with Statin

ADA recommends that when maximum tolerated dose of Statin fails to significantly reduce
LDL cholesterol < 30% from baseline additional drugs like Niacin, Fenofibrate, Ezetimibe
and bile sequestrants can be added which offer additional LDL lowering effect. Current
there is not enough evidence for incremental reduction in CVD with combination therapy
compared to Statin alone 8.
Treatment of other Lipoprotein Fractions

Severe hypertriglyceridemia can be treated with fibric acid derivatives or niacin. These
drugs reduce the risk of acute pancreatitis. Niacin is most effective for increasing HDL.
High doses of niacin were known to raise blood glucose. Some of the recent studies have
shown that at modest doses (7502,000 mg/day) show significant improvements in LDL
cholesterol, HDL cholesterol, and triglyceride and only modest insignificant changes in blood
glucose which can be taken care with some adjustments in treatment 13, 14.
Combination of Statin with fibrate or Niacin can increase the risk of abnormal liver enzymes and also risk of rhabdomyolysis. The risk of rhabdomyolysis increases with higher
dose of Statins also. Many ongoing trials on combination therapy may provide evidence
for cardiovascular outcomes in combination therapy.
A consensus panel of ADA & American college of Cardiology made a recommendation in
2008 that there is a need for focus on non-HDL cholesterol and apolipoprotein B. This is
of particularly for patients having small LDL particles like those with diabetes 15. The panel
also suggested that those patients already receiving Statin in whom the LDL cholesterol
goal would be >70 mg/dl apo B should be measured and treated to <80 mg/dl. For those
patients on Statins with an LDL cholesterol goal of <100 mg/dl, apo B should be measured
and treated to <90 mg/dl 15.
Current ADA Guidelines and Recommendations8

ADA recommends that screening should be carried out in most adult patients, to
measure fasting lipid profile at least annually. In adults with low-risk lipid values (LDL
cholesterol < 100 mg/dl, HDL cholesterol >50 mg/dl, and triglycerides <150 mg/dl),
lipid assessments may be repeated every 2 years.
Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels,
for diabetic patients with overt CVD or without CVD who are over the age of 40 and
have one or more other CVD risk factors.
For lower-risk patients than (e.g., without overt CVD and under the age of 40), Statin
therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains
>100 mg/dl or in those with multiple CVD risk factors.
In individuals without overt CVD, the primary goal is an LDL cholesterol <100 mg/dl
and in individuals with overt CVD, a lower LDL cholesterol goal of <70 mg/dl, using
a high dose of a Statin, is an option.
If drug-treated patients do not reach the above targets on maximal tolerated Statin
therapy, a reduction in LDL cholesterol of 40% from baseline is an alternative therapeutic goal.
Triglycerides levels <150 mg/dl and HDL cholesterol >40 mg/dl in men and >50 mg/
dl in women are desirable. However, LDL cholesterol targeted Statin therapy remains
the preferred strategy.
Combination therapy using Statins and other lipid-lowering agents may be considered
to achieve lipid targets but has not been evaluated in outcome studies for either CVD
outcomes or safety. Effect of various pharmacological agents on lipid parameters is
shown in (Table 5).
69
Table 5: Effect of Various Pharmacological Agents on Lipid Profile

First- line agents
Effect on lipoprotein
17
Clinical trails in
LDL
HDL
Triglyceride
Diabetic subjects
LDL lowering
4S (Simvastatin)
HMG - CoA reductase inhibitor
CARE (Pravastatin)
Triglyceride lowering
Helsinki (Gemfirozil)
Fibric acid deravative
Second- line agetns
LDL lowering
Bile acid binding resins
None
LDL and triglyceride lowering
None
Nicotinic acid
In diabetic patients, nicotinic acid should be restricted to 2g/day: short -acting nicotinic
acid is preferred.
Future Developments
CETP Inhibitors: CETP inhibitors are a newer step towards developing drugs for increasing
HDL cholesterol. The initial trials with Torcetrapib were not encouraging as the trial was
stopped prematurely due to higher incidence of hypertension. Anacetrapib (also known
as MK-0859) is a novel, potent CETP inhibitor also being studied 18.
70
ACAT Inhibitors: ACAT inhibitors are another group of drugs which inhibit cholesterol
esterification in many tissues. Inhibition of ACAT 1 would slow the progression of foam
macrophage. This allows free cholesterol to be available for reverse cholesterol transport.
ACAT-2 is identified in the liver and intestine, so inhibition of this enzyme would reduce LDL
formation. One such a nonselective ACAT inhibitor currently under study is Avasimibe 18.
Glitazars: Another new class of agents called Glitazars have been identified which have
both PPAR and PPAR activity. These drugs will have the lipid benefits of PPAR
activation with the insulin sensitizing action due to PPAR activation. Clinical trails with
Ragaglitazar, Muraglitazar & Tesaglitazar are discontinued because of its adverse events18.
Aleglitazar is the new drug which is under development in this class.
Niacin & Laropiprant: Niacin has complementary lipid-modifying efficacy to Statins and
cardiovascular benefit, but is under utilized because of flushing, mediated primarily by
prostaglandin D2 (PGD2). Laropiprant (LRPT), a PGD2 receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into
a fixed-dose tablet to improve patient compliance20.
Squalene Synthesis Inhibitors: Lapaquistat was the only squalene synthesis inhibitor in
clinical development, & was undergoing Phase III trials. Lapaquistat inhibits a key step in
cholesterol synthesis & reduces production of cholesterol. Unlike Statins, squalene synthesis
inhibitors do not produce depletion of mevalonate, the precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism. However, elevation of liver transaminases
with 100 mg lapaquistat impeded its clinical development & was finally discontinued 21.
Mipomersen: Mipomersen is an apolipoprotein (apo) B synthesis inhibitor which has demonstrated significant reductions in apo B and low-density lipoprotein (LDL) cholesterol in
healthy volunteers. Mipomersen might hold promise for treatment of patients not reaching
target LDL cholesterol levels on stable Statin therapy. Mipomersen also represents a novel,
effective therapy to reduce LDL cholesterol concentrations in patients with homozygous
familial hypercholesterolemia who are already receiving lipid-lowering drugs, including
high-dose Statins 22.
Microsomal Triglyceride Transfer Protein Inhibitors: A potentially effective therapy for
homozygous familial hypercholesterolemia would be to reduce LDL production. The microsomal triglyceride transfer protein is responsible for transferring triglycerides onto apolipoprotein B within the liver in the assembly of very-low-density lipoprotein (VLDL), the
precursor to LDL. Thus, the pharmacologic inhibition of microsomal triglyceride transfer
protein might be a strategy for reducing LDL production and plasma LDL cholesterol levels.
Inhibition of microsomal triglyceride transfer protein is effective in lowering plasma levels
of atherogenic apolipoprotein Bcontaining lipoproteins. The microsomal triglyceride transfer protein inhibitor BMS-201038 was highly effective in reducing plasma LDL cholesterol
levels, with a reduction of more than 50% at the highest dose 23.
Conclusion
Aggressive therapy of diabetic dyslipidemia can help reduce future risk of coronary heart
disease. Current recommendations focus on primarily lowering of LDL levels. For diabetic
patients with CHD the goal of LDL has been reduced to < 70mg/dl. In future APO-B will
also evolve as an important target for treatment. Further data is awaited on combination
therapy with Statins. ACAT inhibitors, Glitazars, CETP inhibitors are under development.
Future looks at aggressive management of dyslipidemia along with achievement of tight
glycemic control.
References
1.
American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;
27(suppl):S68-71.
2.
Taskinen MR. Strategies for the management of diabetic dyslipidemia. Drugs 1999; 58 (suppl1):47-51.
3.
Fagot-Campagna A, Rolka DB, Beckles GL, Gregg EW, Narayan KM: Prevalence of lipid abnormalities, awareness, and treatment in U.S. adults with diabetes (Abstract). Diabetes 49 (Suppl. 1):A78, 2000.
4.
McFarlane SI, Jacober SJ, Winer N, Kaur J, Castro JP, Wui MA, Gliwa A, Von Gizycki H, Sowers JR: Control
of cardiovascular risk factors in patients with diabetes and hypertension at urban academic medical centers.
Diabetes Care 25:718723, 2002.
5.
National Cholesterol Education Program (NCEP) Expert Panel. Executive summary of the third report of the
National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of
high blood cholesterol in adults (adult treatment panel III). JAMA 2001; 285: 2486-97.
6.
Walden C, Knopp R, Wahl P, Beach K, Strandness E. Sex differences in the effect of diabetes mellitus on
lipoprotein triglyceride and cholesterol concentrations. N Engl J Med 1984; 311:953-9.
7.
UK Prospective Diabetes Study Group. UKPDS 27. Plasma lipids and lipoproteins at diagnosis of NIDDM by
age and sex. Diabetes Care 1997; 20:1683-7.
8.
Standards of medical care in diabetes--2010. American Diabetes Association. Diabetes Care. 2010 Jan; 33
Suppl 1:S11-61.
9.
Pyo rala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G. Cholesterol lowering with
71
Simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the
Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997; 20:614620.
10. Knopp RH, dEmden M, Smilde JG, Pocock SJ. Efficacy and safety of Atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart
Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN). Diabetes Care 2006; 29:14781485.
11. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene
AM, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22
Investigators. Intensive versus moderate lipid lowering with Statins after acute coronary syndromes. N Engl
J Med 2004; 350:1495-1504.
12. De Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, Rouleau JL, Pedersen TR, Gardner LH,
Mukherjee R, Ramsey KE, Palmisano J, Bilheimer DW, Pfeffer MA, Califf RM, Braunwald E, A to Z Investigators.
Early intensive vs a delayed conservative Simvastatin strategy in patients with acute coronary syndromes:
Phase Z of the A to Z trial. JAMA 2004; 292:13071316.
13.
Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect
of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral
arterial disease: the ADMIT study: A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA
2000; 284:12631270.
14.
Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse
JB, Robertson DD, Sheehan JP, Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of oncedaily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment
of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 2002; 162:15681576.
15. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL, American Diabetes
Association, American College of Cardiology Foundation. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of
Cardiology Foundation. Diabetes Care 2008; 31:811822.
16. Haffner SM; American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes
Care. 2004 Jan; 27 Suppl 1:S68-71.
72
17. Haffner SM; American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes
Care. Diabetes Care. 2003 Jan; 26 Suppl 1:S83-6.
18. Natarajan P, Ray KK, Cannon CP. High-density lipoprotein and coronary heart disease: current and future
therapies. J Am Coll Cardiol. 2010 Mar 30; 55(13):1283-99.
19. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials. Lancet. 2010 Feb 27; 375(9716):735-42.
20. D. Maccubbin, H. E. Bays. Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant
in patients with primary hypercholesterolaemia or mixed dyslipidaemia. International Journal of Clinical
Practice 2008; 62(12)1959-1970.
21. Elsayed, Raghda K; Evans, Jeffery D. Emerging lipid-lowering drugs: squalene synthase inhibitors. Expert
Opinion on Emerging Drugs 2008;13( 2): 309-322.
22. Fatima Akdim,Erik S.G. Stroes. Efficacy and Safety of Mipomersen, an Antisense Inhibitor of Apolipoprotein
B, in Hypercholesterolemic Subjects Receiving Stable Statin Therapy. J Am Coll Cardiol, 2010; 55:1611-1618.
23. Marina Cuchel, LeAnne T. Bloedon. Inhibition of Microsomal Triglyceride Transfer Protein in Familial Hypercholesterolemia. N Engl J Med 2007; 356:148-56.
24. S. Davis. Diabetic Dyslipidemia and Atherosclerosis. Clinical Cornerstone. 2008; 9(2): S17-S27.

Dr. M. Chenniappan
Consultant Cardiologist
Ramakrishna Hospitals
Woriyur, Trichy - 620 003.
Phone: 0431 - 227 4851.
E-mail: chennidr@city.com
&
Dr. Uday Sankar

Consultant Physician
73
Introduction
Type 2 Diabetes is more a disease of improper insulin utilization in addition to insulin
production. The primary problem in Type 2 DM is insulin resistance where the bodys
cells ( primarily muscle & fat) are unable to utilize insulin to break down the sugar in the
blood after a meal. As the process of insulin resistance continues, the pancreas respond
by increasing the insulin production to keep the blood sugar levels from rising. Some
type 2 diabetics have a 5-10 fold higher insulin levels than normal people. This internal
mileu results in high TGL, low HDL and rapidly progressing atherosclerosis. The risk of
death also increases with the duration of diabetes. It is eight fold in those with 25 years
duration of diabetes alone and 20 fold in those with diabetes & heart disease of the same
duration . If you are an Indian the risk of developing diabetes in your lifetime is one in
two when compared to more than one in three if you are an American.
Prediabetes
The process of development of diabetes mellitus starts even before the patient is born. A
pre diabetes stage always precedes the development of frank diabetes mellitus. Pre diabetes is defined as a Fasting Blood glucose between 100-125mg/dl (0r) a 2 hrs glucose
value after a 75 gram glucose challenge test of 140-199 mg/dl (or) HbA1c of 5.7 to 6.4.
The damage to the heart and circulatory system begins during this period of pre diabetes
which may last 10-20 years.
Diabetes Burden in India
74
The prevalence of pre diabetes and diabetes is among the highest in Indians. A very
striking feature of diabetes in Indians is lower age of onset at least 10-15 yrs earlier
than seen in other populations. One estimate puts that there has been a 3 fold increase
in prevalence of diabetes and a 8 fold rise in pre diabetes in South India in the last 2
decades. Another estimate puts it that it is likely that every third urban dwelling Indian
has diabetes or is likely to develop it soon. The most saddening part is that 50% of diabetes cases remain undiagnosed.
India indeed has the dubious distinction of being the diabetes capital of the world. . The
prevalence of diabetes among Indians is especially high after the age of 55. A very important fact that has come out of lot of studies is that Non diabetic Indians have a higher
Fasting Blood glucose levels than the Westerners. This has given rise to higher proportion
of pre diabetics among Indians. India has the highest number of diabetic patients in the
world and the numbers are expected to be twice that of China and thrice that of the
USA by the year 2030 Table 1
Table1 : Projected Growth of Diabetic Population from 2000 to 2030 in Millions
Countries
2000
2030
India
32
79
China
21
42
United States
18
30
Indonesia
08
21
Pakistan
05
14
Japan
07
09
Bangladesh
03
11
Another striking feature of diabetes in India is that, Indians develop diabetes at a body
weight 10-15 kgs lower than the Western population. The Indians have more pronounced
abdominal obesity than the overall general obesity seen more in the Western population.
Indians with diabetes have higher incidence and prevalence of heart disease when compared to even other Asian diabetics. These multiple factors of insulin resistance, abdominal
obesity, high glycemic load from overly processed foods (especially urban population) and
physical inactivity increase the susceptibility of Indians to diabetes which in turn raises
their susceptibility to heart disease.
Diabetes and Coronary Artery Disease

People with diabetes suffer from Myocardial infarction on an average 10 years earlier
than those without it. Indian diabetics are prone to a Myocardial infarction at an even
younger age when compared to the Western population. 25-50% of diabetics have a silent
Myocardial infarction. . Heart failure is 3-8 times more common in diabetics than in those
without it.. The incidence of heart disease in diabetics when compared to people without
diabetes 14 times higher in those <45 years / 3 times higher in those 45-64 years / 2
times higher in those > 65 yrs.
The diabetic patient develops more severe and aggressive atherosclerosis at a young age.
Diabetics have what is called the Diabetic Dyslipidemia with high Triglyceride levels, Low
HDL levels, high non HDL levels and most importantly a preponderance of small dense
LDL particles which are highly atherogenic.
Pre diabetes and diabetes are detected in up to two thirds of patients with heart disease
who are tested even in the absence of any diabetic symptoms. Diabetes is also strongly
related to stroke. As mentioned earlier unfortunately most of the pre diabetics and
diabetics remain undiagnosed in India before they develop a potentially fatal Myocardial
infarction (or) stroke.
Diabetes and Women

Diabetic women are at a higher risk of developing Myocardial Infarction than diabetic
men. Although women in general are at a lower risk of developing heart disease when
compared to men, diabetes mellitus cancels out the protection offered by the estrogens
and the removes the gender difference in the prevalence of heart disease. Diabetes is
commonly seen in women with premature Ischemic Heart Disease. Studies have shown
that diabetes is three times more common in Indian women than in Indian men with
premature Ischemic heart disease
Following Myocardial infarction diabetic women have twice the rate of recurrence and
less survival than men. Diabetes also increases the risk of heart failure 8 fold in women
compared to 4 fold in men. Diabetic women have a greater degree of diabetic dyslipidemia
when compared to diabetic men.
Diabetes and Cardiac Revascularization

25-30% of patients undergoing a first time PTCA (or) CABG are diabetics and 40% undergoing a repeat PTCA/CABG are diabetics . Diabetics have a higher rate of stent restenosis,
recurrent MI or death after an angioplasty. Despite newer antiplatelet therapy and drug
eluting stents, the outcomes in diabetes after PTCA and stenting are significantly worse
75
than in non diabetics. Several studies have shown that diabetics undergoing CABG have
a 50% lower mortality rate after 5 years compared to those undergoing PTCA/Stenting.
Among CABG patients survival is better in bypass surgeries using the Internal mammary
artery
Diabetes and Cardiovascular Mortality

Diabetic patients not only have a higher risk of developing heart disease but also have
the highest risk of dying from it. Every 4 out 5 diabetics die of Cardiovascular disease.
The longer the duration of diabetes the higher is the risk of death due to heart disease.
One study has shown that compared to those who never had diabetes or heart disease,
the risk of cardiac death was two times with angina, 3 times with diabetes, 4 times with
MI and 8 times when both diabetes and heart disease was present.
Conclusion
Diabetes and heart disease are inevitably intertwined with one tending to lead to the
other within 10-20yrs. Hence there is a clear need for early detection of heart disease in
diabetes. In the Indian context it more imperative that diabetes itself is detected early
and managed aggressively to prevent the development and progression of heart disease
there by preventing morbidity and mortality.
References
76
1.
Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular
events: A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4
years Diabetes Care 1999;22:233-240
2.
Drexel H, Aczel S, Marte T , et al. Is atherosclerosis in diabetes and impaired fasting glucose driven by
elevated LDL cholesterol or by decreased HDL cholesterol ? Diabetes Care 2005;28:101-7
3.
Hong CY, Chia KS, Hughes K, Ling SL. Ethnic differences among Chinese, Malay and Indian patients with
type 2 diabetes mellitus in Singapore. Singapore Med J 2004; 45:154-60
4.
Hu FB, Stampfer MJ, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and
coronary heart disease in women; 20 years of followup. Arch Intern Med 2001;161:1717-1723
5.
Hu FB, Stampfer MJ, Hanifer SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease
prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002; 25:1129-34
6.
Juutiainen A, Kortelainen S, Lehto S, Ronnemaa T, Pyorala K, Laakso M, Gender difference in the impact of
type 2 diabetes on coronary heart disease risk, Diabetes Care 2004; 27:2898-904
7.
Ramachandran A, Snehalatha C, kapur A, et al. high prevalence of diabetes and impaired glucose tolerance
in India; National Urban Diabetes Survey. Diabetologia 2001;44:1094-1101.
8.
Raman kutty V, Joseph A, Soman CR. High prevalence of type 2 diabetes in an urban settlement in Kerala,
India. Ethn Health 1999;4:231-9

Dr M V Muraleedharan
Professor, Department of Endocrinology
Amrita Institue of Medical Sciences
Cochin, Kerala.
Phone: 94470 34041
E-mail: mvmurali46@gmail.com

77
Introduction
Both diabetes and hypertension are common clinical disorders and it is natural that they
coexist in the same patient. However, coexistence of two conditions is much higher than
what would occur by chance. In type 1 disease, incidence of hypertension is 5% at 10
years, rising to 33% in 20yrs and 70% in 40 years after diagnosis of diabetes. The incidence parallels the quantity of albumin in urine, 19% with normoalbuminuria, 30% with
microalbuminuria and 65% with macroalbuminuria. In contrast, 39% of type 2 patients
had hypertension at the time of diagnosis, of which half of them had no albumin excretion but showed increased risk of cardiovascular problems. In diabetic hypertensives,
cardiovascular events, which reduce quality and quantity of life occurred earlier and is
more aggressive. When the two diseases occur together, choice of antihypertensives need
to modified for optimal outcome.
10mm reduction of diastolic BP in a diabetic from 90 to 80mm reduced adverse cardiovascular events by 51%. When diabetic patient is also a hypertensive, grading of hypertension
is different for the same level of blood pressure as diabetes is considered equivalent to
three more cardiovascular risk factors. For the same reason, lower treatment goals are
planned. Blood pressure targets are 130/80 with protein excretion less than one gram and
125/75 with proteinuria exceeding one gram.
78
In diabetes, causation of hypertension is closely related to renal involvement, hyperinsulinemia, fluid retention and extracellular volume expansion and arterial stiffness. Volume
expansion is attributed to hyperinsulinemia (which retain salt and water) and absorption
of sodium along with filtered glucose (which could be significant when there is severe
glycosuria). Arterial stiffness is the result of protein glycation linked to hyperglycemia in
the initial stage and atheromatous disease later.
Aggressive management of hypertension in diabetic is as important as management of glycemia. (UKPDS) This would prevent cardiovascular events and progression of nephropathy. It
is prudent to initiate treatment with nonpharmacologic measures control of obesity, salt
restriction, cessation of smoking and excessive alcohol and consumption of fresh vegetables
and fruit and low fat dairy products when blood pressure is 130-39 systolic and 80-89
diastolic. If target BP is not achieved in three months, pharmacologic treatment is initiated.
A prudent question asked at this situation is the choice of antihypertensives in general and
diabetic patient in particular. UKPDS data affirms that whatever the drug used, reducing
blood pressure produce significant benefits, especially in the diabetic. However, further
analysis of data suggests that in spite of reducing blood pressure, there is a significant
residual cardiovascular and renal disease contributing to mortality. Use of Angiotensin
Converting Enzyme Inhibitors (ACEI) and or Angiotensin Receptor Blockers (ARBs), had
significant benefit in diabetic hypertensives.
Renin Angiotensin Aldosterone System

In response to fall in blood pressure (or circulating vascular volume) and fall in Na content
of glomerular filtrates reaching distal renal tubule secretion of enzyme Renin which enzymatically cleave angiotensinogen from liver to angiotensin I occur. This is further cleaved
by enzyme Angiotensin Converting Enzyme (mainly in lungs) to Angiotensin II. Angiotensin
II has a number of biological actions which include:
Diabetes Care in India Today... and by 2025
Table 1: Biological Sctions of Angiotensin II
Immediate Effects:
Delayed Effects:
Restoration of blood pressure and volume
Mitosis
Vasoconstriction
Procoagulant effect
Aldosterone Production
Inflammatory cytokines
ADH release
Endothelial dysfunction
Destabilize plaques
It has been observed that mortality and morbidity attributed to diabetes at present occur
from involvement of large or small blood vessels. The initial event start as endothelial
dysfunction triggered by a number of factors of which Angiotensin II top the list. (Fig 1).
It is hence logical that blockade of this system with ACEI or ARB would cause significant
impact on vascular events and diabetes related death and disability.
79
Table 2: Table 2: Endothelial Dysfunction and CV Risk
Rise in BP
Increase influx of macromolecules, cytokines and macrophages into mesangium
Proteinuria
Tubulointerstitial injury
Increased Aldosterone, Na reabsorption
Endothelial dysfunction
Growth factors, uncontrolled proliferation of tissues
Increase in apoptosis
Oxidant stress
Stimulation of TGF beta, PDGF PAI 1 VPF, IL6, Osteopontin
fibronectin, FGF TNF PAF
Table 2: ATII Induced Renal Injury- Mechanisms
Angiotensin II cause constriction of both afferent and efferent glomerular vessels, predominantly efferent ones. This increases intraglomerular pressure, proteinuria and glomerular
hyperfiltration which are hallmarks of early renal involvement in diabetic nephropathy.
Causation of renal injury due to AT II can be due to a variety or reasons. (Table 2 ). This
puts ACEI and ARB way ahead of other antihypertensive agents in the management of
diabetic hypertensives. Some workers even think that it would be beneficial to use these
agents in nonhypertensive diabetics because of their renal salutary effect. These drugs (
ACEI and ARBs) are now considered as first line agents in the management of hypertension
in diabetes. The drugs can be used as single (ACEI or ARB) or combined.
Many clinicians managing diabetic hypertensives feel that these agents, in addition to reducing blood pressure have important effects through AT II block. These include decrease in
left ventricular hypertrophy, favourable influence on ventricular remodeling and occurrence
of cardiac failure (may be referred to as pleotrophic effects of these agents). In addition,
RAAS blockade also help to prevent renal injury and deterioration of renal function caused
by AT II. Benefits of using these agents outweigh that of other antihypertensives.
There are important differences between these two modes of renin angiotensin aldosterone
blockade. ACEI does not completely block the production of AT II as AT II can be generated by alternate pathways. ACEI, in addition to blocking ATI to AT II conversion act as
tissue kininase inhibitor and hence block inactivation of substances like bradykinin which
are important vasodilatory agents.
Comparison between ACEI and ARB in their antihypertensive effect has been studied in
number of trials. The results indicate that the two groups of agents are comparable. Patient
tolerance differ like nonproductive cough with ACEI and angioedema .
80
Further evolution of treatment in this area was combining ACEI and ARB Called total
RAAS block. ACEI blocks the formation of AT II while ARB blocks the action of AT II on
its receptors. Total RAAS blockade was studied in a number of trials and it was seen effective in reducing blood pressure but no superiority over either agents alone. However,
side effects were more with total RAAS block.
One of the main reasons for recommending ACEI / ARB for treatment of hypertension,
especially in diabetes was that these agents induced benefit independent of reducing BP.
With this in mind, trials were conducted with target BP less than normal goals (140/90)
and included ACCORD BP and Cardio sis. Results revealed no significant benefits and more
adverse events in persons treated with aggressive reduction of blood pressure.
Placebo controlled trials with mean baseline BP <140/90 included HOPE, EUROPA, PEACE,
CAMELOT, TRANSCEND and NAVIGATOR. Results of these trials are not uniform and there
are inconsistencies.
A stage has come for reappraisal of aggressive RAAS blockade in hypertensives in general
and diabetic hypertensives in particular. The claim that RAAS blockade provide beneficial
cardiovascular outcome other than reducing blood pressure come from trials like HOPE,
IDNT, RENAAL and IRMA II. Recently published data from ONTARGET trials show that this
may not be true and most of the patients benefit from more significant reduction of blood
pressure. ONTARGET cohorts also showed that in aggressively treated patients with RAAS
blockade experienced shorter creatinine doubling time. The claim of reduction of proteinuria and preservation of renal function is also questioned. Many believe that proteinuria
is only an association and not cause of renal dysfunction in diabetic hypertensives.
Summary

RAAS blockade is an important tool in the management of diabetic hypertensives
Benefits of RAAS blockade need to be critically analysed in view of newly evolved trials
Patients on RAAS blockade need to be monitored more closely.
RAAS blockade would continue as important tool in management of diabetic hypertensives.
References
1.
Reno-prevention vs. Reno-protection: a critical re-appraisal of the evidence-base from the large RAAS
blockade trials after ONTARGETa call for more circumspection - Q J Med 2009; 102:155167
2.
The Renin Angiotensin Aldosterone System in Hyper tension: Roles of Insulin Resistance and Oxidative
Stress - Med Clin N Am 93 (2009) 569582
3.
Role of Aldosterone and angiotensin II in insulin resistance: an update Clinical Endocrinology (2009)
81


Dr Subhankar Chowdhury
Professor and Head
82
Department of Endocrinology and Metabolism, IPGME&R.,

Kolkata.
Phone: 98310 76501
E-mail: subhankar.chowdhury@gmail.com
&
Dr Pradip Mukhopadhyay
Assistant Professor
Department of Endocrinology and Metabolism, IPGME&R.,

Kolkata,
Introduction
Macrovascular disease especially those involving the coronary arteries accounts for the
majority of all cause mortality globally. With the recent trends of increasing burden of
diabetes, prevention of coronary artery disease thus remains a major challenge not only
in developing countries, but also in developed countries.
Aetiology of macrovascular diseases are multifactorial, many of which are still uncovered.
Among the known factors, platelets dysfunction is an area where therapeutic interventions
have proved to reduce mortality in several research works. Diabetic thrombocytopathy1 is
thereby a distinct entity which encompasses several morphologic and physiologic changes
that occurs in the anucleate platelets, leading to its altered and increased aggregability,
which ultimately may lead to an often fatal coronary arterial disease. Diabetes is thus
aptly viewed as a pro thrombotic state also. The other aetiologic factors leading to this
prothrombotic state e.g. endothelial dysfunction, impaired fibrinolysis, altered coagulation
in the form of increased level of various coagulation factors are beyond the scope of this
discussion.
Platelets Activation in Health and Disease

Binding of a thrombogenic substance like collagen, thrombin etc to their specific receptors
located on platelets surface triggers a series of events that includes hydrolysis of membrane
phospholipids, mobilization of intracellular calcium and phosphorylation of intracellular
proteins1. In fact, in the site of tissue injury platelets adhere to subendothelial collagen
through collagen GpIa-IIa receptor and this interaction is stabilized at the site of higher
flow by vWF linking collagen to platelets GpIb-IX receptors1. As a result of the initial
cascade, arachidonic acid is released and is converted into thromboxane A2 (TXA2) which
produces vasoconstriction and augments platelet activation process. At the same time,
calcium mobilization and phosphorylation of proteins triggered by the initial stimulus are
critical for release of ADP and other proteins e.g. von Willebrand factor, PAI-1, PDGF etc.
Released ADP in turn binds to platelet purinergic receptors to trigger a conformational
change in Glycoprotein IIb and IIIa on platelet surface which leads to the formation of
a functional heterodimeric GpIIbIIIa receptor complex that binds to fibrinogen and links
adjacent platelets1. Also the TXA2 released in small amount initially binds to its specific
receptor to amplify the aggregation process. Prostacyclin and nitric oxide on the other
hand released from normal endothelium inhibits this activation process and relax vascular
smooth muscle to promote normal flow1.
Known factors which enhance thrombotic obstruction leading to a coronary event include
a rupture of plaque leading to extrusion of lipid rich core into blood, stenotic vessels with
compromised flow, high level of fibrinogen and PAI-I and most importantly the highly
reactive platelets1.
Diabetic Thrombocytopathy1
The increased reactivity of platelets in diabetes as compared to non diabetic persons is
evidentially related to several physiologic changes. These include decreased membrane
fluidity, increased intracellular calcium mobilization, increased TXA2 synthesis, increased
arachidonic acid metabolism, decreased Prostacyclin and NO production and increased
expression of adhesion molecule e.g. GpIIbIIIa and so on. The turn over rate of platelets
83
in diabetes is also increased greatly.
Mechanism of Action of Antiplatelet Agents

The available and investigational antiplatelet agents can be classified according to their
mechanism of action as below:
Cyclo oxygenase (COX-1) inhibitors: Aspirin
ADP P2Y12 receptor antagonist: Thienopyridines e.g. Ticlopidine, Clopidogrel, Prasugrel, Elinogrel, Ticagrelor, Cangrelor.
GpIIbIIIa receptor antagonist: Abciximab, Eptifibatide, Tirofiban
Phosphodiesterase III inhibitors: Cilostazole
TXA2 receptor antagonist: Picotamide, Ridogrel (Investigational agent)
Thrombin receptor antagonist: E5555 etc (Investigational agent)
84
Aspirin: Aspirin blocks the formation of thromboxane A2 in platelets by selectively acetylating the COX-1 enzyme. This blockade is irreversible because platelets being devoid of
nucleus are unable to resynthesize COX-1. Though its strong recommendation in secondary
prevention of CVD in diabetes with a dose of 75162 mg/day is maintained, American
Diabetes Association has recently restricted its use in primary prevention of CVD for those
with type 1 or type 2 diabetes, who are at increased cardiovascular risk only (10-year
risk >10%) 2. This includes men above 50 years or women above 60 years who have at
least one additional major risk factor like family history of CVD, hypertension, smoking,
dyslipidemia, or albuminuria2. Even then, this recommendation is not based on very strong
evidences. For persons with lower risk, such as men below 50 years of age or women
below 60 years of age without other major risk factors, evidence for its use for primary
prevention is controversial 2. Again for persons in these age-groups with multiple other
risk factors, ADA has left the issue over the clinical judgment of the treating physician 2.
Now what are the evidences for such partial withdrawal of recommendation for aspirin
use for primary prevention? Two recent RCT of aspirin specifically in patients with diabetes failed to show a significant reduction in CV end points. The JPAD 3 trial was the first
prospective trial to evaluate the use of low dose aspirin for the primary prevention of CV
events in type 2 diabetes (n = 2,539). Though there was a 20% difference between the
aspirin and non aspirin users in the primary end point (5.4 vs. 6.7%, respectively) after a
median follow up of about four and a half years, it was not statistically significant (P=
0.16). However among patients aged above 65 years (n = 1,363), aspirin was associated
with a 32% reduction in the risk of the primary end point (6.3 vs. 9.2%; P = 0.047). Furthermore, in aspirin-treated patients, the incidence of fatal coronary and cerebrovascular
events (a secondary end point) was significantly lower by 90% (0.08 vs.0.8%; P <0.0037).
However, there were no differences in nonfatal coronary and cerebrovascular events. Again
the POPADAD 4 trial which included patients with type 1 or type 2 diabetes aged above 40
years (n = 1,276) with an ankle-brachial pres-sure index <0.99 but having no symptomatic
cardiovascular disease, who were randomized to aspirin (100 mg) and antioxidants in a
double-blind, placebo-controlled fashion, did not show any benefit with aspirin in primary
prevention of cardiovascular events.
The meta-analysis by the Antithrombotic Trialists collaborators included six large trials of
aspirin for primary prevention in the general population which collectively enrolled over
95,000 participants, including about 4,000 with diabetes5. Overall, aspirin reduced the
risk of vascular events by 12% (RR 0.88). The largest reduction was for non-fatal MI (RR
0.77). Aspirin had little effect on CHD death (RR 0.95) or total stroke (RR 0.95).The net
effect on total stroke reflected a relative reduction in risk of ischemic stroke by 14% and
a relative increased risk of hemorrhagic stroke by 32%. Aspirin reduced CHD events in
men (RR 0.77) but not in women (RR 0.95).Conversely, aspirin had no effect on stroke in
men (RR 1.01) but reduced stroke in women (RR 0.77). However these minor differences in
effect by sex were of borderline statistical significance only. The effect of aspirin on major
vascular events in this meta-analysis was similar for patients with and without diabetes
(RR 0.88 and RR 0.87) respectively.
Aspirin Resistance
A considerable number of patients continue to experience recurrent atherothrombotic
events despite the use of aspirin which led to the development of the concept of aspirin
resistance6. This resistance conceptually involves inadequate or lack of inhibition of the
COX-1 pathway. The prevalence of aspirin resistance varies considerably6, 7 (from 0% of
patients in some studies to about 50% in others). The disparate findings can be attributed
to differences in the definition of resistance, type of assay used, dose of aspirin, and patient population under consideration. Many of the studies used assays that are not COX-1
specific and can involve multiple platelets signaling pathway6.
The proposed mechanisms for the aspirin resistance can broadly be classified into extrinsic
and intrinsic factors. It is well known that in diabetes on one hand the platelet aggregability increases and on the other hand hyperglycemia induced glycation of the proteins
on the platelet membrane reduces the efficiency of acetylation potential of aspirin. Factors such as use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs, which act through
the same pathway, may compete with aspirin and thereby reducing the efficacy. Some
intrinsic mechanisms can also lead to aspirin resistance. Recent studies have established
that platelets may contain COX-2 mRNA and this could provide an alternate pathway for
the platelets to act. Besides, single nucleotide polymorphisms of COX-1 have also been
reported. Alternately, due to inflammatory stimuli there might be an up regulation of an
aspirin insensitive and inducible COX-2 pathway which is mainly expressed in monocytemacrophages and represents an additional source of thromboxane A2. However, it still
remains undetermined whether improved glycemic control enhances the efficacy of aspirin
or whether incremental doses of aspirin are beneficial in the presence of poor glycemic
control.
ADP P2Y12 Receptor Antagonist

Despite having several limitations, Clopidogrel which irreversibly blocks the adenosine diphosphate (ADP) receptor P2Y12 on platelets is still the Thienopyridines of choice in clinical
practice. Its superiority over aspirin was established by the Clopidogrel versus Aspirin in
Patients at Risk of Ischemic Events (CAPRIE) trial 8 which examined the effects of 75mg
Clopidogrel once daily versus 325mg aspirin once daily in a large secondary prevention
population consisting of 19185 patients with recent ischemic stroke, recent MI, or established PAD. About one fifth of these patients were known to have diabetes mellitus. After
a mean follow-up of 1.9 years, primary endpoint (combined incidence of vascular death,
85
MI, or ischemic stroke) was 5.32% with Clopidogrel and 5.83% with aspirin representing
an 8.7% relative risk reduction with Clopidogrel above aspirin (P=0.043). Retrospective
analysis in the diabetic subgroup in the CAPRIE study also showed Clopidogrel (n= 1914)
to have 15.6 % composite vascular primary endpoint compared to aspirin group (n=1952)
with 17.7% of similar events (P=0.042). However in non-diabetes mellitus patients, the
composite vascular primary end point was not statistically significantly different in patients
randomized to treatment with Clopidogrel (12.7%) versus aspirin (11.8%). This discrepant
and somewhat better Clopidogrel response in diabetes mellitus patients may be attributed
to the more potent antiplatelet effects of Clopidogrel over aspirin, leading to more efficient
inhibition of the hyper reactive diabetic platelets.
Whether the dual blockade with a combination of Clopidogrel and aspirin was superior to
aspirin alone was evaluated in the Clopidogrel in Unstable Angina to Prevent Recurrent
Events (CURE) study9. About 12,562 with unstable angina or nonST-elevation myocardial
infarction (NSTEMI) were randomized to treatment with either Clopidogrel (75 mg/day
after a loading dose of 300 mg) or placebo in addition to aspirin therapy (75325 mg/
day) for up to 1 year. Those with dual antiplatelet therapy had a significant 20% reduction
in the first primary outcome (composite vascular death, myocardial infarction, or stroke)
compared with that in patients treated only with aspirin (9.3 vs. 11.4%, respectively; P
< 0.001). However though this was associated with a higher incidence of major bleeding
there were no significant differences in life-threatening bleeding. There were 2840 patients
with diabetes mellitus in the study. Patients on dual therapy experienced an approximately
17% reduction in the first primary outcome. Thus, the effect in the diabetic subgroup was
in the same direction as in the entire study, but had borderline statistical significance.
86
However the beneficial effect of this dual antiplatelet therapy was not consistent in other
studies. In the CHARISMA10 (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial which enrolled about 15, 603 patients with
high-risk, but nonacute, patients with either clinically evident cardiovascular disease or
multiple risk factors (n=3284) Clopidogrel plus aspirin was not significantly (P=0.22) more
effective than aspirin alone in reducing the rate of MI, stroke, or death from cardiovascular
causes and was actually harmful in patients without documented atherothrombotic disease,
thus having a relatively lower risk. However, subgroup analysis of persons with higher
risks e.g. those with prior MI, prior ischemic stroke, symptomatic PAD, dual therapy was
consistent with CURE results showing a benefit of significant 17% risk reduction (P=0.01).
Based on the above evidences ADA currently recommends Clopidogrel monotherapy (75mg/
day) for patients with CVD and documented aspirin allergy2. Dual therapy with aspirin
(75162 mg/day) and Clopidogrel (75 mg/day) is recommended for up to a year after an
acute coronary syndrome2.
However, Clopidogrel has several limitations e.g. delayed onset of action, large inter individual variability in platelet response, and irreversibility of its inhibitory effect on platelets11.
The two-step activation process, involving a series of Cytochrome P-450 (CYP) isoenzymes,
is susceptible to the interference of genetic polymorphisms and drugdrug interactions11.
Patients with a poor response to Clopidogrel have an increased risk of coronary thrombosis.
Clopidogrel Resistance
As with aspirin, the prevalence of Clopidogrel resistance reported in the literature varies
greatly. This is more prevalent in diabetes and highest among patient on insulin therapy
which may explain why diabetic patients at their advanced state of disease receiving insulin continue to have recurrent atherothrombotic events6. The mechanism of Clopidogrel
nonresponsiveness in diabetes with insulin treatment may be explained by the fact that
insulin, stimulating its own receptor on the platelets membrane may lead to loss of Gi
activity, resulting in suppression of cAMP and inhibition of P2Y12 pathway. Again insulin
resistance can also lead to platelet hyperreactivity causing Clopidogrel unresponsiveness
by upregulating P2Y12 pathway. The variability in Clopidogrel action may thus be related
different mechanisms. Clinical factor leading to this variability may be due to poor compliance, under dosing, poor absorption, drug interaction involving CYP 3A4 pathway, insulin
resistance and obesity. Cellular factors like accelerated platelets turnover, increased ADP
exposure, up regulation of P2Y12 pathway, up regulation of P2Y12 bypass pathway can
also be responsible for this variability. Finally genetic factors like polymorphism of CYP,
GpIa, GpIIIa and P2Y12 are also good explanation for this resistance6.
Whereas a dose of aspirin between 75-325 mg is used in clinical practice and a higher
dose is not associated with additional platelet benefit, rather increasing chances of GI
bleeding without definite evidence of overcoming the so called aspirin resistance, if any,
Clopidogrel non responsiveness have been tried to overcome by increasing the dose. The
use of a 150-mg Clopidogrel maintenance dose resulted in greater platelet inhibition than
use of a 75-mg dose in clinical trial. PCI guidelines thus provide a recommendation for
high (600mg) Clopidogrel loading doses with a 150-mg maintenance dose. However large
scale data to assess the safety of high dose Clopidogrel is yet not available12. If elective
CABG is planned in persons taking Clopidogrel, it should be withheld 5-7 days beforehand.
Prasugrel
The other member of this group is also an irreversible ADP P2Y12 receptor antagonist
having some advantages over Clopidogrel. After intestinal absorption, it is rapidly hydrolyzed by esterases to an intermediate metabolite and requires one CYP-dependent oxidation step to generate its active compound. (Clopidogrel requires two-step CYP-dependent
oxidation for the same.) Thus its onset of action is more rapid11. Its inhibitory action is
stronger than Clopidogrel also. Prasugrel shows lower variability in platelet response because of very little or absent susceptibility to genetic polymorphism in CYP isoenzymes11.
However the inhibition of platelets activation is more evident with Prasugrel than with
Clopidogrel. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing
Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction 38 (TRITON-TIMI
38) 13 comparing Prasugrel with Clopidogrel in patients (n = 13,608) with ACS who underwent PCI (median follow up of 14.5 months), the primary end point (composite of CV
death, nonfatal MI, or nonfatal stroke) occurred in 12.1 % of Clopidogrel group compared
to 9.9% of Prasugrel group (P = 0.001). However, there was an increased risk of major
bleeding observed in 2.4% of the Prasugrel group compared with 1.8% of the Clopidogrel
group ( P = 0.03). Most importantly, patients who benefited most from Prasugrel therapy
were diabetic (n=3,146). The primary end point was reduced significantly with Prasugrel
in diabetic subjects compared with patients without diabetes whether or not they were
on insulin. Despite the increased bleeding risk, the prespecied net clinical benefit analysis, defined as the composite of efficacy and bleeding end points, still favored Prasugrel.
After this encouraging result, USFDA also approved Prasugrel for use in unstable angina
87
and MI who undergo PCI. Though the usual maintenance dose is 10 mg per day, 5 mg is
recommended for those weighing less than 60 kg.
Ticagrelor
A new member of this group is rapidly absorbed and does not require further biotransformation for activation. It directly and reversibly binds to the ADP receptor. The half-life
of Ticagrelor is 7 to 8 hours. Thus it has a stronger and more rapid antiplatelet effect
than Clopidogrel. Based on the encouraging results of PLATO trial14, which has shown that
patients having ACS with or without ST-segment elevation, had a significantly reduced
composite of death from vascular causes, MI, or stroke while receiving Ticagrelor as compared with Clopidogrel ( 9.8% vs. 11.7%, P<0.001), USFDA has currently recommended its
use for ACS patients to prevent thrombotic events. The Ticagrelor benefit in PLATO was
not associated with increase in major bleeding also. Ticagrelor therapy can also overcome
non responsiveness to Clopidogrel, and its antiplatelet effect is same in responders and
nonresponders15. The usual maintenance dose is 90 mg twice daily.
How to Choose Then an Agent from this Group?
88
Albert Schmig in the accompanying editorial11 of PLATO trial suggested individualizing this
according to clinical situation by keeping in mind the benefits and risks of these agents.
If a bypass graft (CABG) appears necessary, Ticagrelor therapy may be a choice due to its
reversibility of action. If patients who on Clopidogrel or Prasugrel need elective CABG, it
is reasonable to switch them to Ticagrelor 5 to 7 days before surgery. Prasugrel should be
avoided in favor of Ticagrelor for those with a history of stroke or transient ischemic attacks (Prasugrel increased risk of intra cranial hemorrhage in these groups in clinical trial).
In patients with an excessively high risk of bleeding, it might also be prudent to avoid
the use of both Prasugrel as well as Ticagrelor. Ticagrelor therapy should be discouraged in
patients who have COPD, hyperuricemia, moderate or severe renal failure, bradyarrhythmias
unprotected by pacemakers, a history of syncope, or a need for treatment with an ADPreceptor antagonist for more than 1 year. For other patients with ACS, either Ticagrelor
or Prasugrel may be preferred.
Side Effects Profiles of ADP P2Y12 Receptor Antagonist 1, 9, 14

Ticlopidine, the first member of this group is withdrawn for its potential to cause neutropenia and/or agranulocytosis. Thrombotic thrombocytopenic purpura (TTP) was also reported
with Ticlopidine. Clopidogrel on the other hand did not produce bone marrow toxicity.
TTP is also reported with Clopidogrel only very rarely, which occurred within 2 weeks of
initiation of therapy. Major bleeding occurred more frequently with dual therapy of aspirin
and Clopidogrel in CURE study than aspirin alone (3.7% vs. 2.7% P=0.001) which was more
common from puncture site and gastrointestinal system. There was no increase in fatal
hemorrhage or intracranial hemorrhage. The increased risk of bleeding due to prolonged
persistence of the Clopidogrel effect is of concern when patients need nondeferrable surgery such as urgent coronary-artery bypass grafting. Prasugrel also led to increased major
bleeding compared to Clopidogrel (2.4% vs1.8%, P=0.03). Newer side effects of Ticagrelor
that emerged from PLATO trial have been mentioned earlier. However the reassuring facts
for the beneficial effect of Clopidogrel in combination with aspirin against the threat of
increasing bleeding tendency is that proton pump inhibitor Omeprazole have reduced the
gastro intestinal bleeding events without any adverse effect on CV events in the recently
conducted COGENT trial16.
GpIIbIIIa Receptor Antagonist

The agents in this group block the final common pathway in the process of platelets activation. In the available trials, the glycoprotein IIb-IIIa inhibitors (Tiroban, Eptibatide,
Abciximab) were used by bolus and then a constant infusion for 25 days after admission
for ACS.
In a meta-analysis17 of six trials in ACS patients, in which 22% had diabetes mellitus
(n=6458), glycoprotein IIb-IIIa lockers significantly reduced mortality at 30 days from 6.2
to 4.6% (P=0.007) in diabetes mellitus patients. However in more than 22 000 patients
in these trials without diabetes mellitus, these agents did not improve survival. The effect
of glycoprotein IIb-IIIa inhibitors in diabetic individuals was even greater in patients who
underwent PCI. However the greatest problem is with increasing bleeding events including
intracranial bleeds. Another limiting factor is its cost.
However the results of Abciximab were divergent in two other trials. The ISAR-SWEET
(Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics) trial 18 did not show any impact of Abciximab
on the 1-year risk of death and MI in diabetes mellitus patients undergoing PCI after
pretreatment with a 600mg loading dose of Clopidogrel. On the contrary the ISAR-REACT
2 (Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary
Treatment 2) trial19, clearly showed that Abciximab safely reduces the risk of death, MI in
patients with non-STEMI ACS undergoing PCI after pretreatment with 600mg of Clopidogrel, but this is not so for patients with ECG changes . The benefit was observed across
all subgroups, including DM. Thus, American Heart Association recommends that a GpIIbIIIa receptor antagonist to be administered in addition to aspirin and heparin to patients
with ACS in whom catheterization and PCI is planned. For those patients with continuing
ischemia with an elevated troponin, or with other high risk features, these agents can be
used in addition to aspirin and heparin /low molecular weight heparin even if invasive
management strategy is not planned.
Cilostazol
Though not popular as an antiplatelet agent, this phosphodiesterase III inhibitor holds
promise as an adjunct to dual platelet therapy in patients with drug eluting stents. These
drug eluting stent reduce the risk of restenosis but pose a risk of thrombosis. Cilostazol,
an oral antiplatelet agent, and posses the pleotropic antiproliferative effect to inhibit neointimal hyperplasia. In the DECLARE-DIABETES Trial20 (RCT of triple antiplatelet therapy as
compared with dual antiplatelet therapy after drug-eluting stent implantation in diabetic
patients) decreased angiographic restenosis and repeat revascularization significantly. De-
89
spite having 23 RCT, available evidence is limited by small study effects. The major drawback
of cilostazol therapy is its high prevalence of side effects (e.g., migraine, palpitations, and
gastrointestinal disturbances) which frequently lead to drug withdrawal6.
Conclusion
Antiplatelet therapy has revolutionized the preventive management of macrovascular complication especially in persons with diabetes. Their role has been undisputedly proved for
secondary prevention of coronary events. Despite several limitations, aspirin is still the
cheapest and most cost effective agent for this purpose and can be continued for a long
time for those who can tolerate it. Newer agents are especially helpful for ACS patients
who may or may not go for percutaneous intervention.
References
90
1.
Colwell JA, Nesto RW: The platelet in diabetes: focus on prevention of ischemic events. Diabetes Care
2003;26:21812188,
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American Diabetes Association. Standards of Medical Care in Diabetes2010. Diabetes Care 2010;33(Suppl.
1):S32S33
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Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y.

Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Lowdose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized
controlled trial. JAMA 2008;300:21342141
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Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J,
Macfarlane P, Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, OBrien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R. The prevention of progression of
arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and
antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; 337: 1840
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Antithrombotic Trialists (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R,
Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A. Aspirin in the primary
and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from
randomized trials. Lancet 2009;373:18491860
6.
Angiolillo DJ: Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and
Future Directions. Diabetes Care 2009; 32:531-40.
7.
Singla MK, Lahiri P, Mukhopadhyay P, Pandit K, Chaudhuri U, Chowdhury S. A study of aspirin resistance
in type 2 diabetes. J Indian Med Assoc 2008; 106: 720-723, 740.
8.
CAPRIE Steering Committee: A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischemic events (CAPRIE).Lancet 1996; 348:13291339.
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Yusuf S, Zhao F, Mehta SR, et al.: Effects of Clopidogrel in addition to aspirin in patients with acute coronary
syndromes without ST-segment elevation. N Engl J Med 2001; 345:494502.
10. Bhatt DL, Flather MD, Hacke W, et al.: Patients with prior myocardial infarction, stroke, or symptomatic
peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49:19821988.
11. Ticagrelor Is There Need for a New Player in the Antiplatelet-Therapy Field? Schmig A. N Engl J Med
2009; 361:1108-11.
12. Angiolillo DJ, Shoemaker SB, Desai B, et al.: A randomized comparison of a high clopidogrel maintenance
dose in patients with diabetes mellitus and coronary artery disease: results of the OPTIMUS (Optimizing
anti-Platelet Therapy In diabetes Mellitus) study. Circulation 115:708716, 2007
13. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus Clopidogrel in patients with acute coronary
syndromes. N Engl J Med 2007; 357:2001-15.
14. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus Clopidogrel in patients with acute coronary syn-
dromes. N Engl J Med 2009; 361:1045-57.

15. Gurbel PA, Bliden KP, Butler K, et.al. Response to Ticagrelor in Clopidogrel nonresponders and responders
and effect of switching therapies: the RESPOND study. Circulation. 2010; 121:1188-99.
16. Bhatt DL, Cryer BL, Contant CF.et.al. Clopidogrel with or without Omeprazole in Coronary Artery Disease.
N Engl J Med 2010; Oct 6 Online First.
17. Angiolillo DJ: Antiplatelet therapy in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2007;
14:124131.
18. Mehilli J, Kastrati A, Schuhlen H, et al. Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a
Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) Study Investigators. Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions
after treatment with a high loading dose of clopidogrel. Circulation 2004; 110:36273635.
19. Kastrati A, Mehilli J, Neumann FJ, et al., Intracoronary Stenting and Antithrombotic: Regimen Rapid Early
Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute
coronary syndromes undergoing percutaneous coronary intervention after Clopidogrel pretreatment: the
ISAR-REACT 2 randomized trial. JAMA 2006; 295:15311538.
20. Lee SW, Park SW, Kim YH, et al.: Drug-eluting stenting followed by cilostazol treatment reduces late
restenosis in patients with diabetes mellitus the DECLARE-DIABETES Trial (A Randomized Comparison of
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Patients). J Am Coll Cardiol 2008; 51:11811187.
91

Dr Navneet Agrawal
92
Diabetes, Obesity & Thyroid Centre,

Gwalior
Dr Sanjay Kalra
BRIDE, Karnal
&
Dr Swati Agrawal
Introduction
Diabetes Mellitus (DM) is a very common metabolic disorder with a high and increasing
prevalence worldwide. Diabetes is a metabolic cum vascular syndrome of multiple etiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and
protein metabolism resulting from defects in insulin secretion, insulin action, or both
leading to changes in both small blood vessels (Microangiopathy) and large blood vessels
(Macroangiopathy).
Micro and macrovascular beds are altered in diabetes by various changes in neovascular
mechanism. However, from the vascular point of view diabetes is paradoxical disease. In
some organs such as kidney and retina there is an increase in neovascularization, whereas
in coronary artery disease, peripheral artery disease and wound healing there is marked
inhibition of angiogenesis.
Definition
Angiogenesis is the process of formation of new capillaries network (microvascular) in response to hypoxia or other stimuli. The process of angiogenesis involves the local secretion
of angiogenic factors from both hypoxic endothelium and supporting pericytes that induce
endothelial proliferation and sprouting of neovessels. This is different from arteriogenesis, a
process of growth and expansion of existing arteriole networks in response to acute arterial occlusion (e.g. arterial occlusion) or physical forces (e.g. exercise induced shear stress).
Mechanism of Angiogenesis in Diabetes

Angiogenesis is a complex multistep process involving interaction between a number of
pro and anti angiogenic mediators, endothelium and the extracellular matrix. (Table1).
Table 1: The angiogenesis is characterized by
1.
2.
3.
4.
5.
6.
Extracellular matrix degeneration

Endothelial Cell (EC) proliferation
EC survival
EC migration
EC morphology changes
EC anastomosis
The various cytokines involved in the process of angiogenesis includes members of Fibroblast Growth Factor family (FGF), Vascular Endothelial Growth Factor family (VEGF),
Platelet Derived Growth Factor family (PDGF), TGF- and angiopoietins. These factors are
secreted by endothelium and act in both an autocrine and paracrine manner to promote
the growth of new vessels. NO is released by endothelium through activation of the endothelial NO synthase, which causes VEGF release and microvasculature dilation. The factors
involved in the dysregulation of angiogenesis are summarized in (Table 2).
93
1. Vascular Endothelial Growth Factor (Vegf) Signalling Pathway

VEGF
VEGF receptors 1, 2 (Flt-1, Flk-1)
Flk-1 phosphorylation (activation)
Activation of serine-threonine protein kinase Akt-1
Endothelial nitric oxide synthase (eNOS)
Normal Flt-1 activation
2. Hypoxia
a. Upregulation of hypoxic-inducible factors (HIF) subunits
i. VEGF
ii. PDGF
iii. Ang 2 (angiopoietin 2)
iv. SDF-1 (Stromal-Derived Factor 1)
3. Chronic Inflammation
a. Interleukin-1
b. Interleukin-6
c. Tumor necrosis factord. CCL-5
e. Cyclo-oxygenase-2 (COX-2)
4. Oxidative stress
94
reactive oxidative species (ROS)

5. Advanced Glycation End Products (AGE): in Tissue and Serum
a. Glycated albumin: H1F1 over expression
b. Glycated FGF (Fibroblast Growth Factor)
c. Glycated HGF (growth factor)
d. Glycated PDGF (Platelet Derived Growth Factor)
e. Glycated TGF (Transforming Growth Factor)
f. IGFBP-rP2 (insulin like growth factor binding protein-related protein-2)
6. Advanced Lipoxidation End Products (ALE)
a.
b.
c.
d.
e.
f
CXCL-10
CCL-2
COX-2
1,2 Integrins
Interleukin 6
Interleukin 8
Table 2 : Molecular Mechanisms of Angiogenesis / Arteriogenesis in Diabetes
The VEGF family includes VEGF (A-D) and placental growth factor. VEGF interact with different tyrosine kinase receptors (Flt-1, Flk-1, Flt-4). They act as mitogens for vascular endothelial
cells and also stimulate endothelial progenitor cell mobilization from the bone marrow.
The FGF expression is stimulated by hypoxia and hemodynamic stress. FGF induces endothelial cell proliferation, survival and differentiation and is also involved in the migration of
endothelial cells, smooth muscle cells macrophages and fibroblasts. These effects are mediated through the tyrosine kinase receptor FGFR1 leading to activation of protein kinase C.
There is abnormal VEGF signaling in diabetic patients. Defective VEGF signaling results in
impaired Flk1 activation that affects the various processes of angiogenesis including endothelial cell growth and migration, monocyte and endothelial progenitor cell recruitment
and EPC release by bone marrow. At the same time decreased VEGF sensing due to impaired
Flk1 activation results in increased serum VEGF levels that lead to pathologic angiogenesis.
Angiogenic Stimulating Conditions in Diabetes

The pathophysiology of diabetes is characterized by hyperglycemia, nonenzymatic glycation
and lipoxidation end products, chronic inflammation, and oxidative stress. Therefore the
vascular endothelium is exposed to a large amount of abnormal molecules, which result
in imbalance in the signaling pathways and dysregulation of angiogenesis.
Table 3: Dysregulation of neovascularization results in
1.
2.
3.
4.
5.
6.
Accelerated atherosclerosis
Atherosclerotic plaque destabilization
Enhanced angiogenesis in microvascular beds
Abnormal wound healing
Defective arteriogenesis
Endothelial progenitor cells in bone marrow: impaired release and function
Hyperglycemia and AGE Products

Diabetic patients presenting with poor glycemic control has high levels of Advanced Glycation End Products (AGE) which are known to promote tissue fibrosis in organs with
end-stage damage. This results in extensive reduction of tissue perfusion and consequently ischemia-induced angiogenesis. In addition, AGE activates synthesis of various proangiogenic proteins, such as insulin-like growth factor binding protein-related protein- 2
(IGFPB-rP2) in skin fibroblasts and in renal mesangial cells.
Hyperglycemia itself is an angiogenic enhancer and negatively impact many aspects of
neovascularization. High glucose levels stimulate the transcription of many antigenic genes
including Transforming Growth Factor (TGF) in vascular smooth muscle cells. This growth
factor may in turn up-regulate the expression of VEGF, which has been described in diabetic nephropathy animal models.
Advanced Lipoxidation End Products (ALE)

Advanced lipoxidation end products increases the expression of a wide range of inflammatory factors, such as CXCL10, CCL2, COX-2, integrins, IL6, IL8 and inducible NOS (iNOS)
in monocytes. Most of these molecules are established angiogenic activators.
Hypoxia
Hypoxia is probably the major inducer of angiogenesis both in physiological and in pathological situations. The presence of hypoxic environment triggers cells to up regulate VascuDiabetes and Angiogenesis
95
lar Endothelial Growth Factor (VEGF), Stromal-Derived Factor-1 (SDF-1), platelet-derived

growth factor (PDGF) or angiopoietin- 2. Therefore, angiogenesis process is dependent on
oxygen homeostasis.
Chronic Inflammation
DM is characterized by a chronic inflammatory state with concomitant cytokine and growth
factor secretion. In fact, inflammatory-induced release of a huge amount of factors (e.g.
IL1, IL6, TNF, CCL5), lead to angiogenic stimulation.
Oxidative Stress
Diabetes is characterized by the presence of oxidative and nitrosative stress. There is evidence which indicates that ROS activate signaling pathways that promote angiogenesis.
Angiogenesis and Specific Complications

Diabetic Retinopathy
Proliferative Diabetic Retinopathy (DR) is a progressive disorder characterized by the presence of retinal vessel microaneurisms, hemorrhages, exudates and edema. One of the
primary changes in the vascular process of DR is the loss of pericytes in retinal capillaries,
which may lead to vascular failure and chronic hypoxia. HIF transcription factors, then
promote the rapid formation of neovessels, ultimately resulting in exacerbated angiogenesis. The sudden establishment of angiogenic vessels leads to the assembly of leaky and
malfunctioning vascular structures, which is further enhanced by the presence of a delicate
basement membrane
96
Vascular Endothelial Growth Factor (VEGF), a potent stimulator of angiogenesis, has been
implicated in ocular angiogenesis and in the pathogenesis of proliferative diabetic retinopathy. VEGF is released by several distinct cells within the eye. Retinal production of
VEGF is enhanced by hypoxia, AGEs, and oxidative stress. VEGF may also be involved in
the pathogenesis of macular edema.
Recently, it has been shown that Pigment Epithelium Derived Factor (PEDF), a glycoprotein
secreted by retinal pigment epithelium and originally described as a neurotrophic factor, is
a potent antiangiogenic agent. In ischemia induced retinal neovascularization, intraocular
concentration of VEGF is high, while that of PEDF is low. This factor is known to prevent
VEGF and erythropoietin in retinal endothelial cells. Recombinant PEDF (or PEDF agonists)
could prove of major value in limiting or preventing proliferative retinopathy; furthermore,
PEDF neurotrophic properties could be of value in diabetic neuropathy.
In addition, hyperglycemia enhances the overexpression of fibronectin, a glycoprotein present in ECM. Increased fibronectin enhances the availability of fibronectin fragments that
present pro-angiogenic properties. These fragments may therefore account for the aberrant
angiogenesis in retinopathy.
Diabetic Nephropathy
In kidney, podocytes are able to secrete VEGF, which in turn, takes part in the capillary hyper permeability of macromolecules in glomeruli. VEGF is overexpressed in diabetic
kidneys and its role as a neurotrophic and neurogenic agent has recently been reported.
Glomerular hypertension may be another important driver in the progression of abnormal

angiogenesis in diabetes. Angiotensin II stimulates the production of VEGF, and it has
been shown that inhibiting Angiotensin-Converting Enzyme (ACE) reduces retinal VEGF
over expression and hyper permeability in experimental insulinopenic diabetes.
Another relevant angiogenic markers present in diabetic nephropathy is Transforming
Growth Factor (TGF) and its type II receptor. This factor is markedly excreted in the urine
in diabetic patients. This emphasizes the angiogenic enhancement in diabetic patients.
Therapeutic Implication of Angiogenesis

As the understanding of the mechanisms underlying the diabetic neovascularization has
increased, novel therapeutic strategies have been proposed. ACE inhibitors and ARB have
demonstrated improvement in microvascular complications. Statins have demonstrated
improvement in the endothelial release of proangiogenic cytokines, increase number and
function of circulating EPCs and upregulate the Akt pathway to promote angiogenesis.
Antioxidant therapy has also demonstrated beneficial effects.
The implication of VEGF in vasculoproliferative diabetic retinopathy led to the intravitreal
use of antiVEGF agents in the management of these patients. Accordingly, three VEGF
antagonist pharmacological agents: Pegaptanib (Macugen), Ranibizumab (lucentis) and
Bevacizumab (Avastin) are currently available for DR treatment. The first two are actually
approved for age-related macular degeneration by the Food and Drug Administration (FDA),
and clinical trials are ongoing for their clinical use in other ocular vasculoproliferative
disorders including DR. The clinical utility of angiogenesis modulation is summarized in
(Table 4).
Table 4 : Therapeutic use of Angiogenic Mechanism
1.

2.

- VEGF antagonists
- Pegaptanib
- Ranibizumab
- Bevacizumab
Wound Healing
- Growth factors
- PDGF
- EGF
- Bioactive matrices
- Tissue engineering biomaterials
- Placental extract
- Hyperbaric oxygen
- Nicotine (angiogenic promoter)
Although inhibition of VEGF could be very useful in controlling diabetic retinopathy, it

might trigger undesired side effects including impaired wound healing, abrogation of
collateral vessel growth, hypertension and proteinuria, which are prevalent features of
diabetic patients. Therefore, a careful evaluation of the molecular vascular events and their
association with other diabetic processes (e.g. chronic oxidative stress, inflammation, etc)
must be accomplished before addressing these pathways towards treatment.
97
Wound healing is a major complication of diabetes with extensive morbidity rates where
angiogenesis is effectively impaired. Vascularization in wound healing can be promoted
by several interventions. These include therapeutic agents involving growth factors, bioactive matrices, mechanical systems, tissue engineering biomaterials and hyperbaric oxygen
therapy (HBO). HBO for instances is already in use and stimulates wound healing by
promoting growth factor synthesis at the wound bed, and by mobilizing EPCs
Conclusion
Vascular complications, both micro and macro, contribute to the bulk of morbidity and
mortality linked with diabetes. Angiogenesis mediates these complications in different ways.
It makes sense therefore to target this process by pharmacological strategies to optimize
vascular health. However, many questions still remain regarding the use of angiogenesis
as a therapeutic approach. More detailed studies are required to elucidate the inherent
molecular mechanisms that hold the angiogenic paradox, and to predict which patients
could benefit from each therapeutic approach.
References
98
1.
Simons M. Angiogenesis, Arteriogenesis, and Diabetes, Paradigm Reassessed? Journal of the American College of Cardiology,2005;46:835-7
2.
Soares R. Angiogenesis in Diabetes. Unraveling the Angiogenic Paradox. The Open Circulation and Vascular
Journal, 2010; 3: 3-9
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Tchaikovski V, Waltenberger J. Angiogenesis and Arteriogenesis in Diabetes Mellitus: Signal Transduction

Defects as the Molecular Basis of Vascular Cells. Therapeutic Neovascularization, 2007: 33-77
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Agrawal N, Singh S, Singh N,Kalra S, Srivastava G : Oxidative stress in the pathogenesis of diabetic nephropathy. The Internet Journal of Family Practice, 2010 ;9
5.
Folkman J, Shing Y. Angiogenesis.J. Biol. Chem.1992; 267(16): 1093110934
6.
Agrawal N, Singh S, Singh N, Kalra S, Srivastava G : Oxidative stress and diabetes. The Internet Journal
of Geriatrics and Gerontology, 2010; 6(1):
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Glotzbach JP, Wong VW, Gurtner GC. Neovascularization in Diabetes. Expert Rev. Endocrinol. Metab, 2010;
5(1), 99-11
8.
Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate
hypoxia-initiated angiogenesis. Nature 1992;6: 843-845
9.
Martin,A,; Komada.M.R.;Sane, D.C.Abnormal angiogenesis in Diabetes mellitus. Med. Res. Rev., 2003; 23:11745
10. Kanesaki Y, Suzuki D, Uehara G et al. Vascular endothelial growth factor gene expression is correlated with
glomerular neovascularization in human Diabetetic Nephropathy. Am J Kidney Dis 2005; 45 (2): 288-294
Recent Trends and Future Perspectives in the

Management of Peripheral Neuropathy
Dr Vijay Viswanathan
M V Hospital for Diabetes &
Prof. M. Viswanathan Diabetes Research Centre,
[WHO collaborating centre for Research, Education and Training in Diabetes]
No.5, West Mada Church Street, Royapuram, Chennai 600013

&
M Divya

Management of Peripheral Neuropathy.
99
Introduction
Neuropathy is one of the most common of all the long-term complications of diabetes,
affecting upto 50% of patients1. They are heterogeneous affecting different parts of the
nervous system that present with diverse clinical manifestations.
Diabetic peripheral neuropathy (DPN) is the degeneration of the peripheral nerves that
starts in the distal extremities and then moves proximally. It is a multi-factorial disorder
arising from hyperglycemia and/or insulin deficiency, and is characterized by a complex
pathogenic network of interrelated metabolic, neurotrophic, and vascular defects 2.
DPN is by far the most common of all the diabetic neuropathies and may be divided
into the following two main types: acute sensory neuropathy and chronic sensorimotor
neuropathy.
In the past, a lack of awareness and inappropriate management of DPN has led to much
unnecessary morbidity and substantial health care costs. At least half of all foot ulcers,
the end stage of such neuropathy, can be prevented by appropriate management and
patient education3.
Pathogenesis of Diabetic Peripheral Neuropathy

There is an increasing understanding of the pathogenesis of diabetic neuropathy in recent
years, and new drugs that target the pathophysiological mechanisms are currently being
studied 4. The development and outcome of foot ulcers are related to the interplay between
numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and
microvascular and/or macrovascular disease.
100
As with other diabetic microvascular complications, such as retinopathy and nephropathy,

DPN is thought to result from multiple factors 5, 6.
Molecular studies have elucidated the sequence of events in the development of diabetic
peripheral neuropathy and identified several key pathways like protein kinase C (PKC),
advanced glycation end products, aldose reductase, polyol and hexosamine pathway. These
pathways are therefore potential therapeutic targets.
Putative mechanisms for the development of DPN include glycolysation of neural proteins,
microangiopathy, the development of neural autoantibodies, and ischemia from basement
membrane thickening of the nerve capillaries (vaso nervorum). Abnormalities of the polyol
pathway and defects in the metabolism of myoinositol and protein kinase C3 leading to
neuronal demyelination have also been described in DPN.
Peripheral neuropathy affects 30% of hospitalized and 20% of non-hospitalized individuals
with diabetes 7.
The pathophysiology of diabetic neuropathy includes increased oxidative stress yielding
advanced glycosylated end products (AGEs), polyol accumulation, decreased nitric oxide/
impaired endothelial function, impaired (Na+/ K+)-ATPase activity, and homocysteinemia.
Not only are nerve cells more likely to be destroyed in a hyperglycemic environment, but repair mechanisms are also defective. Reduced levels of neurotrophic agents, including nerve
growth factor and insulin like growth factor, have been noted in experimental diabetes 8.
(i) Oxidative Stress / Protein Glycosylation

In hyperglycemia, glucose combines with protein, yielding glycosylated proteins, which
when damaged by free radicals combine with fats producing AGEs that damage sensitive
tissues.
Enhanced production of reactive oxygen species (ROS) or defective scavenging of free
radicals results in increased oxidative stress in PN. Markers of oxidative stress include
plasma 8-iso-prostaglandin F2a, superoxide anion generation, and lag time peroxidation
by peroxynitrite.
(ii) Polyol Accumulation
Glucose passively diffuses into nerve cells without insulin. Inside the cell glucose is converted to sorbitol and other polyols by the enzyme aldose reductase. Because polyols do not
passively out of cells, they concentrate within neurons creating an osmotic gradient that
allows excess sodium and water to follow 9. In addition to osmotic effect, polyol-pathway
linked metabolic changes are involved. Fructose is also a byproduct of the polyol-pathway
activation via the sorbitol dehydrogenase-driven conversion of sorbitol to fructose. High
fructose levels result in increased AGE precursors, which is another source of oxidative
stress. Accumulation of sorbitol and fructose in nerve cells decrease (Na+/ K+)-ATPase
activity.
(iii) Nitric Oxide Deficiency / Impaired Endothelial Dysfunction:
The Arginine Connection
Nitric oxide plays an important role in controlling (Na+/ K+)-ATPase activity 10 a diminution of which has been implicated in the pathogenesis of PN. Hyperglycemia results in
an excess of endothelial superoxide radicals that result in reduced stimulation of NO on
(Na+/ K+)-ATPase activity, this activity is inhibited by L-arginine.
(iv) Hyperhomocysteinemia
Hyperhomocysteinemia is associated with impairment of endothelial function, providing a
mechanism for its possible involvement in diabetic complications, including neuropathy.
A synergistic effect is present between AGEs and homocysteine, resulting in endothelial
damage.
Therapeutic agents and vascularization techniques used to treat DPN are the following
Protein Kinase C Inhibitors

There is mounting evidence that protein kinase C (PKC) is a critical conductor in the
metabolic pathologies associated with diabetic neuropathy 11. PKC is an intracellular signaling molecule and activation of it plays an important role in the development of diabetic
complications 12.
It is a super family of 12 isoenzymes that can be classified into conventional PKC (cPKC),
novel PKC (nPKC), and atypical PKC (aPKC). Increased levels of glucose can cause an
increase in intracellular diacylglycerol (DAG), which activates PKC.
Hyperglycemia leads to activation of PKC 1 and 2 isoforms, which has been shown to
contribute to the development and progression of diabetic microvascular complications
(retinopathy, nephropathy, and neuropathy) through various biochemical mechanisms 13.
101
Preferential activation of the PKCb isoform by elevated glucose is reported to occur in

a variety of vascular tissues. There is overwhelming evidence indicating a role for PKC
activation in contributing to the development of diabetic vascular complications. Pharmacological therapies that can modulate this pathway, particularly with PKC isoform selectivity, show great promise for treatment of vascular complications, even in the presence of
hyperglycemia 14.
LY333531 (Ruboxistaurin) is being studied in Phase 3 trials for the treatment of diabetic
peripheral neuropathy and diabetic retinopathy - as well as diabetic macular edema, a
manifestation of diabetic retinopathy. LY333531 improved symptoms associated with diabetic peripheral neuropathy and underlying pathophysiology as measured by a composite
score of nerve function. These results demonstrate a correlation between the change in
symptoms and the change in nerve function. Based upon these results, we believe that
LY333531 may help treat, and repair, diabetic microvascular damage 15.
Aldose Reductase Inhibitors

Activation of the polyol pathway due to increased aldose reductase activity is one of the
several mechanisms that have been implicated in the development of various secondary
complications of diabetes 16. Oxidative stress leads to the generation of free radicals that
affects lipids present in the myelinated structures of nerves. Hyperglycemia induces an
increase in superoxide and peroxynitrite ions, and antioxidant defense moieties are reduced
in diabetic neuropathy 17.
102
The increased production of nitrates combines with reactive oxygen species to form peroxinitrate, which highly damages the nerves. The end-result of this oxidative/ nitrosative
assault is the loss of axons and disruption of the microvasculature in the peripheral
nervous system.
Inhibition of aldose reductase disrupts metabolic disturbances associated with the polyol
pathway and the pathology of diabetic complications. Therefore, it is reasonable to use
therapies that reduce oxidative and nitrosative stress 18.
Aldose reductase (AR) inhibitors have received considerable attention as potential treatments for diabetic neuropathy, and a number of them have been developed 19. Numerous
aldose reductase inhibitors, including alrestatin, sorbinil, tolrestat, ponalrestat, zopolrestat,
zenarestat, and lindolrestat, were investigated in the 1980s and 1990s, but they were
withdrawn from clinical trials secondary to adverse effects or lack of efficacy.
Recently, three aldose reductase inhibitorsepalrestat, fidarestat, and ranirestat have been
evaluated in placebo-controlled clinical trials 20. However, these agents have not achieved
worldwide use because of limited efficacy or unacceptable adverse effects.
Epalrestat (5-[(1Z, 2E)-2-methyl-3-phenylpropenylidene] - 4-oxo-2-thioxo-3-thiazolidineacetic acid) is a noncompetitive, reversible inhibitor of aldose reductase, an enzyme of
the polyol pathway. Although the polyol pathway may play a role in the development of
diabetic neuropathy, genetic factors should be considered. Genetic polymorphisms in the
5 end of the aldose reductase gene and variability in the expression of aldose reductase
have been observed in patients with diabetes.
Data from experimental studies indicate that epalrestat reduces sorbitol accumulation in
the sciatic nerve, erythrocytes, and ocular tissues in animals, and in erythrocytes in humans.
In one study, epalrestat was found to attenuate high glucose-mediated neutrophil-endothelial cell adhesion through inhibition of protein kinase C and stimulation of endothelial
nitric oxide production 21.
Epalrestat is currently the only aldose reductase inhibitor approved to treat subjective
and objective symptoms of diabetic neuropathy; however, it is approved only in Japan.
Epalrestat may serve as a new therapeutic option to prevent or slow the progression of
diabetic neuropathy. Future long-term, comparative studies in diverse patient populations
are needed for clinical application.
Fidarestat is a potent new aldose reductase inhibitor. Fidarestat treatment normalized the
elevated sorbitol content of erythrocytes under fasting as well as postprandial conditions.
Fidarestat is considered to be a potent and promising ARI, possibly useful for both preventing and treating diabetic neuropathy. Further studies are needed to clarify how much
the occurrence and progression of diabetic neuropathy is inhibited by normalizing sorbitol
elevation with fidarestat treatment 22.
Ranirestat previously known as (AS-3210) is the firstdrug to address the underlying cause
of diabetic sensorimotor polyneuropathy (DSP). In a multicenter, double-blind, randomized,
placebo-controlled study, significant improvement in the summed motor (peroneal, tibial,
and median) nerve conduction velocity (NCV) was observed. Treatment with ranirestat appears to have an effect on motor nerve function in mild to moderate DSP 23.
For people with diabetes and for those whom the exact cause of neuropathy is unknown
combination of nutrient therapies has eliminated the problem. Best results are achieved
with an approach that includes alpha-lipoic acid, gamma-linolenic acid, B complex vitamins,
acetyl-L-carnitine, methylcobalamine and the thiamine derivative benfotiamine.
Alpha-lipoic acid (ALA), also known as lipoic acid (or thioctic acid), is a sulfur-containing
fatty acid found inside every cell of the human body. Lipoic acid plays a key role in a
variety vital energy-producing reaction in the body that turns glucose into energy.
It is potent biological antioxidants that slows the oxidative damage in cells, and in many
cases stabilize or even reverse cell damage. It works on both water and fat-soluble free
radicals that cause oxidation and cell damage in the body. Alpha-lipoic acid increases
glucose uptake in the cells and reduces symptoms of diabetic complications including
cataract formation, vascular damage, and polyneuropathy.
Gamma linolenic acid (GLA) is an essential fatty acid found in borage oil, grape seed oil,
black currant oil, and evening primrose oil and it reverses nerve damage in diabetics suffering from peripheral neuropathy. In a double-blind, placebo-controlled study using 480
mg of GLA daily, all the diabetics given this fatty acid experienced gradual reversal of
nerve damage and improvement in the symptoms related to the peripheral neuropathy,
while those on placebo gradually worsened. GLA rebuilds the myelin sheath around the
nerves.
Methylcobalamin is the neurologically active form of vitamin B12. It has the unique
ability to provoke the regeneration of nerves without adverse side effects. B12 facilitates
methylation, the process that creates and maintains nerves and brain chemicals. High
doses of methylcobalamin have been used to treat degenerative neurological diseases in
rodents and humans.
103
Although a number of ARIs have been developed, none have achieved clinical success
for diverse reasons, one being that not all ARIs penetrate human peripheral nerves 24, 25.
Advance Glycation End Products Breakers

The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Many
experimental studies show that effects of AGE formation plays a role in the pathogenesis
of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired
wound healing. Several mechanisms have been proposed by which AGEs lead to diabetic
complications such as the accumulation of AGEs in the extracellular matrix causing aberrant
cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different
cell types and activation of key cell signaling pathways with subsequent modulation of
gene expression, and intracellular AGE formation leading to quenching of nitric oxide and
impaired function of growth factors 26.
Elevated levels of AGEs have been documented in the peripheral nerves of subjects with
diabetes. The AGE-RAGE axis is a likely mechanism linking microangiopathy and neuropathy,
and is supported by the colocalization of CML, RAGE, NF- B, and IL-6 to epineurial vessels, perineurium and endoneurial vessels. It has been demonstrated in murine models 27,
that AGEs worsen diabetic neuropathy by reducing sensorimotor conduction velocity and
decreasing blood flow to peripheral nerves.
The best found chemically characterized AGEs in humans are pentosidine and N-carboxy
methyl lysine (CML) 28. Evidence has shown that elevated skin pentosidine levels in individuals with DM correlates with the severity of the complications 29.
104
Currently, there are a number of ways to prevent or decrease glycation and glycationinduced tissue damage. Due to detrimental effects of AGEs, researchers attempt to find
inhibitors of the advanced glycation process 30. Although not in the area of neuropathy
or wound healing, recent clinical studies have shown that the AGE-breakers may be able
to decrease adverse vascular effects of glycation with few side effects.
There are a number of therapeutic strategies targeting the AGE pathway, some of which
are currently under experimental and/or clinical evaluation 31. They include:
Inhibition of AGE formation
Putative cross-link breakers
RAGE blockade
AGE clearance (and)
Reducing exogenous exposure
Agents that Reduce/ Inhibit AGE formation

Aminoguanidine [also known as Pimagedine (Alteon, Ramsey, NJ)] was one of the first
inhibitors of AGE formation studied32 and is acts as a nucleophilic trap for carbonyl intermediates. It prevents a range of diabetic vascular complications in animal studies.
Pyridoxamine is a derivative of vitamin B6. It prevents the degradation of protein-Amadori
intermediates to protein-AGE products 33, 34.
OPB-9195 is a thiazolidine derivative. It prevents the progression of glomerular sclerosis

and reduced urinary albumin excretion35 in association with decreases in renal TGF- and
VEGF expression36.
Methylene bis 4, 4-(-2 chlorophenylureido phenoxyisobutyric acid) (LR-90) has been investigated in a number of animal studies. LR-90 inhibits albuminuria and reduced serum
creatinine concentration and circulating AGE levels in diabetic rats without any effect on
glycemic control. LR-90 has recently inhibited S100b-induced expression of RAGE and other
proinflammatory genes in human monocytes.
Putative Cross-Link Breakers

Cross-link breakers cleave pre-formed AGE cross-links, thereby promoting their clearance
by the kidney and liver 37. Whether these agents are actually able to break AGEs crosslinks in vivo is controversial, but the prospect of reversing the AGE burden in a diabetic
patient with heavily modified proteins is extremely desirable.
The actions of the prototype putative cross-link breaker N-phenacylthiazolium bromide
(PTB) were first reported over 10 yrs ago. In in vitro experiments, PTB was shown to cleave
cross-links. Subsequently, it was shown in diabetic rat models to decrease tissue AGE accumulation 38.
Subsequently, a more stable derivative of PTB was generated, known as ALT-711 or alagebrium (3-phenyacyl-4, 5-dimethylthiazolium chloride). In a series of studies in various
models of diabetic complications, alagebrium was shown to confer end-organ benefits. With
respect to diabetic renal disease, alagebrium was shown to attenuate the development of
albuminuria in diabetic rats in association with modest effects on blood pressure and a
reduction in renal TGF- and collagen deposition.
Poly (ADP ribose) polymerase (PARP) inhibits glyceraldehyde-3-phosphate dehydrogenase,
resulting in increased AGE formation. PARP inhibitors have been used in animal studies,
resulting in improved neuropathy 39.
Benfotiamine has improved nerve conduction velocity in the peroneal nerve 40 in diabetic
patients, and a short 3-wk clinical study showed alleviation of painful neuropathy 41, but
long-term human data is still lacking.
Soluble Receptors
Another approach to intervene in AGE accumulation is via the soluble form of RAGE,
sRAGE. Soluble RAGE competes with cellular associated RAGE receptors for AGE binding
and thereby reduces endogenous activation. Several studies have shown that soluble RAGE
is able to modify AGE-mediated activation of pathways implicated in the development of
diabetic complications.
Newer Revascularization Techniques

Diabetic foot wounds affect an estimated 15% of all patients with diabetes. These wounds
are typically multifactorial in origin. Neuropathy of the foot and impaired wound healing are frequently associated with peripheral arterial occlusive disease. Successful wound
healing and limb salvage requires prompt recognition and treatment 42. When associated
with significant ischemia, diabetic foot ulcers require arterial revascularization to achieve
wound healing.
105
Patients with diabetes mellitus have an increased incidence of atherosclerotic vascular

disease and infection involving the lower extremities. Two types of vascular disease are
seen in patients with diabetes 43-46. The first is a nonocclusive microcirculatory dysfunction involving the capillaries and arterioles of the kidneys, retina, and peripheral nerves.
This microvascular abnormality is relatively unique to diabetes and most likely contributes
to the eye (retinopathy), kidney (nephropathy), and nerve (neuropathy) complications of
diabetes. The second type of diabetic vascular disease is macroangiopathy.
Lower limb revascularization is indicated to prevent limb loss in patients with leg ischemia.
Three methods for revascularization are employed by the vascular surgeons. The first is
arterial bypass, especially distal bypass. The second is endovascular interventional therapy,
including percutaneous transluminal angioplasty (PTA) with or without stenting. The last
one is transplantation of autologous stem cells.
Arterial bypass includes anatomical bypass and extra-anatomical bypass. Over the past
three decades, bypass grafting has become the standard method for femoropopliteal-distal
artery repair.
Proximal bypass to popliteal or tibial-peroneal arteries may restore foot pulses. However,
bypass grafting to the popliteal or even tibial arteries cannot reach this goal due to a more
distal obstruction. Similarly, although excellent results have been reported with peroneal
artery bypass 47, the peroneal artery is not in continuity with the foot vessels and may
not achieve maximal flow, especially to the forefoot, to achieve healing 48.
Femoro-popliteal bypass has achieved wide acceptance in limb salvage surgery for arteriosclerotic occlusive disease 49, 50. Autogenous vein grafting to the dorsalis pedis artery
represents a technical advance that provides durable and effective limb salvage 51.
106
A decade ago, percutaneous transluminal angioplasty (PTA) of the lower limb artery had
limited application as a primary revascularization strategy for patients with critical limb
ischemia (CLI). However, at present, PTA has become a feasible, safe, and effective procedure
for the treatment of diabetic lower limb ischemia. In a report by Willenberg et al 52, the
successful rate of infrapopliteal artery PTA was 93.8% and the limb salvage rate was 88.1%.
It is difficult to treat patients with poor arterial outflow or with a poor general condition.
The effect of medical treatment alone is far from ideal, especially in patients with diabetic
foot. A high percentage of amputation is inevitable in those patients 53.
Neovascularization is the result of several processes, including angiogenesis, arteriogenesis,
and potentially, vasculogenesis. In adults angiogenesis is stimulated mainly by tissue hypoxia via activation of hypoxia-inducible factor (HIF)-1 expression. Vasculogenesis is the
process of an in situ formation of blood vessels from circulating endothelial progenitor
cells (EPCs) and vascular progenitor cells.
Recently, there have been some reports of the successful use of vascular progenitor cells
from autologous bone marrow cells 54-56 to treat diabetic lower limb ischemia. Autologous
bone marrow mononuclear cell transplantation is effective in alleviating symptoms in
lower limbs with critical ischemia. This technique is one of the effective methods for the
treatment of diabetic lower limb ischemia, especially in those who could not undergo
arterial bypass graft surgery or angioplasty due to poor run-off or their poor general
medical condition.
Following successful revascularization secondary procedures may be performed for both

limb and foot salvage. Chronic ulcerations may be treated by ulcer excision, orthroplasty,
or hemiphalangectomy 57.
The use of endovascular therapy (EVT) for lower extremity atherosclerosis is markedly
increasing while open surgical bypass is in decline. The results of EVT for critical limb
ischaemia (CLI) are difficult to evaluate, especially for patients with diabetes. Approximately, 4050% of diabetic patients with CLI can be initially treated with EVT. The primary
therapeutic goals are relief of rest pain, healing of ischaemic lesions, and maintenance of
functional status. Haemodynamic assessment is critical following both open and EVT for
CLI and aids in determining the need for further revascularization; additional interventions
are required in 2030% of CLI patients depending on the degree of ischaemia, anatomical
disease extent, and mode of initial therapy 58.
Management of DPN
The maintenance of near-normal glycaemic equilibrium seems currently to be the best
way not only to prevent PDN but also to treat it. It must be remembered that there are
numerous causes of peripheral neuropathy, of which diabetes is probably the most common. The management of the disease is complex, and the key to success depends partly on
discovering the underlying pathological processes in each particular clinical presentation.
Any patient with diabetic neuropathy should be considered to be at potential risk of foot
ulceration or injury and should receive preventive education and referral to a podiatrist
as necessary. Optimal treatment time requires good control of blood sugar, managing
symptoms, and fastidious attention to foot care.
Future Recommendations
A Multidisciplinary approach that embraces patient education and motivation, preventive
measures, vigilance for risk factors, and utilization of the most effective therapeutic options
is recommended. In the near future more clinical trials are needed to assist in identifying
an efficacious treatment for PDN.
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110
Diabetic Retinopathy: With Special

Reference to Fundus Photography
Dr T K Ramesh
Ramesh Eye Clinic and Ophthalmic Micro Surgical Centre
26, Sajjan Rao Road, V.V. Puram,
Bangalore-560004.
e-mail: drramesh57@hotmail.com
Ph: 93412 53121

111
Summary
The incidence of diabetes mellitus and hence diabetic retinopathy related blindness is
increasing. Laser treatment at the appropriate early stages prevents or postpones vision loss. Effective and large scale programs are being used for the early diagnosis of
patients at risk of vision loss. Fundus photography is useful for this purpose. Intraocular
injections, especially the anti VEGF drugs, have been shown to be beneficial in diabetic
maculopathy. Systemic factors affecting the course of Diabetic Retinopathy should not
be neglected. All health care providers should be aware of these developments to guide
their diabetic patients.
Introduction
Diabetes mellitus is projected to affect about 438 million people by 2030 AD. Diabetics
are at special risk of blindness because of Diabetic Retinopathy (DR) in addition to other
diseases like Cataract and Glaucoma. Globally DR is one of the frequent causes of preventable blindness. In India Diabetic retinopathy as a cause of blindness has ascended to
the 6th position from the 17th position. We will look at innovative public health programs
initiated for mass screening for DR, fundus photography and high speed long distance image transmission and discuss the current use of anti Vascular Endothelial Growth Factors
(VEGF) drugs in the management of DR.
Current and Future Screening Procedures for DR

Need for screening
112
DR is a leading public health problem. It is asymptomatic in majority of patients. LASER

photocoagulation is a proven and effective modality for the prevention or postponement of
vision loss in DR and has to be used in the appropriate early stages. In order to prevent
blindness the DR has to be diagnosed in the early stages before it becomes symptomatic in
the form of vision disturbance due to Diabetic Maculopathy, Vitreous hemorrhage, Retinal
detachment or Neovascular glaucoma and hence we need screening programs to identify
patients at risk of blindness.
Challenges in Screening for DR

Screening for DR is hindered by several factors related to patients, health care providers,
skilled manpower, equipment, and public health policies.
Patients at risk of blindness due to DR are asymptomatic in the early stages of the disease.
Majority of such patients are not aware that diabetes can cause blindness. Even if they
are aware of the risk of blindness they may not fully appreciate the need for periodic eye
examination and proper control of all systemic factors which influence the retinal condition. Paramedical staff involved in the care of the systemic condition of diabetics are
too busy to spend time regarding DR. This situation is changing with the development of
institutes dedicated for diabetic care where trained health educators using modern audio
visual aids help in convincing the patients about eye care.
There is a shortage of skilled manpower for conducting retinal examination. A large number
of paramedical ophthalmic assistants or optometrists are being trained in several institutions. They are being trained in slit lamp examination and indirect ophthalmoscopy.
Refractionists who attend to patients giving spectacles were not discussing about DR with
their patients. Many patients seek the advice just for glasses rather than a complete eye
examination. Such refractionists who can not do a retinal examination are being educated
to refer all diabetics to an ophthalmologist for retinal examination.
General medical practitioners and medical officers who see diabetic patients are good first
line medical contacts for diabetics but because these doctors are busy with so many
systemic problems to take care , DR does not take the importance what it deserves. In
addition they do not have access or training to use the slit lamp and ophthalmoscope.
Similar situation exist for diabetologists. Dilation of pupil is a must if one does not want
to miss DR. Unfortunately narrow angle glaucoma is a common condition in the age group
where DR is common. It will be disastrous if such eyes receive mydriatics. Such patients
have to be identified by slit lamp examination and gonioscopy before dilating drops are
instilled into the eye. This facility is not available in all diabetic clinics.
The Answer to these Challenges

The challenges to screening for DR are being met in various ways. Health education by all
routes is being taken to make the general public, patients and paramedical staff regarding
DR and the importance of screening even if patients are asymptomatic.
Health check up camps: Most general health check up camps State, NGO or industry
sponsored now includes an ophthalmologist to screen for DR. Diabetic Institutes have
dedicated eye department with a trained retina specialist to screen for and treat DR.
Importance of DR is stressed for all medical students as also general medicine and ophthalmology Post graduates. General ophthalmologists are encouraged through CME programs
to Screen all potential patients for DR. Even if they are asymptomatic.
The recent developments in screening for diabetics are the use of Digital fundus photography; mobile vans and high speed image transmission have been highly successful in
overcoming the challenges. Portable Non- mydriatic digital fundus cameras are available.
Trained technicians are obtaining the fundus photographs of diabetics. Since they are not
fully trained to take management decisions the images are transmitted to a base hospital
where a trained retina specialist will review the images and advise each patient appropriately though the patient is several hundred kilometers away. This is extremely helpful
because this large number of diabetics need not travel to the base hospital for screening.
Further tests and advised can be tailored to the needs of the individual patients. Since
all photographs are stored in an economical digital format it is easy to classify, store and
retrieve them periodically. These photographs are useful to explain the condition to patients and to educate every one both public and all levels of medical staff. The large
number of Digital fundus photos collected and documenting how the retinal condition
has changed will be extremely useful for research in all aspects of DR.
Optical Coherence Tomography (OCT)

Is another advanced non invasive imaging technique which has become an integral part of
assessment and management of DR particularly Diabetic Maculopathy. Macular edema is
now classified based on OCT findings and is useful in deciding about the need for intraocular injections. The patterns noticed on OCT in diabetic macular edema are:
113
Focal macular edema.
Diffuse macular edema.
Cystoid macular edema.
Macular edema with subretinal fluid.
Macular edema with vitreomacular traction but without Traction Retinal Detachment.
Macular edema with vitreomacular traction and with Traction Retinal Detachment.
OCT thus gives live noninvasive images of retina nearing that of histological sections taken
after biopsy and selection from the list of treatment options like medical treatment, LASER,
Intravitreal injections, Surgery etc. has become more scientific.
Digital Fundus fluorescein angiography is still useful in the diagnosis and management of
Diabetic retinopathy. It gives us the vascular status of the fundus. In view of the risks
of anaphylactic reactions to Intravenous Fluorescein injections the non invasive and in
many ways more informative OCT imaging is being used more and more.
114
Advanced Diabetic Maculopathy with Severe Hard Exudates at the Fovea Centralis.
Advanced Proliferative Diabetic Retinopathy with Traction

Retinal Detachment and hemorrhage.
115
Clinically Significant Macular Edema,

Macular Hard Exudates and Leakage on Fluorescein Angiography

Fluorescein Angiography Demonstrates Extensive

Areas of Capillary Non Perfusion and Macular Edema
116
Fundus Photograph and fluorescein Angiography showing Macular hard exudates.
PDR. Optic Disc Neovascularization and Clinically Significant

Macular Edema.Fluorescein Angiograph
117
Proliferative Diabetic Retinopathy (PDR),Macular hard exudates,

Neovascularization on the Optic di

Proliferative Diabetic Retinopathy, Severe Optic Disc Neovascularization.

Patient can be asymptomatic
118
Role of Intraocular Injections in DR

The diabetic retinopathy study and the early treatment diabetic retinopathy study clearly
established the beneficial effects of LASER treatment in appropriate stages of both proliferative DR and diabetic maculopathy and is still the major weapon in the management
of most of the cases of DR, but there are several situations where LASER treatment
alone will not be sufficient. Vascular Endothelial Growth Factors (VEGF) are now proved
to play a vital role in the development of both diabetic maculopathy and Proliferative
Diabetic Retinopathy (PDR). Anti VEGF drugs are a logical extension of this knowledge
in the treatment of DR. Several anti VEGF drugs have been studied systematically and
they are now being used extensively in the management of DR. These include pegaptanib
(macugen; Pfizer, Inc., USA.), ranibizumab (Lucentis; Genentech, Inc., Sanfrancisco USA) and
bevacizumab (Avastin; Genentech, Inc).
Pegaptanib sodium is apegylated RNA aptamer directed against the VEGF-A165 isoform.
Intra vitreal injection of pegaptanib 0.3 mg has been shown to reduce central retinal
thickening and also reduce the need for additional Photocoagulation in diabetic macular
edema. It has also been shown to revert diabetic retinal neovascularization rapidly.
Ranibizumab is a recombinant humanized monoclonal antibody fragment with specificity
for all isoforms of human VEGF-A. Intra ocular injection of Ranibizumab has been shown
to reduce macular thickness in diabetic macular edema. Phase III trials - the RISE study and
the RIDE study will provide more definitive data regarding its usefulness in the long run.
Bevacizumab is a recombinant full-length humanized monoclonal antibody active against

all isoforms of VEGF-A. The lower cost and ease of availability has made it the most vigorously studied anti VEGFmedication for Diabetic Macular Edema. Intravitreal injections
of 1.25mg. has been shown to reduce macular edema and improve vision in Diabetic
maculopathy.
Intravitreal injections of Bevacizumab have also been shown to be beneficial in proliferative diabetic retinopathy in several case series reports. The beneficial effects include rapid
regression of vitreous hemorrhage and retinal neovascularization, reducing the need for
vitrectomy, and regression of iris neovascularization. Cases of rebleed following LASER pan
retinal photocoagulation have also been helped by this injection. It can also be used as
an adjuvant to vitrectomy.
Intravitreal Triamcinolone injections 4mg has been used to treat diabetic macular edema.
Though it is an inexpensive drug the risks include development of glaucoma and cataract.
Disadvantages of intraocular injections: The long term safety and efficacy of these intravitreal injections need to be studied further. The potential complications to such injections
include endophthalmitis, retinal detachment, cataract, glaucoma, etc. Intravitreal injection
of bevacizumab may have some relation to cases of stroke or myocardial infarction or acute
rise of blood pressure reported after such injections and care has to be taken regarding
such risks. It is reported that patients often require repeated injection of antiVEGF drugs
which makes the procedure so much more expensive, inconvenient and risky. Intraocular implants of dexamethasone have been developed to eliminate the disadvantages of
repeated injections and to achieve long term efficacy but will need a surgical procedure.
Systemic Drugs and Status of Systemic Condition in the Management of

Undoubtedly treatment of the several factors which have an influence on diabetic retinopathy is vital in the overall management of DR. Long-term good control of the glycemic status is shown to be beneficial in reducing the risk of blindness but patients should
not expect that the retinal changes and visual symptoms will revert to normal just by
control of the glycemic status. This should not lead to neglect of glycemic control. It
is vital to reduce and maintain proper serum lipid profile with diet, exercise or systemic
drugs especislly in patients with significant hard exudates in the macula. Attention to
maintaining proper renal function is extremely important especially in patients with diffuse macular edema. Similarly the control of hypertension and correction of anemia due
to renal involvement or other causes is an integral part of the management of DR which
should not be forgotten.

119
References
1.
American Diabetes Association: All about diabetes [article online]. Available from http://www.diabetes.org/
about-diabetes.jsp. Accessed 22 Oct 10
2.
Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM, Saydah SH, Williams DE, Geiss
LS, Gregg EW: Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population:
3.
National Health and Nutrition Examination Survey 19992002. Diabetes Care 29:12631268, 2006
4.
Hee MR, Puliafito CA, Wong C, et al. Quantitative assessment of macular edema with optical coherence
tomography. Arch Ophthalmol 1995; 113:1019298.
5.
Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomography of central serous chorioretinopathy.
Am J Ophthalmol 1995; 120:6574.
6.
Wilkinson CP, Ferris FL III, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic
macular edema disease severity scales. Ophthalmology 2003; 110: 167782.
7.
Age-Related Eye Disease Study Research Group. The Age- Related Eye Disease Study (AREDS) system for
classifying cataracts from photographs: AREDS report no. 4. Am J Ophthalmol 2001; 131:16775.
8.
Funatsu H, Yamashita H, Sakata K, et al. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology 2005; 112:806 16.
9.
Takahashi H, Shibuya M. The vascular endothelial growth factor (VEGF)/VEGF receptor system and its role
under physiological and pathological conditions. Clin Sci (Lond) 2005; 109(3):227 41.
10. Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of Pegaptanib,
an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005;
112:174757.
120
Diabetic Kidney Disease:

Clinical Manifestation, Diagnosis & Treatment
Dr D Maji
Prof. & Head Department of Medicine

Vivekananda Institute of Medical Sciences, Kolkata.
&
Dr Semanti Chakrabarty
Resident, Department of Medicine

Vivekananda Institute of Medical Sciences, Kolkata.

Diagnosis and Treatment
121
Introduction
India is facing a major health care burden due to the high prevalence of type 2 diabetes
and there are indications that this would increase further in the next few decades. Diabetes is preventable and so are its complications. One such microvascular complication of
diabetes is diabetic nephropathy. Nonetheless attention towards diabetic nephropathy is not
directed until the patient has progressed towards the stage of renal failure. Nephropathy
due to diabetes can be diagnosed very easily and can be prevented. Diabetes mellitus
causes considerable morbidity and mortality due to micro and macro vascular complications. One such complication is diabetic nephropathy which causes chronic renal failure in
30% of diabetic patients in India. Early diagnosis and detection of risk factors for diabetic
nephropathy is important step for prevention of diabetic nephropathy. Indias national
CKD registry organized under the auspices of Indian society of nephrology has given data
from 45,885 subjects admitted to 166 kidney centres in India up to January 2010.It is
noted that CKD secondary to diabetes heads the list at 31.2%.Overt diabetic nephropathy
is characterized by persistent albuminuria (>300mg/24hr or >200g/min) on at least 2
occasions separated by 3-6 months. This is equivalent to total proteinuria >500mg/24hrs.
Diabetic nephropathy is clinically defined by the presence of persistent proteinuria of > 500
mg/day in a diabetic patient who has concomitant diabetic retinopathy and hypertension
and in the absence of clinical or laboratory evidence of other kidney or renal tract disease.
122
Racial differences in the prevalence of diabetic renal disease have been reported. Asian
subjects have significantly (p < 0.01) higher prevalence (52.6%) of diabetic end stage
renal disease (ESRD) when compared with the Caucasians (36.2%). Migrant Asian Indians
had 40 times greater risk of developing ESRD when compared with the Caucasians. The
prevalence of diabetic nephropathy in type 2 diabetic subjects is reported to be 5-9%
from various Indian studies. Patients with diabetic nephropathy, especially with type 2
diabetes, have a high cardiovascular risk. The risk for cardiovascular disease (CVD) was 3
fold higher in South Indian NIDDM subjects with nephropathy when compared with their
non-nephropathic counterparts. Thus, in type 2 diabetes, many patients may not reach
end stage renal disease due to premature death from CVD.
The exact cause of diabetic nephropathy is unknown, but various mechanisms postulated
are hyperglycemia (causing hyperfiltration and renal injury), AGE and activation of cytokines. Hyperglycemia increases the expression of transforming growth factor beta (TGF)
in the glomeruli and of matrix proteins specifically stimulated by this cytokine. TGF may
contribute to both the cellular hypertrophy and enhanced collagen synthesis observed in
diabetic nephropathy. In a study from southern India, it was shown that TGF- 1 levels
are elevated in type 2 diabetic subjects. Treatment with insulin and angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) appears to decrease the
levels of TGF- 1. Hyperglycemia also may activate protein kinase C, which may contribute
to renal disease and other vascular complications of diabetes. In addition to the renal hemodynamic alterations namely decreased glomerular filtration rate and renal plasma flow,
patients with overt diabetic nephropathy (dipstick positive proteinuria and decreasing GFR)
develop systemic hypertension.
Hypertension is an adverse factor in all progressive renal diseases and seems especially so
in diabetic nephropathy. The deleterious effects of hypertension are directed at the macro
and microvasculature.
Genetics
Familial factors may play a role in the development of diabetic nephropathy. Certain ethnic
groups, particularly American blacks, Hispanics, and Native Americans, may be particularly pre disposed to renal involvement as a complication of diabetes. It was found that
proteinuria was present in 50% and microalbuminuria in 26.7% of the diabetic siblings
of probands with diabetic nephropathy. In contrast, the prevalence of proteinuria and
microalbuminuria among diabetic siblings of probands with normoalbuminuria was 0%
and 3.3% respectively (P=0.057 for microalbuminuria). Some evidence has suggested that
polymorphism in the gene for the angiotensin-converting enzyme contributes in either
predisposing to nephropathy or accelerating its course. In a study from south India18, it
was shown that a positive association exists between the Dallele (ID and DD genotype) of
the ACE polymorphism and proteinuria in South Indian type 2 diabetic patients. However,
definitive genetic markers have yet to be identified.
Evaluation of Diabetic Kidney Disease

One of the earliest changes of renal function in diabetes is an increase in GFR, or hyperfiltration which is observed in many patients with type 1 diabetes and in a lower
percentage of those with type 2 diabetes. The next observable change is development of
microalbuminuria. Persistent microalbuminuria as noted by repeated testing is associated
with changes in both glomerular structure (mesangial expansion and basement membrane
thickening) and permeability and thus is sometimes referred to as incipient nephropathy.
These changes occur in 30-50% of patients with type 1 diabetes within 5-10 years after
onset of diabetes and may be present in 20 to 30% of those with type 2 diabetes at initial diagnosis, presumably because considerable duration of undiagnosed diabetes. Diabetic
patients with persistent microalbuminuria are at markedly increased risk of developing
overt DN, which is heralded by development of proteinuria about 15 years after disease
onset. This progresses to proteinuria in nephrotic range, hypertension and progressive renal
insufficiency.
Diabetic patients with microalbuminuria (MAU) are at a high risk for developing overt
nephropathy and cardiovascular complications. Early screening for MAU in diabetic patients
allows for aggressive intervention with a view to prevent ESRD.
Measurement of Albuminuria or Proteinuria

The main advantage of searching for microalbuminuria early in course of diabetes is that
it predicts a high renal risk and thus allow targeted intervention.80% of patients with
type 1 diabetes with microalbuminuria go on to develop clinical nephropathy. In people
with type 2 diabetes the proportion is closer to 40%. It also predicts a high cardiovascular
risk. The ADA and NIH recommend annual assessment of urine albumin excretion to assess kidney damage in all people with type 2 diabetes and people who have had type 1
diabetes for 5 years or more.
Table 1: Urinary Albumin Excretion Rate (UAER)
Condition
normoalbuminuria
microalbuminuria
24 hr (mg/day)
>30
30-300
Overt nephropathy
>300
123
Management of Diabetic Nephropathy

The major therapeutic approaches for diabetic nephropathy are
a) Intensive glycemic control
b) Antihypertensive treatment with a particular focus on agents that interrupt the RAS
c) Restriction of dietary protein
People with diabetes should have their HbA1c measured at least twice a year. Target
HbA1c <6.5. They should work with health care provider regarding optimal treatment of
diabetes with insulin/oral hypoglycemic, meal planning, physical activity and blood glucose
monitoring.
Table 2: Stages of Diabetic Kindney Diseases
Stage
Normoalbuminuric /
normotensive
Assessment
Screen yearly for
microalbuminuria. Assess
cardiovascular risk factors
Persistent microalClose monitoring of lipids,

buminuria / normotensive BP, glycaemic control and
urinary albumin excretion
Persistent
Follow urinary albumin
excretion, creatinine
microalbuminuria /
clearance, BP
hypertensive
124
Management
Optimize glycaemic control.
Target HbA1c<6.5. Systolic BP
target<130 mmHg. Add lipid
lowering agent
Add ACE inhibitor or ARB
Titrate ACEI or combine with

ARB. Aim for BP<130/80.
Consider addition of a diuretic
and low sodium diet
Monitor urinary protein, BP, Aggressive BP control. Aim for
lipids, creatinine clearance
BP<125/75mmHg.Add lipid
lowering drug, low protein diet
Prepare for dialysis or
Initiate dialysis when GFR is 10transplant
12ml/min(usually equating to
a creatinine clearance of <15
ml/min or serum creatinine>6
mg/dl
Proteinuria(>1g/24hrs)
Declining glomerular
filtration rate
Glycemic Control
In both type 1 and type 2 diabetes, hyperglycemia has been shown to be a major determinant of progression of diabetic nephropathy. Several studies, including the Diabetes Control
and Complications Trial, have indicated that intensified glycaemic control slows the rate
of development of both microalbuminuria and overt proteinuria in patients with type 1
diabetes without albuminuria. For patients with type 2 diabetes, there are two long term
studies comparing large numbers of patients, which document the positive effect of improved glycaemic control on the manifestation of microalbuminuria and macroalbuminuria.
Hypertension Control
Hypertension is one of the most important factors that accelerate the progression of
diabetic renal disease. Various drugs such as the -blockers, -blockers, calcium channel
blockers, ACEI and ARB are available to target hypertension. But the key to initiate treatment is not to get everyone to one particular class of drug, but to treat effectively with the
best drug for individual patients. Even though -blockers, -blockers and calcium channel
blockers remain important anti-hypertensive agents in diabetic patients, they should be
considered as third line drugs in combination with ACEI and ARB. Studies like HOPE19,
Steno20 and BRILLIANT studies have demonstrated the effectiveness of ACEI in terms of
reducing albumin excretion rate independent of their blood pressure lowering capacity.
Recently, the IRMA22 and the IDNT23 trials conducted respectively in microalbuminuric and
nephropathic type 2 diabetic subjects have shown that treatment with ARB (Irbesartan) is
renoprotective and slows the progression of glomerulopathy. This protection is independent
of reduction in blood pressure with minimal drug specific serious adverse events. The IRMA
trial showed that treatment with Irbesartan reduced the number of patients attaining the
primary end-point of developing overt nephropathy. This reduction was dose dependent,
Irbesartan 300 mg (5.2%) showing more beneficial effect than irbesartan150 mg (9.7%)
and the placebo group (14.9%). Similarly the IDNT trial showed that the risk of developing
the primary end-point (doubling of serum creatinine and onset of ESRD) in the Irbesartan
300 mg group was 20 times lower than the placebo group and 23 times lower than the
Amlodipine treated group. Irbesartan was found to be renoprotective, independent of its
beneficial effect in lowering 24-hour blood pressure in patients with type 2 diabetes and
persistent microalbuminuria, in a sub-study of the IRMA 2 trial 4. In a recent study by
Herman et al., it was shown that treatment with losartan in type 2 diabetic patients with
nephropathy reduced the incidence of ESRD and resulted in decrease in cost associated
with ESRD. Losartan significantly reduced the number of days with ESRD over 3.5 years
when compared with the placebo and conventional therapy group.
125
Conclusion
Diabetes is the leading cause of chronic kidney disease and kidney failure. People with
diabetes should be screened regularly for kidney disease by measuring eGFR and urinary
albumin excretion. Drugs used to lower blood pressure can slow the progression of kidney
disease significantly. ACEI and ARBs have proven effective in this respect. Intensive management of blood glucose has shown great promise for people with diabetes, especially
for those in early stages of chronic kidney disease.
Various studies conducted have shown that the major pathogenic features associated with
diabetic nephropathy namely atherosclerosis demonstrated as increased carotid intimal
media thickness, endothelial dysfunction (increased endothelin levels and abnormal flow
mediated dilatation) and non-dipping of blood pressure occurs at the stage of normoalbuminuria itself. Only worsening of these parameters occurs at the stage of nephropathy.
Intervention at the stage of normoalbuminuria might help in a great way to prevent
diabetic nephropathy.

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Es LA. Increased end-stage diabetic nephropathy in Indo-Asian immigrants living in the Netherlands. Diabetologia 2002; 45: 337-341.
6.
John L, Sundar Rao PSS, Kanagasabapathy AS.Prevalence of diabetic nephropathy in non-insulin dependent
diabetics. Indian J Med Res. 1991; 94: 24-29.
7.
Chugh KS, Kumar R, Sakhuja V, Pereira BJ, Gupta A. Nephropathy in type 2 diabetes mellitus in Third World
Countries. Chandigarh Study. Int. J. Artif. Organs 1989; 12: 299
8.
Acharya VN, Chawla KP. Diabetic Nephropathy: A review journal of post-graduate medicine. 1978; 24(3):
138 146.
9.
Viswanathan V, Snehalatha C, Terin Mathai, Muthu Jayaraman, Ramachandran A. Cardiovascular morbidity

in proteinuric South Indian NIDDM patients. Diabetes Res Clin Pract 1998; 39: 63 - 67.
10. Doi T, Vlassara H, Kirstein M et al. Receptor specific increase in extracellular matrix production in mouse
mesangial cells by advanced glycosylation end products is mediated via platelet derived growth factor. Proc
Natl Acad Sci USA 1992; 89: 2873 7.
11. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end-products in tissue and the biochemical basis
of diabetic complications. N Engl J Med 1988; 318: 1315 21.
126
12. Esposito C, Gerlach H, Drett J, Stern D, Vlassara H. Endothelial receptor-mediated binding of glucose modified albumin is associated with increased monolayer permeability and modulation of cell surface coagulant
properties. J Exp Med 1992; 170: 1387 407.
13. Bucala R, Tracey KJ, Cerami A. Advanced glycosylation products quench nitric oxide and mediate defective
endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 1991; 87: 432 8.
14. Vijay V, Snehalatha C, Mamtha B Nair, Ramachandran A. Markers of endothelial dysfunction in hyperglycaemic Asian Indian subjects. Journal of diabetes complications 2004; 18: 47 52.
15. Mamtha B Nair, Vijay Viswanathan, Snehalatha C, Suresh Mohan R, Ramachandran A. Flow mediated dilatation and carotid intimal media thickness in South Indian type 2 diabetic subjects. Diabetes Research and
Clinical Practice 2004; 65: 13 19.
16. Vijay V, Snehalatha C, Mamtha B Nair, Kumutha R,Ramachandran A. Levels of transforming growth factor
beta 1 in south Indian type 2 diabetic subjects (Unpublished data).
17. Vijay V, Snehalatha C, Shina K, Lalitha S, Ramachandran A. Familial aggregation of diabetic kidney disease
in Type 2 diabetes in South India. Diabetes Research and Clinical Practice, 1999; 43: 167-171.
18. Vijay Viswanathan, Yanqing Zhu, Karthik Bala, Stephen Dunn, C.Snehalatha, A.Ramachandran, Kumar Sharma.
Association between ACE gene Polymorphism and diabetic nephropathy in South Indian patients. JOP.J.
Pancreas (Online) 2001; 2(2): 83 87.
19. Gerstein HC, Yusuf S, Mann JFE, Hoogwerf B, Zinman B, Held C et al. Effects of ramipril on cardiovascular
and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE
sub study. Lancet 2000; 355: 253 259.
20. Gaede P, Vedel P, Jensen GVH, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease
in patients with type 2 diabetes. N Engl J Med 2003; 348: 383 393.
21. Agardh CD, Garcia Puig J, Charbonnel B, AngelKort B,Barnett AH. Greater reduction of urinary albumin
excretion in hypertensive type 2 diaebtic patients with incipient nephropathy by lisinopril than by nifedipine.
J Hum Hypertens 1996; 10: 185 192

22. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33.
Lancet 1998; 352: 837 53.
23. Hans-Henrik Parving, Hendrik Lehnert, Jons Brochner- Mortensen. The effect on Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes mellitus. NEJM 2001: 345; 870 878.
24. Edmund J. Lewis, Lawrence G Hunsicker, William R Clarke et al. Renoprotective effect of the angiotensin
receptor antagonist Irbesartan in patients with nephropathy due to type 2 diabetes mellitus. NEJM 2001:
345: 857 859.
25. Herman WH, Shahinfar S, Carides GW, Dasbach EJ Gerth WC, Alexander CM et al. Losartan reduces the costs
associated with diabetic end-stage renal disease. Diabetes care 2003; 26: 683 687.
26. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Executive Summary. New York, 2002; pp. 78 81.
27. Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. The
Seventh Report of the JNC on prevention, detection, evaluation and treatment of high blood pressure,
JAMA 2003; 289: 2560 72.
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and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995; 44: 968-983.
29. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long term results of the Kumamoto study on optimal diabetes
control in type 2 diabetic patients, Diabet Care 2000; 23 (2): B21 9.
30. UK Prospective Diabetes Study Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33.
Lancet 1998; 352: 837 53.
31. American Diabetes Association: Clinical Practice Recommendations: Diabetes Care 2002; 25 (Suppl l):85 89.
32. Viswanathan V, Snehalatha C, Varadharani MP, Nair BM, Jayaraman M, Ramachandran A. Prevalence of
albuminuria among vegetarian and non-vegetarian south Indian diabetic patients. Indian J Nephrol 2002;
12: 73 76.
33. Vijay V, Snehalatha C, Mamtha B Nair, Ramachandran A. Comparative assessment of cystatin C and creatinine
for determining renal function. (Unpublished data).
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various types of nephropathy. Pharmacol Res. 2004; 49293 8.
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Disorder 2003; 3: 301 7
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onMRNA levels for extracellular matrix components and diabetic glomeruli. Diabetes 44; 895 899: 1995.
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146 9.

127
Neuropsychiatric Screening in T2DM

128
Dr Sailesh Lodha
Senior Consultant & In charge Endocrinology & Diabetes

Fortis Escorts Hospital, JLN Marg, Jaipur-302017.
Ph- +91-141-2547000. cell- +91-9829019055
Introduction
In a chronic disorder like diabetes treatment adherence is major challenge. Poor compliance could be due to various reasons among which neuropsychiatric problems are an
important issue.
Assessing a diabetic in toto includes psychosocial status. Neuropsychiatric screening should
include patients attitudes about illness, expectations from the treating physician and hospital. Quality of Life, affects mood available financial, emotional and social support.
Neuropsychiatric issues in diabetes have a significant influence on patient outcomes and
quality of life.
It is common for patients to experience emotional distress from living with diabetes and
the effect of its complications. Diabetes Burnout and diabetes Overwhelmus are the
terms have been used to display the distress of diabetes.
Schizophrenia and Diabetes

Schizophrenia is an independent risk factor for diabetes. Development of glucose intolerance, diabetes and ketoacidosis is reported with atypical antipsychotics. Patients with
schizophrenia are more likely than general population to be overweight or obese. Antipsychotics contribute to weight gain. Structured weight control and exercise programs
can yield good results.
Depression in Diabetics
Patients with diabetes and depressive symptoms have mortality rates nearly twice as high
as persons with diabetes and no depression. Depression may be due to biochemical changes
of diabetes like hyperglycemia, inflammation, activation of hypothalamic -pituitary -adrenal
axis or it could be due to the life style factors associated with diabetes. Also neurohormonal changes induced by depression like hypercortisolism can lead to insulin resistance
and diabetes. Behavioral factors associated with depression, including lack of physical
activity and poor diet, increase the risk of diabetes. All diabetics should be screened annually for depression. Two simple two questions mentioned below, help in screening the
patients and it is clinically effective.
1. During the past month, have you often been bothered by feeling down, depressed
or hopeless?
2. During the past month, have you often been bothered by little interest or pleasure
in doing things?
Common side effects of antidepressants which are relevant to diabetes are sedation, weight
gain and related with an impact on cardiovascular system.
Alleviating depressive symptoms in these patients has a positive impact on improving their
mental and physical functioning, treatment adherence with disease self management and
medication regimens, diabetes outcomes like a better HbA1c.
Diabetic Peripheral Neuropathy (DPN)

All patients with DPN should be screened for psychiatric co morbidities. They may be at an
increased risk of committing suicide due to the co-occurrence of unrecognized psychiatric
illness and inadequately managed pain.
129
Diabetes Related Emotional Distress

One third of the diabetics have serious concerns like worry about the future and the
possibility of diabetic complications. The Problem Areas in Diabetes (PAID) is a good tool
to assess diabetes related emotional distress. The PAID is a measure of diabetes-specific
emotional distress that was developed by the Joslin Diabetes Center, Boston. This selfadministered questionnaire consists of 20 items that cover a range of emotional problems
frequently reported in type 1 and type 2 diabetes. Each item is scored 0 to 4 (Not a
problem to Serious Problem). The sum of the 20 items is multiplied by 1.25 to yield a
final score 0-100. Psychometric reports to date on the PAID have shown it to: (i) have
consistently high internalreliability (i.e. a = 0.90); (ii) have sound ( r = 0.83) 2-month
testretest reliability using a sample of stable patients; (iii) to correlate strongly with a
wide range of theoretically related constructs such as general emotional distress, depression, diabetes self-care behaviours, diabetes coping, and health beliefs; and (iv) to be a
statistically significant predictor of glycaemic control in a study that tracked a managed
care population control for 1 year.
Cognitive Dysfunction in Diabetes

Elderly patients with diabetes have an increased risk of developing cognitive problems.
One-third of the elderly diabetics have cognitive dysfunction and its presence is associated
with poor diabetes control.
130
Cognitive functions that enable complex behaviors are particularly important for patients
with diabetes. But older patients with diabetes and concomitant cognitive dysfunction
may find it cumbersome to adhere to the complicated treatment regimens like multiple
daily insulin injections, multiple oral medications and various diet related instructions. Elderly population is at an increased risk of hypoglycemia due to various reasons including
omission of meals, incorrect dose or timing of insulin injections and/or oral medications,
associated renal dysfunction. Diabetes has been associated with increased incidence of
functional disabilities and increased risk of falls and fractures. Executive dysfunction is
correlated with inability to perform lower-extremity tasks, leading to higher risk of falls.
The useful cognitive questionnaires and tests are described below
The Mini Mental State Examination (MMSE) is one of the most commonly used cognitive
screening measures because it is quick and easy to administer The MMSE includes specific
questions related to attention, orientation, memory, calculation, and language. The measure
scoring is based on 30 total points and impairment is indicated by a score of 24 or lower.
This is a good tool to screen for memory function.
The clock-Drawing Test (CDT) is a simple validated measure of cognitive function. In this
test, participants are presented with two sheets of paper: one provides written instructions,
the other serves as a response sheet. The instructions direct participants to draw a clock
and set the time to ten minutes after eleven.
CDT Scored by Mendez method It uses a 20-point scale. System of scoring has been shown
to be most accurate in predicting deficit in cognitive function and correlates with MMSE.
The Clock-In-a-Box (CIB) test is a modified CDT aimed at screening cognitive dysfunction
in the medical setting. This test was developed specifically to be a fast and reliable index
of executive function. In this test, as an added step participants are asked to draw a clock
in the blue box. The total score is the sum of the memory and executive function sub
scores. Total score in CIB is used to assess overall cognitive function.
Geriatric Depression Scale (GDS): The 15-item Geriatric Depression Scale is used to screen
for depressive symptoms in older individuals. This measure is scored based on a 15-point
scale, and impairment is indicated by a score of 5 or higher.
Patients with diabetes need to be evaluated for barriers to safe and effective diabetes
control. Screening for subtle cognitive dysfunction is important when complicated treatment regimens are used. Glycemic targets should be individualized; patients with diabetes
and executive dysfunction may need special education and skills to manage their disease.
Sexual Dysfunction and Diabetes

Both psychological and physiological factors can contribute to sexual dysfunction in diabetics. Sexual dysfunction can be a symptom of co-occurring psychiatric illness, a consequence
of medical illness or a side effect of concomitant medication. Several scales have been
developed like the Changes in Sexual Functioning Questionnaire (CSFQ), which can be
incorporated into a routine initial clinic visit. Screening for depressive and other psychiatric
symptoms like psychosis, anxiety, substance use disorders which may be interfering with
desire and arousal is essential.
References
1.
Jacobson AM. Pychological care of patients with insulin dependant diabetes mellitus.N Engl J Med
1996;334:1249-53
2.
Rubin RR.Counselling and psychotherapy in diabetes mellitus.In:SnoekFJ,Skinner TJ eds.psychology in diabetes

care.New York.NY:Wiley, 2000:235-63
3.
Welch GW , Jacobson AM Polonsky WH.The problem areas in dibetes scale.An evaluation of its clinical
utility. Diabetes Care 1998 :20;760-6
4.
Snoek FJ, Pouwer F,Welch GW ,Polonsky WH. Diabetes related emotinal distress in Dutch and US diabetes
patients:cross cultural validity of the problem areas in diabetes scale. Diabetes Care 2000; 23:1305-9
5.
Psychiatric Disorders and diabetes mellitus.Maria D Llorente, Julie Malphurs eds.2007 Informa health care.
6.
Medha Munshi,Laura Grande .Cognitive dysfunction is associated with poor diabetes control in older adults.
Diabetes care 2006 ;29:1794-99
131
Gestational Diabetes:
Screening and Treatment
Dr R S Hariharan
Formerly Professor and Head Dept. of Diabetology,

Madras Medical College & Govt. General Hospital, Chennai - 3
132
Director
Hariharan Diabetes & Heart Care
Hospitals (P) Ltd. Nanganallur, Chennai 61.
e-mail: hariharanhospitals@yahoo.in
Ph: 044 2232 5275 / 2234 6565
&
Dr R H Lakshmi
Consultant Physician & Diabetologist
Introduction
Gestational Diabetes is a controversial entity, with conflicting guidelines and treatment
protocols. Studies continue to show that diagnosis and management of this disorder have
beneficial effects on maternal and neonatal outcomes.
Screening for Gestational Diabetes

Recommendations for screening for Gestational Diabetes vary from Universal Screening
to Selective Screening of pregnant woman with risk factors for Gestational Diabetes. Risk
factors for Gestational Diabetes include current glycosuria, Diabetes in a first degree
relative, history of glucose intolerance (including previous Gestational Diabetes), marked
obesity and a previous infant with macrosomia1. Though a small percentage of women
may be safely excluded from testing, universal screening appears to offer better outcome2.
Expert consensus recommends a two-step testing consisting of a 50-G non fasting one hour glucose challenge screening test between 24 and 28 weeks gestation, followed by a
100G. 3 hour Oral Glucose Tolerance Test (OGTT) in women with a positive screening test 3.
It would be advisable to screen for Gestational Diabetes at the first antepartum visit in
women with high risk of GDM. In the Indian context, screening at the first booking, end
of first trimester, end of second trimester and middle of third trimester would result in
unearthing more pregnant women who would benefit from screening for GDM.
Screening cut offs are 130mg% and 140mg%. The lower cut off has a 90% sensitivity
as against a 80% sensitivity for the higher cut off4. Random blood glucose measurements
for screening have poor specificity5.
133
Diagnosis of Gestational Diabetes

The diagnostic test for GDM consists of a 100G 3 hour Oral Glucose Tolerance Test in
women who test positive on the screening test. Some recommend a single step testing
for GDM by adopting the 100 G OGTT itself as the screening and diagnostic test. Gestational Diabetes is diagnosed if any two or more plasma glucose values meet or exceed
the following values on the OGTT6. (Carpenter and Coustan modification of O Sullivan
and Mahans criteria).
Table 1: Diagnosis criteria for Gestational Diabetes
Plasma Glucose
(in mg%)
Fasting
95
1hour
180
2hours
155
3hours
140
The World Health Organization recommends simultaneous screening and diagnosis using a
75 G oral glucose tolerance test.7
Table 2: WHOs 75 G OGTT criteria
WHOs 75 G OGTT
Plasma Glucose in mg%
Fasting
126
2 hours
140
American Diabetes Association recommends diagnosis of GDM with a 75G OGTT, but applying Carpenter and Coustans cut-off values: 8
Table 3: ADA Criteria
ADAs 75G OGTT

Plasma Glucose
in mg%
Fasting
95
1 hour
180
2 hour
155
(Two or more values abnormal)

The author finds (i) a 50G non-fasting oral glucose challenge test recommended by
OSullivan with 130mg% cut-off and (ii) Carpenter and Coustans modified criteria of
OSullivans 100G OGTT suitable for Screening and Diagnosis, respectively.
Treatment of Gestational Diabetes & Glucose Targets

The plasma glucose values in pregnant women without GDM have been found to vary
from 69 to 75mg%, of fasting and 105 to 108mg% of one-hour post-prandial.9, 10 However,
the current treatment goals are substantially higher than these levels and differ among
expert organizations.
Most authorities recommend measurement of fasting glucose combined with post-prandial
testing (one or two-hour). Although there is no specific consensus regarding specific glucose
targets, values outlined in Table 1 are accepted by many: 11
Table 4. Treatment Targets for Women with Gestational Diabetes
134
Test
Fasting
One-hour post-prandial
Two-hour post-prandial
Glucose Levels in mg%

< 96
< 140
< 120 to 127
The author finds a glucose target of < 90mg% fasting and < 120mg% two-hour postprandial suitable in his practice.
Treatment Strategies
Medical Nutritional Therapy (MNT) is the first-line therapy for women with GDM. Pharmacotherapy is indicated when MNT results in inadequate glucose control.
Insulin is the first-line pharmacological therapy for GDM. Single, mixed or mixed and split
insulin regimens with short-acting regular insulin and intermediate-acting insulin such as
isophane (NPH) are recommended. Insulin is typically started at a dosage of 0.7units per Kg
per day (based on pre-pregnancy weight), given in divided doses. Two-thirds of the total
daily dose of insulin is given in the morning, while the remainder is given before dinner. An
equal amount of regular and intermediate acting insulin is often required in our patients.
Short-acting insulin analogues such as Lispro and Aspart are being increasingly used in
pregnancy. The U.S. Food and Drug Administration categorizes the short-acting insulin
analogues as Class B drugs in pregnancy. However, ADA and American College of Obstetricians and Gynaecologists have yet to officially recommend their use. There are as yet little
data available on the use of long-acting insulin analogues such as glargine and detemir
in pregnancy. Thus NPH is the intermediate-acting insulin of choice in GDM.
Patients controlled on diet alone do not require active glucose management in labor.
Most patients who require insulin are also euglycaemic in labor and do not require active
management of glucose levels.12 However, it is advisable to monitor the blood glucose
during the peripartum period.
Most women with GDM do not require insulin therapy following delivery. Approximately
50% of women with GDM develop Type 2 Diabetes Mellitus within 5 to 10 years.13 They
are also at risk of earlier GDM in subsequent pregnancies.
Role of Oral Hypoglycaemic Agents (OHAs) in GDM

Traditionally, Oral Hypoglycaemic agents have not been recommended for use in pregnancy.
The main objections for their use in pregnancy are based on a perceived risk for the development of congenital anomalies, fetal compromise and fetal hypoglycaemic episodes
through direct stimulation of the foetal pancreas.14, 15, 16
Langer, et al17 demonstrated the safety of Glibenclamide in pregnancy. He found that the
second-generation Sulphonylureas, especially Glibenclamide, do not significantly cross the
placenta due to its high protein-binding capacity of 99.8%.
GDM patients who are characterized by mild hyperglycaemia are excellent candidates
for therapy with Glibenclamide or other oral antidiabetic drugs (Metformin, -glucosidase
inhibitors, etc.)
It has been demonstrated that elevated blood glucose level and not the mode of therapy
affected the rate of congenital anomalies.18
Metformin is categorized as a class B drug. Its use in PCOS reduces the incidence of GDM
in women with PCOS from 23% to 3%.19, 20: However, there is no justification to maintain
a PCOS woman on Metformin throughout pregnancy if she does not develop GDM. Use
of Metformin in the classical GDM, which is a disease of the second half of pregnancy,
is a viable alternative to insulin.
The -glucosidase inhibitors, being only locally active in the intestines, may be used in GDM
without fear of adverse effects.21
Thiazolidinediones are classified as pregnancy category C, and to date no data of their
use in pregnancy are available.
Summary
Screening, for GDM followed by good glycaemic control of pregnant women with GDM
have implications for the positive health of the mother and the developing child not only
during the index pregnancy but also for the future development of Diabetes in both.
References
1.
Metzger BE, Coustan DR, Summary and recommendations of the Forth International Workshop-Conference
on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care. 1998; 21(suppl2) 8161-B167.
2.
Naylor CD, Sermer M, Chen E, Farine D. Selective screening for gestational diabetes mellitus. Toronto Trihospital Gestational Diabetes Project Investigators N Engl J Med. 1997; 337(22):1591-1596.
3.
Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International
Workshop-Conference on Gestational Diabetes Mellitus (published correction appears in Diabetes Care. 2007;
30(12):3154). Diabetes Care. 2007; 30 (suppl 2): S251-S260.
135
4.
Metzger BE, Coustan DR, Summary and recommendations of the Forth International Workshop-Conference
on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care. 1998; 21(suppl2) 8161-B167.
5.
Agarwal MM, Dhatt GS, Punnose J, Zayed R. Gestational diabetes: fasting and postprandial glucose as first
prenatal screening tests in a high risk population. J Reprod Med. 2007; 52(4):299-305.
6.
Americal Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 2004;27 (suppl 1): S88-S90.
7.
Alberti KG, Zimmet PZ, Definition, diagnosis and classification of diabetes mellitus and its complications.
Part1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet
Med. 1998; 15(7): 539-553.
8.
American Diabetes Association. Gestational diabetes mellitus. Diabetes Care. 2003; 26 (suppl 1): S103-S105.
9.
Yogev Y, Ben-Haroush A, Chen Review after 1 month, Rosenn Becozym C Forte 0 - 0 - 1 after food , Hod
M, Langer O, Diurnal glycemic profile in obese and normal weight nondiabetic pregnant women. Am J
Obstet Gybecol. 2004; 191(3): 949-953.
10. Parretti E, Mecacci F, Papini M, et al. Third-trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: correlation with sonographic parameters of fetal growth. Diabetes Care. 2001; 24(8):
1319-1323.
11. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International
12. Metzger BE, Buchanan TA, Coustan DR, et al. Summary and recommendations of the Fifth International
13. Kim C, Herman WH, Vijan S. Efficacy and cost of postpartum screening strategies for diabetes among women
with histories of gestational diabetes mellitus. Diabetes Care. 2007; 30(5): 1102-1106.
14. Kemball ML, Mclvert C, Milner RDG, et al. Neonatal hypoglycemia in infants of diabetic mothers given
sulphonylurea drugs in pregnancy. Arch Dis Child 1970; 45:696-701.
136
15. Farquar JW, Isles TE. Hypoglycemia in newborn infants of normal and diabetic mothers. S Afr Med J 1968;
9:237-45.
16. Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal Chlorpropamide
therapy. Pediatrics 1968; 42:824-5.
17. Schade DS, Jovanovic Lalitha, Schneider J. A placebo-controlled randomized study of Glimepiride in patients
with type 2 diabetes mellitus for whom diet therapy is unsuccessful. J Clin Pharmacol 1998; 38:636-41.
18. Langer O, Conway D, Berkus M, et al. There is no association between hypoglycemic use and fetal anomalies
(abst). AmJ Obstet Gynecol 1999; 180(1):S38.
19. Glueck CJ. Wang P, Kobayashi S, et al. Metformin therapy throughout pregnancy reduces the development
of gestational diabetes in women with polycystic ovary syndrome Fertil STeril 2002; 77:520-5.
20. Glueck CJ, Goldenberg N, Wang P, et al. Metformin during pregnancy reduces insulin, insulin resistance,
insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal
assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum
Reprod 2004; 19(3):510-21.
21. Coniff RF, Seaton TB, Shapiro JA, et al. Reduction of glycosylated hemoglobin and post-prandial hyperglycemia by Acarbose in patients with NIDDM. Diabetes Care 1995; 18:817-20.

Type 2 Diabetes During Pregnancy
Dr Sunil Gupta
Managing Director
Sunils Diabetes Care n Research Centre

42, Lendra Park, Ramdaspeth Nagpur 10
E-mail: mail@dcrc.com & drsgupta_ngp@rediffmail.com
Ph: 0712-2428111, 222, 333
Fax. No. 0712-2428555.

Type 2 Diabetes during Pregnancy
137
Introduction
In the developing world, type 2 diabetes predominates, and the numbers of type 2 diabetic
women of childbearing age are increasing. If the current trends, in obesity and physical
inactivity persist and women continue to delay childbirth until their late twenties or beyond, the numbers of pregnant women with type 2 diabetes will inevitably rise1. Women
with pre-existing type 1 or Type 2 diabetes mellitus, who become pregnant, is termed as
pre-gestational diabetes mellitus. In pre-insulin era, maternal, mortality amongst them was
33% and perinatal, mortality was 65%.2. After discovery of insulin, maternal and fetal/
neonatal survival improved dramatically.
Classification
Diabetes in pregnancy has been traditionally grouped according to the pioneering work
of Priscilla White 3 who classified diabetes according to onset, duration, and complications
to predict perinatal outcome (Table1). An important distinction in classification is the existence of micro or macrovascular complications of diabetes. If no vascular complications
exist, then placental growth and development are most often not impeded and the risk
for Intra Uterine Growth Restriction (IUGR) is smaller. However, with vascular complications such as those noted in the lower half of Table 1, the risk for IUGR increases with
increasing severity. 4
Table 1 The White Classification of the Diabetic Pregnancy (3)
138
Description
Gestational Diabetes, insulin not required
Gestational Diabetes, insulin required
Age of onset, > 20 y (maturity onset diabetes)
Duration, <10y, no vascular lesions
Age of onset, 1019 y
Duration, 1019y, no vascular lesions
Age of onset, <10 y
Class
A1
A2
B1
B2
C1
C2
D1
Duration, > 20 y
Benign Retinopathy
Calcified arteries of legs
Calcified arteries of pelvis
Nephropathy
Many failures
Cardiopathy
Proliferating Retinopathy
Renal transplant
D2
D3
D4
E
F
G
H
R
T
Fetal Growth
No vascular disease
Risk for macrosomia
Vascular disease
Risk for intrauterine
Growth restriction
Metabolism in Pregnancy
Pregnancy itself is a diabetogenic state that exacerbates preexisting diabetes. Metabolism,
changes dramatically during pregnancy. Both basal and postprandial glucose metabolism
gradually change over the course of pregnancy to meet the nutritional demands of the
mother and fetus. As, pregnancy progresses fasting glucose decreases5 and fasting insulin
increases. Despite a decrease in fasting glucose in pregnancy, basal hepatic glucose production increases and hepatic insulin sensitivity decreases. The first and second phases of
insulin secretion increase, and insulin sensitivity decreases. In women who are pregnant
and obese, hepatic insulin sensitivity further decreases6. Insulin resistance in pregnancy is
likely caused by the combined metabolic effects of hormones in the maternal circulation,
specifically human placental lactogen, progesterone, prolactin, and cortisol and various
cytokines. The increase in insulin resistance generally parallels placental mass and the
increase in placental hormones.
Management
Despite the advances made in care of pregnant women with diabetes, several problems
still remains, such as 7

A high incidence of spontaneous abortions (SABs) in infants of diabetic mother (IDMs)
Care of women with severe complications of diabetes.
Care of difficult patient who often present late for antenatal care and / or is noncompliant.
Fetal organogenesis is largely complete by 8 wk after the last menstrual period (6 wk

post conception). Poorly controlled diabetes during early weeks of pregnancy, in many
cases before a woman even knows that she has conceived, significantly increase the risk
of 1st trimester SAB or delivering an infant with a major anomaly. Many women with
type 2 diabetes remain undiagnosed and untreated during the critical stages of organogenesis, imposing the same high risk of congenital anomalies as in poorly controlled type
1 diabetes8. Women diagnosed early in pregnancy with gestational diabetes who remain
diabetic postpartum can be assumed to have previously undiagnosed type 2 diabetes; this
probably explains why they have a higher perinatal mortality than women diagnosed later
in pregnancy 9, 10. At present, pregnancies of women with type 2 diabetes may be more at
risk than those in type 1 diabetes, due to a combination of poor glycaemic control early
in pregnancy and other common risk factors including obesity, greater age and parity
and the tendency of women from ethnic minority groups to seek obstetric care late in
pregnancy 8, 11. Preconception counseling is as important with type 2 diabetes as it is for
type 1, but only few type 2 diabetic women actively seek or participate in this 8. More
proactive screening for diabetes is needed among high-risk non-pregnant women; otherwise the diagnosis will continue to be made in pregnancy, and the opportunity missed
for vital preconception counseling.
Pre-Pregnancy Counseling
Pre-Pregnancy counseling should begin from onset of puberty and continue until menopause. These women should be divided in two categories. Those who are planning pregnancy
within next year and those wishing to delay pregnancy. For those, not planning pregnancy,
should be informed about risk of pregnancy, importance of appropriates birth control and
prepregnancy planning. For women contemplating pregnancy soon, a pre-conception
counseling is must. This includes 7

139
Contraceptive advice
Risk of pregnancy, maternal and fetal/ neonatal
Importance of maintaining euglycemia
Genetic counseling
Personal commitment by women and her partner and the family.
Planned pregnancy is the major objective of preconception counseling. It should emphasize

women about the risk to IDM and she should also be assured that risk can be reduced
by effective control of hyperglycemia. Physician should inform regarding worsening of
retinopathy, nephropathy and neuropathy during pregnancy. Presence of ischemic heart
disease is contraindication for pregnancy due to significant maternal mortality. Frequently
asked questions during counseling are:
What is the Risk of Diabetes to IDM Child?

Women with diabetes may be assured that it is very rare for newborn to develop diabetes.
If she has type 1 diabetes and is > 25 yrs old, the chance of child developing diabetes is
~1%, if she is <25 yrs old, chance increases to ~ 4% 12. If both parents have type 1 diabetes, the risk is not known, but is expected to be higher. The risk of offspring of women
with type 2 diabetes to eventually develop type 2 diabetes is about double the risk of
general population 13. A hyperglycemic intrauterine environment appear to be involved in
the pathogenesis of type 2 diabetes/prediabetes in adult offspring of primarily Caucasian
women with either diet treated GDM or type 1 diabetes during pregnancy 14.
140
Does Diabetes Impact a Womens ability to Conceive?

A variety of abnormalities in female reproductive function of women with diabetes include
delayed menarche and early menopause, delayed ovulation, and an increased incidence of
menstrual cycle irregularities 15 that may occur with a frequency twice that of control
subjects. In a retrospective analysis 16, there was a positive correlation between increased
duration of diabetes and later onset of menarche, even when the subjects maternal menarche was taken into account. A survey among women of reproductive age with diabetes
found that approximately 20% failed to conceive within 2 years of attemption, a rate
that is higher than expected among the nondiabetic population. Failure to conceive
was associated with earlier onset of diabetes and with higher daily doses of insulin. The
mechanisms underlying impaired fertility in women with diabetes are not entirely clear.
They may be related to abnormal function of the hypothalamic- pituitary axis, such as a
decreased luteinizing hormone response to gonadotropin- releasing hormone reductions
in basal concentrations of luteinizing hormone and follicle- stimulating hormone, low
thyrotropin concentrations leading to low circulation thyroxine and impaired prolactin synthesis or release, or impaired synthesis of corticosterone. Diabetes may also modify female
reproductive function through the direct effect on insulin- dependent mechanisms of cells
in the ovary itself. Indeed, ovarian weights are reduced in rats with alloxan induced
diabetes, possibly because of decreased responsiveness of the ovaries to gonadortopins. It
has also been observed that granulose cells isolated from women with diabetes demonstrate
impaired insulin stimulated synthesis of the ovaries to gonadortopins. It has also been
observed that granulose cells isolated from women with diabetes demonstrate impaired
insulin stimulated synthesis of progesterone, even in cases of fair diabetic control. Thus,
it appears that the hyperglycemic milieu in diabetes may affect various aspects of reproductive function17.
Do women with Diabetes have an Increased risk of

Spontaneous Abortion (SAB)?
The rate of SAB in prospective, well designed studies of pregnancies in women with type
1 diabetes has ranged from 15-30 % A recently published large retrospective study from
Denmark found that the rate of SAB among women with type 1 diabetes was 17.5%
compared to 10-12% in the non-diabetic population. Several investigators have reported
an association between SAB and poor glycemic control in the first trimester, as reflected
by higher HbA1c concentrations. Further SAB was related to glycemic control in the period
close to conception than the period immediately before the abortion itself. Most authors
speculate that the toxic milieu in which the embryo is developing is the causative factor in the increased risk of SAB in diabetic pregnancies; this may result in degeneration
of the embryo and the appearance of a blighted ovum or in an increased rate of lethal
malformations incompatible with intrauterine life17. Other possible mechanisms are abnormal placentation and vascularization, and perhaps an increased incidence of chromosomal
abnormalities. Whether there is a threshold of hyperglycemia above which the risk of SAB
is increased in women with diabetes remains unknown. The Diabetes in Early Pregnancy
(DIEP) study demonstrated that increasingly higher first-trimester HbA1c concentrations
were associated with increasing rates of SAB, with no evidence of a threshold effect 18
Studies have confirmed that normalizing blood glucose levels before and during the early
weeks of pregnancy can reduce the risk of major anomalies as well as of SABs, in IDMs,
to near that of nondiabetic population.19. (Table-2)
Do the infants of Women with Diabetes have an Increased

Risk of Congenital Malformations?
Congenital Malformations (CM) are the leading cause of perinatal mortality in pregnancies
complicated by diabetes. CM account for 50% of perinatal deaths, compared with 20-30%
in infants of nondiabetic mothers 20. Women who have pre-gestational diabetes (either
type 1 or type 2) are at increased risk for having a malformed fetus 21, 22. Women with
fasting hyperglycemia first detected during pregnancy are likely to have undiagnosed pregestational diabetes and they too have an increased incidence of congenital malformations
in their offspring23. Higher first trimester HbAlc concentrations are correlated with an
increased frequency of CM 24, 25. The presence of diabetic vasculopathy in the mother was
also associated with an increased risk of CM in some studies 24. The overall incidence of
malformations as reported in published surveys remains between 4.2% - 9.4% 26, 27, several
fold higher than in the background population. Prevention of major CM should focus
on preconceptional and early postconceptional glycemic control of women with diabetes.
In a meta-analysis, Balsells and colleagues28 compared type 1 and 2 diabetes and found that
women with type 2 had lower HbA1c at the first visit but a higher rate of perinatal mortality (odds ratio, 1.50; 95% CI, 1.151.96). Despite a milder glycemic disturbance, women
with type 2 diabetes had no better perinatal outcomes than those with type 1. (Table-3).

141
Table 2. Potential Perinatal Morbidity / Mortality in infants of Diabetic Mothers (6)
Asphyxia
Birth injury
Cardiac hypertrophy, Congenital anomalies
Erythrmia and hyperviscosity
Heart failure, Hyperbilirubinemia, Hypocalcaemia, Hypoglycemia, Hypomagnesaemia
Increased blood volume, Intrauterine growth retardation
Macrosomia
Neurological instability: irritability
Organomegaly
Respiratory distress, Respiratory distress syndrome
Small left colon syndrome, Stillbirth
Transient hematuria
Table 3. Congenital Malformations in Infants of Diabetic Mothers (6)
142
Anomaly
Caudal regression
Spina bifida, hydrocephalus,
Or other CNS defect
Anencephalus
Heart anomalies
Anal/rectal atresia
Renal anomalies
Agenesis
Cystic kidney
Ureter duplex
Situs inversus
Ratios Of Incidence
252
2
3
3
4
3
5
6
4
23
84
Pre- Pregnancy Assessment

Microvascular and Macrovascular Complications
Until recently, women with advanced diabetes were frequently advised to avoid pregnancy
for fear of aggravating the underlying disease and its complications, as well as risking an
unfavorable perinatal outcome, In reality, many women with advanced diabetes can now
gain access to specialized prenatal care and in most instances, can expect a successful pregnancy without significantly compromising their health or the well-being of their offspring.
Diabetic Nephropathy
Several factors associated with pregnancy could, hypothetically, increase the risk of nephropathy. During normal pregnancy, there is a 40-60% increase in glomerular filtration
rate29. Since it is generally accepted that the primary insult leading to diabetic nephropathy
is glomerular hyperfiltration, this could accelerate the development and the progression of
nephropathy. Secondly, pregnancy- induced hypertension and preeclampsia affect 15-20 %
of all women with diabetes and an even greater proportion of those with nephropathy. 30
Because systemic hypertension plays an important role in the progression of nephropathy,

hypertensive disorders of pregnancy might be expected to exert a detrimental effect in
this context. Lastly, the increase protein intake recommended in diet of pregnant women
can result in the increased glomerular filtration rates and may exacerbate glomerular hyperfiltration subsequently accelerating the course of diabetic nephropathy. Conversely, the
strict glycemic control that is commonly recommended and instituted during pregnancy
may actually have a beneficial effect on nephropathy. Although proteinuria often increased
markedly during pregnancy in women with microalbuminuria or overt nephropathy this
is usually an acute and transient phenomenon. In most cases, proteinuria subsides after
delivery and returns to pre-pregnancy level. Most women can be reassured that pregnancy
is not associated with development of nephropathy or with accelerated progression of
preexisting nephropathy. The only exception is in women with moderate or advanced renal
disease in whom pregnancy may have a detrimental effect on progression to end stage
renal disease. Therefore, renal function should be determined in all patients with diabetes
using a 24- hours urine collection, preferably before pregnancy or at the first prenatal visit.
Does Diabetic Nephropathy Affect the Course and Outcome of Pregnancy?

Pregnant women with diabetic nephropathy have an increased risk of developing hypertensive complications of pregnancy. Many of these women have preexisting chronic
hypertension and even in those that do not, preeclampsia is a common complication.
It appears that preeclampsia develops in up to 50% of women with nephropathy 31, 32, 33
There is an increased risk of fetal complications in pregnancies compromised by diabetic
nephropathy. Approximately 25-30% of these pregnancies are delivered prior to 34 weeks
gestation and approximately 50% are delivered before 37 weeks 31, 32, 33 due to deteriorating
maternal status and /or fetal jeopardy. An increased risk of fetal distress and fetal growth
restriction occurs in approximately 20% of pregnancies. Perinatal survival of infants born
to mothers with diabetic nephropathy has been consistently close to 100% during the past
two decades. However, the increased rate of prematurity in this population is associated
with an increased risk of long-term infant morbidity. Thus although women with diabetic
nephropathy may usually expect to deliver a viable fetus and take home a reasonably
healthy infant, this group of patients is the one most likely to have a complicated course
of pregnancy, requiring expert care and intensive management (Table-4).
Table 4. Guidelines for Preconceptional and Prenatal Management of Women
with Diabetic Nephropathy (17)
Obtain a 24-hour urine collection at the first prenatal visit and once each trimester for
total protein and creatinine clearance. Proteinuria may often increase during pregnancy
to nephrotic ranges , but will usually subside following delivery, and is not, in itself, an
indication for delivery. In the presence of massive proteinuria, serum albumin levels should
be monitored and supportive management of peripheral edema should be given. If serum
creatinine is > 1.5 mg/dl or if creatinine clearance is < 75 ml/minute, the patient and her
family should be advised that the risk of maternal and fetal complications is high, and that
it is possible that pregnancy will accelerate progression of nephropathy towards end stage
renal disease.
Aggressively manage hypertensive patients to maintain blood pressure < 130/80.
Patients with chronic hypertension that are treated with ACE inhibitors should be switched
to an alternative medication as soon as the pregnancy test becomes positive. Methyldopa
and nifedipine or alphaadrenergic blockers can be used for control of blood pressure.

143
Obtain urine culture to rule out the co-existence of a urinary tract infection.
Serial sonographic assessments of fetal growth should be obtained on a regular basis at
least every 4 weeks from 20 weeks gestation onwards. Maternal modified activity is often
prescribed to optimize the function of the feto-placental unit particularly in the presence
of maternal hypertension or evidence of fetal growth restriction.
Antenatal fetal testing should start at 28-32 weeks, depending on the severity of the
underlying disease and on fetal status as determined by sonogram.
Timing of delivery should be guided by usual obstetric indications, taking into account
maternal and fetal status.
Does Pregnancy Affect the Onset and Progression of Diabetic Retinopathy?
144
Strict glycemic control during pregnancy would be expected to have a beneficial effect
on retinopathy because intensified glycemic control of diabetes is associated with significantly slower development and progression of retinopathy in patients with type 1 and
type 2 diabetes 34, 35 At the same time other studies have shown that rapid normalization
of blood glucose can cause acute progression of retinopathy 36, so that institution of
strict glycemic control during pregnancy may actually be associated with deterioration of
retinopathy. Recent evidence indicates that over a longer period of follow-up of up to
four years, patients who have been managed with intensive insulin therapy have, overall,
a slower progression of retinopathy compared to patients managed less intensively despite
the risk of rapid initial progression. The development of pregnancy- induced hypertension
or preeclampsia is associated with an increased risk for progression of retinopathy during
pregnancy. Another theoretical concern related to pregnancy is that the abrupt increases
in blood pressure that occur with maternal expulsive efforts during delivery may cause
acute retinal hemorrhages in mothers with preproliferative changes.
Unlike nephropathy the presence of retinopathy does not seem to have an adverse effect
on pregnancy outcome. Some women have coexisting retinopathy and nephropathy but it
appears that in these patients the increased risk of adverse pregnancy out come is related
to the presence of nephropathy and not retinopathy. (Table-5)
Table 5. Guidelines for Preconceptional and Prenatal Management of
Women with Diabetic Retinopathy (17)
Preconceptional ophthalmologic evaluation should be encouraged. Preconceptional

management allows gradual institution of strict glycemic control prior to pregnancy that
may decrease the risk of progression related to abrupt glycemic control.
Phototherapy and other treatment should be instituted in women with proliferative
retinopathy. Women should be instructed not to conceive until the proliferative process has
been completely stabilized.
Fundoscopic examinations once each trimester and approximately 12 weeks postpartum should be performed in all women with diabetes, but particularly those with diabetic
retinopathy.
Management of labor and delivery should be determined according to usual obstetric
guidelines, regardless of retinopathy.
Does Pregnancy Affect the Clinical Course and Manifestations of Diabetic

Neuropathy?
Very little is known about the effects of diabetic neuropathy on the course and outcome of
pregnancy or about the effects of pregnancy on the natural course of diabetic neuropathy.
In asymptomatic patients, specific tests are required to diagnose autonomic neuropathy involving the cardiovascular system, and these are not routinely performed during pregnancy.
Autonomic neuropathy involving the gastrointestinal system may also be difficult to determine during pregnancy, since nausea, vomiting and constipation are common symptoms
of normal pregnancy. Thus, the reported prevalence of diabetic neuropathy in pregnancy
varies widely between 8.5-32%. Exacerbation of autonomic neuropathy during pregnancy
has been reported by some authors whereas others have noticed transient improvement
in symptoms during pregnancy. Of particular importance is the association of autonomic
neuropathy with an increased risk of severe hypoglycemia. The blunted counterregulatory
responses to hypoglycemia in women with diabetic neuropathy appear to diminish even
further during pregnancy17.
Does Diabetic Neuropathy Affect the Course and Outcome of Pregnancy?

In a prospective study of 100 women with type 1 diabetes, Airkensen et al identifies 23
women with autonomic dysfunction. A complication of pregnancy was more than twice as
likely to occur in this group compared to the group with no autonomic dysfunction. Additional limited information on this issue comes from case reports, suggesting an increased
risk of poor perinatal outcome. The presence of gastroparesis is particularly relevant in
that, with the hyperemesis of pregnancy, it results in exacerbation of nausea and vomiting.
The result is irregular absorption of nutrients, inadequate nutrition, and aberrant glucose
control. In summary, from the few reports of pregnancy in women with autonomic neuropathy, it seems that pregnancy does not alter the natural course of diabetic autonomic
neuropathy. Although a successful outcome of the pregnancy is possible in the presence of
symptomatic diabetic neuropathy, significant maternal and perinatal morbidity may occur 17.
How Does Hypertension Affect the Course of Pregnancy in Women with

Diabetes?
Hypertension is a very common co-morbidity among the diabetic population, with a prevalence of up to 3 times higher than that nondiabetic age-matched group. In pregnant
women with chronic hypertension treated with antihypertensive medications, blood pressure values are usually controlled at no less than 140/90 mmHg in order to maintain
adequate placental perfusion and to decrease the risk of fetal growth restriction. However,
in women with diabetes and chronic hypertension, aggressive control of hypertension
should be initiated preconceptionally in order to decrease long term macrovascular and
microvascular complications, maintaining blood pressure values below 130/80 mmHg. Aggressive control of maternal hypertension is of utmost importance to optimize pregnancy
outcome, but the choice of antihypertensive medications is somewhat limited. The use of
ACE- inhibitors during pregnancy is contraindicated due to their potential adverse effects
on the fetus 37. The most widely used medications are Methyldopa, Nifedipine, and alphaadrenergic blockers, for a targeted blood pressure in the range of 130/80.

145
Table 6. Maternal Complications in Diabetic Pregnancy (6)
Hypoglycemia, Ketoacidosis
Pregnancy induced hypertension
Pyelonephritis, other infections
Polyhydramnios
Preterm labor
Worsening of chronic complications-retinopathy, nephropathy, neuropathy,
cardiac disease
What are the Risks Associated with Pregnancy in Women with Diabetic
Coronary Artery Disease?
146
Women with diabetes have a 3-fold risk of atherosclerosis and fatal myocardial infarction. In women who have pre-existing coronary artery disease, the cardiovascular changes
associated with pregnancy and delivery can result in inadequate myocardial oxygenation,
leading to myocardial infraction and heart failure. Increased cardiac output decreased
systemic vascular resistance with shunting of blood away from the coronary arteries,
increased oxygen consumption during physical activity, increased vascular return during
uterine contractions and acute blood loss at delivery may all contribute to an absolute or
relative decrease in the ability of the coronary blood flow to meet the demands of the
myocardium. Additionally, these women are extremely vulnerable to myocardial damage
and pulmonary edema in the immediate postpartum period. After a vaginal delivery there
is an immediate 60-80% increase in cardiac output 38 due to release of venocaval obstruction, auto transfusion of utero placental blood and rapid mobilization of extravascular
fluid, resulting in increased venous return and stroke volume. These fluid shifts are less
pronounced after cesarean delivery using controlled analgesia 17. (Table -7)
Table 7. Guidelines for Preconceptional and Prenatal
Management of Women with Diabetic Coronary Artery Disease.
A thorough preconceptional cardiac evaluation should be conducted by a cardiologist to

determine the extent of coronary artery disease and myocardial function.
The patient should be made aware of the serious maternal risks associated with pregnancy. The risk of maternal death should be explicitly discussed with the patient and her
family. It is impossible to quantify this risk but it is most likely related to the degree of cardiac dysfunction. The option of termination of pregnancy should be specifically discussed
with the patient and her partner.
Maternal and fetal status should be followed carefully in the patient who decides to
continue her pregnancy. Maternal physical activity should be limited to the bare minimum,
and follow-up visits with the perinatologist and the cardiologist should be scheduled every
week from the second trimester onwards. Antenatal fetal testing should begin at 28 gestational weeks, and serial sonograms should be performed to monitor fetal growth.
Adequate glycemic control should be attained without risking hypoglycemia.
The patient should deliver at a tertiary care centre. Anesthesia during labor and delivery
should be planned well in advance. Maternal hemodynamic status should be monitored closely
during labor, delivery, and following delivery with the aid of necessary invasive measures. Maternal effort should be kept to a minimum, and delivery should be assisted electively.
Close and careful monitoring during the first 48 hours following delivery should be
instituted , due to the increased risk of hemodynamic decompensation.
A method for permanent sterilization should be discussed well in advance, so that the
procedure, if desired, might be performed following delivery.
Table-8. Potential contraindications to Pregnancy (7)
Ischemic heart disease

Active proliferative retinopathy, untreated
Renal insufficiency: creatinine clearance <50 ml/min or serum creatinime> 2 mg
/dl or heavy proteinuria ( >2 g/24 h) or hypertension (blood pressure> 140/90
mmHg despite treatment)
Severe gastroenteropathy : nausea/vomiting, diarrhea
Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is an uncommon occurrence in treatment-compliant women
with type 1 diabetes, despite the increased risk for this complication associated with the
ketogenesis of normal pregnancy. However, DKA is a common complication in undiagnosed
diabetes. 39 Any pregnant woman with vomiting or dehydration and blood sugars greater
than 200 mg/dl should have electrolytes, plasma bicarbonate, and serum acetone levels
measured to confirm DKA diagnosis. Arterial blood gasses should be obtained if the plasma
bicarbonate is low and acetone is present. Several management algorithms are available.
40, 41
The precipitant of DKA is often infection, which should be diagnosed and treated
promptly. Resolution of DKA can be slower in pregnancy. DKA is often associated with a
nonreassuring fetal heart rate tracing, which in most cases resolves once the metabolic
acidosis improves. However, despite improved management, DKA remains an important
cause of fetal loss in diabetic pregnancies. 42
Pre- Pregnancy Management

After prepregnancy counseling, assessment and fitness for safely undertaking a pregnancy,
women should plan to achieve her glycemic goals before conception. She should meet
dietician to plan her diet. Folate given periconceptually and in early pregnancy decreases
the risk of neural tube defects in offspring. Thus multivitamin plus up to 400 mg Folate
from preconception through 1st trimester is recommended43. Women should than be placed
on intensive human insulin regimen consisting of 2-4 injection daily, with combination of
short and intermediates acting insulin. Exercise should be encouraged. Women should be
taught to monitor blood glucose at home, to achieve the goal of premeal as < 90mg and
2hr. postmeal < 120 mg%. The risk of hypoglycemia should be explained to them. Serial
HbA1c levels can be done monthly to confirm normalization of blood glucose preconceptually. Women should quit smoking, alcohol and avoid unnecessary drugs. Patients with
type 1 diabetes may require more frquent dtermination of blood glucose concentrations,
including at 2-3 AM, to avoid episodes of hypoglycemia. Patients with type 2 diabetes
who are treated with oral hypoglycemic medications are tobe switched to insulin therapy
although there are no data linking the use of these in early pregnancy to an increased
risk of congenital malformations. Thyroid function test should be performed at baseline.

147
Monitoring: HbAlc Measurement

The HbAlc value reflects as integration of ambient blood glucose levels over a period of 4-6
week before its measurement. For this reason, it has been especially useful in evaluating
the degree of diabetic control in the critical early weeks of pregnancy. Its level has been
directly correlated with increased incidence of congenital anomalies in IDMs. It is therefore important to measure HbAlc, when the diabetic women first presents with her plans
for pregnancy and to continue serial measurements every 4-6wk. The pregnant women
should have HbAlc level drawn every 4-6wk to document her degree of glycemic control
throughout the pregnancy 7. Diabetic women should aim for HbA1c value less than 5%
through out pregnancy 44
Table 9. Target Plasma Glucose Levels
Fasting
Premeals
1 hour after meals
2 hours after meals
2-6 am
(42)
Capillary whole-blood glucose

60- 95mg/dl
60-100 mg/dl
< 140 mg/dl
< 120 mg/dl
> 60 mg/dl
Monitoring: Self - Monitoring of Blood Glucose (SMBG)
148
All women with pre-existing diabetes should do daily SMBG during pregnancy by glucometer. Under closely controlled situations, both accuracy and precision of SMBG device
are generally acceptable for clinical use. Anemia falsely elevates and erythremia falsely
depresses SMBG values. This is of concern during pregnancy, when changes in hematocrit
are common. An ideal profile of blood glucose testing includes eight tests each day: once
before each meal and 1-2hr. after each meal, bedtime and at 2-3am. The goals of glycemic
control are an given in Table 9. Test schedules should be individualized on the basis of
frequency of insulin injections and SMBG readings. All reading should be recorded with
time, food and insulin dosage details7.
Should Women with Diabetes Expect an Increased Incidence of Obstetric

Complications?
Preeclampsia: The rate of preeclampsia in women with diabetes is generally accepted as
being higher than the 5-7% in the general population45. Poor glycemic control nulliparity,
retinopathy and duration of diabetes were independent predictors of preeclampsia. Reece
et al 24 reported that acute hypertensive complications occurred in 51.6 % of pregnant
women with diabetic microvascular disease, compared with 32.9 % among those without
microvascular disease. Specifically, in women with diabetic nephropathy, most authors report a high incidence of preeclampsia / PIH or superimposed preeclampsia, in excess
of 30% 17, 32, 33. Reducing HbA1c by improving glycemic control both before and during
pregnancy resulted in a significantly lower incidence of preeclampsia. Kovilam et al 46
found that each increment of 1% in the glycohemoglobin concentration during pregnancy
conveyed a 37% increase in the risk of preterm delivery.
Polyhydramnios: Polyhydramnios is considered a frequent complication of diabetic pregnancy, In a review by Cousins, (30) the overall incidence of Polyhydramnios was 17.6%
in patients with Whites classes B and C and 18.6% in patients with classes D, R, and F.
Polyhydramnios was associated with poor glycemic control throughout the entire pregnancy, especially during the first two trimesters. It is unclear why polyhydramnios is more
common in women with diabetes and why it is associated with poor glycemic control.
Polyhydramnios in this circumstance may be related to increased glucose content in the
amniotic fluid, creating an osmotic pressure that equilibrates in the presence of an increased volume of amniotic fluid. In addition, if maternal hyperglycemia is associated
with fetal hyperglycemia, this could be associated with fetal polyuria and hence, cause
polyhydramnios.
Infection: Pregnancy is also generally thought to constitute a state or relative immune
deficiency, specifically, impaired cell-mediated immunity. Thus, pregnancy in the patient
with diabetes is likely to represent an additional risk factor for infection. 17
Diagnostic Testing and Fetal Surveillance: Diagnostic testing and fetal surveillance include various forms of testing performed during pregnancy to assess the normalcy and
development of the fetus (Table 10). One can only look for known problems with specific
tests. Therefore, no assurance can be made that everything will be fine, no matter how
many normal test results are reported 7. (Table 10)
Table 10. Diagnostic Testing and Fetal Surveillance
Test
Purpose
Optimal Gestational Age (Wk)
Comments
Ultrasound
Establish correct
Screen for structural
anomalies
After 7.5
7-12 wk; very accurate 1528 wk; accuracy + 2wk > 28

wk: not reliable Only detects
major anomalies (spinal, cardiac) but cannot guarantee
normalcy
Determine macroso- 28 to term

mia and polyhydramnios
Indications of fetal effects of

maternal diabetes
-Fetopraotein
Detect open fetal

defect
High: possible open fetal

anomaly Low: possible chromosomal aneuploidy
Genetic testing
Test for Tay-Sachs,

sickle cell disease,
thalassemia
16
Can be performed in both

parents before marriage in
couples at risk
Genetic amnio- Test for chromosomal 16

centesis
defects
Small risk of complications;

diabetes does not increase risk
of chromosomal abnormalities
Chorionic villus Test for chromosomal 8-10

sampling
abnormalities
Increased rate of miscarriage
Fetal activity
Simple; inexpensive
Screen for fetal well- 32-40

being

149
Contraction
stress (oxytocin)
Test for fetal distress
35-40*
May not detect the metabolically sick fetus
Nonstress
Screen for fetal well- 35-40*

being
False-positive results in a
sleeping, immature, or normal
fetus
Biophysical
Evaluate chronic and

acute fetal problems
May be the most reliable

profile via ultrasound
Amniocentesis
Optimize delivery
timing for lung
maturity
35-40*
Before nonemergency induction of labor or cesarean

section
* Depending on clinical situation
Medical Nutrition Therapy (MNT)

An adequate diet, appropriate weight gain and maintenance of normoglycemia are critical for
maintaining maternal body tissues and for optimal fetal growth and development. Medical
nutrition therapy in women with diabetes should be directed by a dietician familiar with diabetes 47. Daily caloric requirements in pregnancy can be calculated from prepregnancy weight
and are estimated to be 30 kcal/kg per day for women of normal body mass index. Studies
have explored that women weighing more than their IBW require fewer calories to maintain
pregnancy, without affecting fetal outcome 45. Recommended calorie intake and distribution is
shown in Table 11 & Table 12.
150
Table 11. The Jovanovic Diet (50)
% of Ideal Body Weight

80% to 120%
121% to 150%
> 151%
Daily Calories per kg Body Weight

30
24
12 to 15
Table 12. The recommended calorie distribution(50)
40-50% - Carbohydrate
20%
- Protein
30-40% - Fat.
10% of Calories at breakfast

20-30 % of Calories at lunch
30-40 % of Calories at dinner
30 % of Calories as snacks
The recommended distribution of total calorie from carbohydrate, protein & fat is shown in
Table 12. Monitoring carbohydrate intake is the key to achieving good glycemic control, which
can be obtained through counting carbohydrates and adjusting the insulin dose required, or
through maintaining a fixed amount of carbohydrates and a fixed dose of insulin per meal.
Carbohydrates of low glycemic index lead to a blunted postprandial glucose level and improve
ease of glycemic control. Studies have shown that up to 40% Carbohydrate in diet reduces
post prandial spikes and diet with low glycemic index reduces need for insulin 48. Diet for
women with type 2 diabetes often includes a program to lose or maintain weight. However,
in pregnancy, weight loss should not be a goal and following the general guidelines for weight
gain in pregnancy is recommended 49. Women are encouraged to consume vegetables and fruits,
choose whole grain foods over processed grain products, include fish approximately once a
week, choose lean meats and nonfat dairy products, and drink water and calorie-free drinks
(in moderation) instead of regular sugar-sweetened drinks. Women are recommended to use
liquid oils for cooking instead of solid fats and cut back on high-calorie foods such as potato
chips, cookies, cakes, and full-fat ice cream. Certain women with hyperlipidemia or renal disease
may require more targeted medical nutrition therapy. The recommended weight gain during
pregnancy depends on prepregnancy weight of diabetic women as shown in (Table 13)
Table 13. Recommended Weight Gain During Pregnancy (7)
Prepregnancy Weight Status

< 90% Desirable body weight
Desirable body weight
>135% desirable body weight
Recommended Weight Gain (lb)

28-40
25-35
15-25
Artificial Sweeteners
Use of artificial sweetness is generally safe in pregnancy. Studies have found no adverse
effect on fertility, birth weight or fetal morbidly, mortality with the use of artificial
sweeteners in pregnancy. The U.S. Food and Drug Administration (FDA) has, approved five
nonnutritive sweeteners (acesulfame, aspartame, neotame, saccharin, and Sucralose) and
several reduced-calorie sweeteners (e.g., erythritol, mannitol, sorbitol) for use in the United
States, including during pregnancy 51. Because phenylalanine is one of the metabolites of
aspartame, pregnant women with phenylketonuria must consider food containing aspartame as additional sources of phenylalanine.
Postpartum Nutritional Management

Breast feeding is recommended for women with diabetes. Energy demands of lactation
exceeds by 640kcal per day during first 6 months postpartum. It is normal for women
to lose weight for 1st 6 months at the average rate of 0.5-1 kg /month after 1st month
postpartum. Rapid weight loss (>2kg /month) is not recommended.
Management of Morning Sickness

Morning sickness-nausea or vomiting during pregnancy affects up to 70% of pregnant
women. The symptoms begin 6wk after the start of the last menstrual period and last
for 6-12wk. Nausea is worse when stomach is empty. Dietary Tips for controlled nausea is
given in Table 13. Insulin dose need to be adjusted with help SMBG during morning sickness to prevent hypoglycemia. If vomiting is severe, then hospitalization, IV fluids, potassium replacement, close monitoring of blood glucose, ketonuria and sometimes antiemetic
medications may be needed. (Table-14)
Table 14, Tips for Controlling Nausea (7)
Eat dry crackers or toast before rising

Eat small meals every 2.5-3 h
Avoid caffeine
Avoid fatty and spicy foods
Drink fluids between meals, not with meals
Take prenatal vitamins after dinner or at bedtime
Always carry food
151
Insulin During Pregnancy in Preexisting Diabetes

Metabolic Alterations During Gestation: During pregnancy, metabolism adapts to meet
maternal needs and to provide fuel for the growing fetoplacental unit52. Beginning in
early gestation, glucose reaches the fetus by facilitated diffusion it crosses the placenta
at a rate faster than would be predicted physiologically. Similarly, aminoacids are actively
transported to the fetal circulation against a concentration gradient of particular importance is a decrease in the maternal plasma concentration of the gluconeogenic amino
acid alanine. Loss of glucose and gluconeogenic substrate to the fetus occurs concomitantly and conspires to cause maternal hypoglycemia during early pregnancy. Toward the
end of the 1st trimester, it is common for insulin requirements in women with diabetes
to diminish by 10-20% of the dosage taken before conception. Moreover blood glucose
control during the 1st trimester is more unstable than usual and nocturnal hypoglycemia
is especially common 7.
At 18-24 wk gestation, the so-called diabetogenic stress of pregnancy begins, and daily
insulin requirement typically begins to increase. In late pregnancy, basal insulin levels
are higher than normal to gravid levels, and eating produces a two-to threefold greater
outpouring of insulin52. These increases in plasma insulin are opposed by diminished responsiveness to insulin action due to placental production of contrainsulin hormoneshuman placental lactogen, prolactin, estrogen, and progesterone and increased maternal
production of cortisol.
152
During the 2nd and 3rd trimesters, insulin requirements gradually increase to as much as
twice the total daily dosage of insulin needed before pregnancy. Placental growth and
the production of contrainsulin hormones plateau at ~ 36 wk. As a result, the dosage of
insulin necessary to maintain euglycemia increases very little, if at all, from 36 wk until
term. A decrease in insulin requirement after 36 wk should not necessarily be interpreted
as an indication of a failing fetoplacental unit.
After delivery of the placenta, human placental lactogen, estrogen, and progesterone rapidly clear from the circulation. Pituitary growth hormone and gonadotropin remain suppressed, despite the falling placental hormones. The result is a state of panhypopituitarism
In addition, high prepartum dose of insulin create stores of bound insulin that continue to
be released. whereas the need for insulin diminishes. Therefore, it is sometimes unnecessary
to resume subcutaneous insulin injections for as long as 48-72 h postpartum.
Insulin Therapy
The primary goal of insulin therapy is to achieve the acceptable glycemic control throughout the pregnancy without causing hypoglycemia. Pregnant diabetic women, who cannot
achieve the glycemic goals with exercise and diet, should be put on insulin therapy. Hyperglycemia resulting from meals can be treated with rapid acting insulin that is absorbed
quickly enough to blunt peak postprandial glucose elevations, while basal (NPH) insulin is
used to cover the fasting hyperglycemia53 initially, clinicians feared that nonhuman insulin
would trigger insulin antibody responses in the fetus after crossing the placental barrier.
Studies have now proved the safety of using rapid-acting insulin analogs, such as lispro
or aspart, that mimic the normal physiologic first phase insulin secretion by the pancreas
54
. They lower post-prandial levels without increases in hypoglycemia and improved patient satisfaction and compliance (ease of taking only 15 minutes before meals) without
an increase in adverse fetal outcomes55. See figure-1 for action profile of various Insulins.
Insulin dosage regimens depend directly on the patients weight and number of weeks of
gestation. There is smooth rise in insulin requirements throughout pregnancy. The formula
for determining a patients 24-hour insulin requirement, Big I is:
Big I = Weight x k
Where weight is in kilograms and k=0.7 units of insulin for the first trimester, 0.8 for the
second trimester, 0.9 for the third trimester, and 1.0 for term.56. When using this algorithm
in pregnancy, Big I is divided in half to give the daily basal insulin requirement (0.5 Big
I) and daily bolus insulin requirement (0.5 Big I).
Glargine, a long-acting insulin analog is classified as Pregnancy Category C according to
the FDA. In vitro studies suggest that glargine might stimulate insulin-like growth factor 1,
and use in human pregnancy has caused concern for macrosomia. However, many women
treated with glargine for their basal insulin requirements have become pregnant with no
adverse outcome. Several retrospective reports are now in the literature noting the safety
of glargine insulin in pregnancy 57, 58.
Until long-acting insulin analogs have been proved safe in pregnancy, the recommended
protocol for insulin therapy in pregnancy is short acting insulin or rapid acting analogue
with each meal along with NPH insulin before dinner is the best regimen for most of
pregestational diabetic women. This gives better precision & flexibility 59.
Figure -1
153
Preterm Delivery and Insulin doses 7

Preterm delivery can be particularly hazardous and presents a special therapeutic dilemma
in diabetic pregnancy. B- Sympathominetics, the most commonly used tocolytic agents, are
capable of causing rapid and extreme elevations in maternal glucose concentration and
possibly ketoacidosis. Corticosteroids, used to accelerate fetal lung maturation, can further
exacerbate hyperglycemia. However, if no attempt is made to half preterm labor, respiratory
distress syndrome in the premature infant may result. The following protocol may be used
to adjust insulin dosage when corticosteroids are needed to enhance fetal lung maturity:
Give 12 mg dexamethasone orally on two successive mornings.During the 2 days of steroid
therapy, double the total daily dosage of insulin.
Check blood glucose concentration every 4 h, and give supplemental short-acting insulin
as needed.
Insulin Pumps
Insulin pumps are commonly filled with lispro or aspart. Basal insulin administration is
continuous through the pump and should be approximately 50% to 60% of the total daily
insulin requirement; the remaining daily requirement is administered as boluses with meals
and snacks. Most people will require at least three infusion rates: 2300-0400hr, 0400900hr, and 0900-2300 hrs. From 0400 to 1000 hrs, cortical and growth hormone levels
rise, and basal rate of insulin must be increased. A meta-analysis of randomized controlled
trials evaluating the differences between the uses of continuous insulin infusion versus
multiple-dose insulin did not show any statistical difference in pregnancy outcome or
glycemic control60. Other investigators found less hypoglycemic episodes with the pump 61
Insulin During Labour and Delivery7

Intrapartum glycemic control plays a major role in the well-being of the neonate. Maternal
hyperglycemia is the major cause of neonatal hyperglycemia. At the onset of active labor,
insulin requirements decrease to 0, and glucose requirements are relatively constant at
~2.5 mg.kg-1.min 52.
154
The goal is to maintain plasma glucose concentration between 70 and 90 mg/dl.

On the evening before elective induction, the usual bedtime dose of NPH insulin may
be given.
On the morning of induction, insulin is withheld and an IV infusion of normal saline

begun.
Once active labor commences or plasma glucose level falls to <70mg/dl, normal saline
should be changed to 5 % dextrose
Glucose level should be monitored hourly, and if it is < 60 mg /dl, the infusion rate
should be doubled for the subsequent hour.
If the plasma glucose concentration rises to > 140 mg/dl, 2-4 U short- acting insulin
can be given IV or subcutaneously each hour until the glucose value is within the
range of 70-90 mg/dl.
With Elective Cesarean Delivery

The bedtime dose of intermediate acting insulin may be given on the morning of surgery
and every

8 h if surgery is delayed.
A dextrose infusion as described above may be started if the plasma glucose falls to
< 60 mg/dl
Alternatively, glycemic control before elective cesarean delivery can be achieved with
an infusion
of 1-2 U/h I V. short-acting insulin given simultaneously with 5 g/h dextrose. The
insulin infusion should be discontinued immediately before surgery.
Hourly blood glucose determinations are mandatory for individualization of these

protocols.
Postpartum Insulin Requirements 7

After delivery, insulin requirements diminish precipitously. As a result, it is often unnecessary to administer subcutaneous insulin for 24-72 h. Insulin requirements should be
recalculated, based on postpartum weight and should be started when either postprandial
or fasting glucose is > 150 mg/dl.
Breast Feeding: Several investigators have reported that patterns of glucose control may
be erratic in lactating diabetic women. Episodes of hypoglycemia appear to be common.
Hypoglycemia is most likely to occur within an hour after breastfeeding, which can be
avoided by eating a small snack before breastfeeding rather than making frequent adjustments of the insulin dosage 62. Nocturnal hypoglycemia is particularly common. Therefore,
blood glucose should be periodically checked during the night, and the evening dose of
intermediate insulin should be decreased if hypoglycemia is documented.
Oral Antidiabetic Agent in Women with Type 2 Diabetes During Pregnancy

Ideally, women with type 2 diabetes should stop oral antidiabetic agents and start insulin
before pregnancy. If women develops pregnancy on OHA, then OHA should be withdrawn
on the first given opportunity. To date, there are no data on use of Thiazolidinediones in
pregnancy and are thus contraindicated in women seeking pregnancy. The evidence that
oral hypoglycemic agents are terato-genic in human pregnancy is confounded by the high
background risk of congenital anomalies in poorly controlled type 2 diabetic pregnancies
8
and by the differing abilities of oral antidiabetic agents to cross the human placenta63.
Langer et al 64 recently compared Glibenclamide (given after 11th week of gestation) in
randomized trial with insulin in 404 women with GDM. Glibenclamide was as efficacious
and safe as insulin, at least in managing GDM. This study also showed that cord serum
insulin concentrations were similar in two groups and that Glibenclamide was undetectable in cord blood, thus confirming that it crosses placenta minimally. Glibenclamide is
therefore unlikely to be teratogenic or accelerate fetal growth through feral hyperinsulinemia. However US- FDA has not yet approved its use in pregnancy65. Metformin is a
popular drug in treatment of Poly Cystic Ovary Syndrome (PCOS) . When these women
become pregnant the fetus is exposed to the drug during 1st trimester. Physician faces the
dilemma, whether to withdraw the drug during pregnancy and if yes, when? In a study
by Glueck etal , women with PCOS received Metformin to reduce the occurrence of GDM
from 31% to 3% No major fetal malformation or fetal hypoglycemia reported in 34 live
births. Metformin was also found to decrease the rate of pregnancy loss to 11% compared
to 50% among untreated women. Recent trial showed no adverse effect of Metformin
in terms of anomalies. Large New Zealand Australian study (MIG Trial) is expected to
answer most of Metformin related queries. Data of 379 pregnancies form Cape Town,
South Africa suggest that Metformin and Glibenclamide are not teratogenic, but that it is
155
advisable to replace Oral Glucose Lowering Agent, in particular Glibenclamide, with insulin
when women book for pregnancy care to reduce perinatal mortality 66.
Oral Antidiabetic Drugs During Lactation

Insulin does not cross into breast milk, but sulfonylureas do. Glibenclamide and Glipizide
indicated their passage in to breast milk, Metformin is expected to cross breast milk, but
infant exposure to drug was only 0.26% Thus it seem to be a safe drug 67 it is recommended not to start oral antidiabetic drug in post partum phase if the baby is breastfed.
Conclusion
Now that we have been forewarned of the growing pandemic of type 2 diabetes in pregnancy, we need to become forearmed. The thrust must be in education for care provider
i.e. enhanced recognition of this growing entity and a heightened awareness of the need
for pre-pregnancy counseling about preconception glycemic control. With education, close
monitoring and newer therapeutic modalities, pregnant women with diabetes can have
healthy newborns. Close attention to diet, glycemic control metabolic stress and early
diagnosis and monitoring of complication can make pregnancy a successful experience
for women with diabetes.
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159


Mrs. Kamlesh Sethi
Dietitian
160
Department of Dietetics
UCMS & GTB Hospital, Delhi-110095
e-mail: kamleshsethi@ymail.com
&
Dr. R Avasthi
Professor
Department of Medicine
UCMS & GTB Hospital, Delhi-110095
E-mail: rajnishavasthi@yahoo.co.in
Introduction
Worldwide prevalence of type 2 diabetes is increasing rapidly and it is closely related with
socioeconomic growth and lifestyle changes and high prevalence of obesity. In the United
States it is now estimated that two-third of adult Americans are overweight with BMI more
than 25 kg/m2 and 32% are obese with a BMI >30 kg/m2. There are currently 24 million
people with diabetes in USA in addition to approximately 58 million people with impaired
glucose tolerance and 24% of the adult meeting ATP-III criteria for metabolic syndrome.
The situation is worse off in the Asian subcontinent and India has been labeled as world
capital of diabetics with current estimate of known diabetics being over 32 million with
nearly 98 percent being affected by type 2 diabetes. In addition, there is significant pool
of patients with IFG and IGT. Metabolic syndrome is being increasing recognized in the
urban population.
Essentially the treatment strategies in type 2 diabetes are directed towards intensive glycemic management so as to lower A1C level which has been shown to have a beneficial
effect on cardiovascular disease complications. Lifestyle directed intervention and nutritional management however remain the central theme of any management scheme for
type 2 diabetes. The nutritional management in Indian subjects is specially a challenging
area in view of various socioeconomic factors demography, ethnic background and variably
practiced cooking habits and beliefs.
The Goal of Dietary Modification in the Type 2 Diabetes

There is definitive and strong suggestive evidence in type 1 diabetes that intense control
of serum glucose level to within the normal range delays the complications. Diabetes
prevention programme has provided conclusive evidence that intervention with pharmacotherapy and lifestyle modifications can prevent type 2 diabetes, in a significant number of
at-high risk individuals. Further, interventions for supervised weight loss can mitigate both
cardiovascular risk as well as new onset diabetes in certain insulin resistance states. There
is enough evidence that nutritional management is important component to achieve and
maintain good glycemia. Other goals of dietary therapy include regulation of serum lipid,
weight control, and targeted treatment of complications such as hypertension, coronary
arteries disease and renal failure.
The goals of dietary management are:

To maintain or improve health through the use of appropriate and healthy food
choices.
To achieve and maintain optimal metabolic and physiological outcomes including

- Reduction of risk for microvascular disease by achieving near normal glycaemia
without undue risk of hypoglycemia;
- Reduction of risk of macrovascular disease including management of body
weight, dyslipidemia, and hypertension
Address the specific nutritional requirements of special people with diabetes, particularly, pregnant and lactating women, elderly adults and those receiving insulin or
insulin secretagogues for treatment.
161
Metabolic Problems in Type 2 Diabetes

The metabolic dysregulation in diabetes adversely affects the carbohydrate and lipid metabolism in the body and causes secondary pathophysiologic change in multiple organ
systems. Other than the pathognomonic hyperglycemia, subjects with diabetes also harbour
several forms of dyslipidemia, the most common of them being raised triglycerides and low
HDL-cholesterol value. The disease does not itself increase the levels of LDL-cholesterol,
yet the peculiar dense LDL particle found in type 2 diabetes are more atherogenic as they
tend to get easily glycated and are especially susceptible to oxidation5. Dietary alterations,
which promote a better glycemic and lipid control, contribute improved overall healthy
and thus outcomes.
Nutritional Recommendations in Type 2 Diabetes Mellitus

The nutritional requirements of a diabetic are the same as in the normal adult person.
The diabetic diet need not completely change from the normal diet which is high in carbohydrate, with carbohydrate content 60-65%, fat 15-25% of total calories and balance
is derived from proteins. Thus even a regular diet is suitable for a diabetic, but individual
diet plan is important for providing nutrients as per his/her requirement according to age,
sex, weight, height, physical activity and physiological needs of the patients.
Before recommending diet for diabetic patient, detailed information of day-to-day activity along with his/her current dietary history and comorbidities are taken. On the basis
of nature of physical activity, weight and diet history, the daily requirement of calories
are calculated.
162
a. Energy / Calories
The focus of dietary plans should be on balancing energy intake to energy expenditure
and the quality of carbohydrate and fat rather than quantity alone. To calculate caloric
requirement ideal body weight based upon height is available for Indian subjects (Table
1). These act as quick guides in assessing the requirements of calories. More recently Body
Mass Index (BMI) calculated by formula (kg/m2) and based upon weight in kilograms and
height in meters has gained popularity in assessment of nutritional status. Consensus
statement for diagnosis of obesity recommends following cut offs:
Normal BMI: 18.0-22.9 kg/m2
Overweight: 23.0-24.9 kg/m2
Obesity: >25.0 kg/m2
Table 1: Body weight ideal for height for Indian men and women
Height without shoes (approximate equivalents)

Meters
Feet
Inches
1.50
4
11
1.53
5
0
1.55
5
1
1.58
5
2
1.60
5
3
1.63
5
4
1.65
5
5
1.68
5
6
1.70
5
7
1.73
5
8
1.75
5
9
1.78
5
10
1.80
5
11
1.83
6
0
1.85
6
1
1.87
6
2
Weight in kilograms
Men
Women
52-56
49-53
54-58
51-54
55-59
52-55
58-60
53-57
58-62
54-59
59-64
56-60
61-65
58-61
62-67
59-64
64-69
61-65
66-71
62-67
68-73
64-68
69-74
66-70
71-76
67-72
73-78
69-74
75-81
78-83
BMI does not accurately reflect fat mass or its distribution and is not considered the best
predictor of diabetes. The consensus statement recommends waist circumference as criteria
for abdominal obesity for Asian Indians as >90 cm in males and >80 cm in females.
HAMWI method is a simple and quick tool used by nutritionists for calculation of ideal
body weight.
Females: 100 lbs (45.5 kg) for the first 5 feet + 5 lb (2.3 kg) for each additional inch
(10% of small / large frame).
Males: 106 lbs (48.0 kg) for the first 5 feet + 6 lb (2.7 kg) for each additional inch (10)
for small / large frame).
For example, we can calculate the ideal body weight of a medium frame man with height
5 ft 5 inch, 48.0 kg for first five feet + 2.7 x 5 inch, i.e. 48.0 kg + 13.5 kg = 61.5 kg
Thus the ideal body weight of the man is 61.5 kg.
Energy requirements for diabetic patients based upon their classification as normal, overweight or obese as discussed previously can be calculated as per table given below. This
is depicted by the individuals activity level.
163
Energy Requirement for Diabetic Patients

Table 2: Energy Requirement (kcal / kg/ IBW/day)
Activity
Sedentary
Moderate
Heavy
Obese
20-25
30
35
Normal
30
35
40
Overweight
35
40
45-50
The value of IBW is utilized for calculating the energy requirement of normal / under /
overweight patients.
The recommended dietary allowances for normal Indian is given in Table below. The calories
recommended for diabetics are lower as compared to normal individuals.
Table 3: Recommended dietary allowance for Normal and Diabetic Indian individuals
Group
Men
Women
Body
Particulars
weight (kg)
60
Sedentary
50
164
Boys
Girls
35.4
31.5
Energy
(kcal/day)
2425
Proteins (d/day)
Fats (g/day)
60
20
Moderate
2875
Heavy
Sedentary
3800
1875
Moderate
2225
50
20
Heavy
2925
+15
30
Pregnant
+300
+25
45
Lactating
+550
+18
45
0-6 months
+400
6-12 months
10-12 years
10-12 years
2190
1970
54
57
22
22
Source: Nutrient Requirements and Recommended Dietary

Allowances for Indians, Indian Council of Medical Research, 1989
The Total daily intake of calories then distributed in different

macronutrient like carbohydrate, protein fat.
Table 4: Distribution of Macronutrient in Total Calories
Carbohydrate
Protein
Fat
% of total calories
60-65
15-20
15-25
b. Carbohydrate
Carbohydrate are the most significant source of energy in the diet in developing countries
up to 85% of energy in the diet is provided by carbohydrate in case of some developed
countries this figure is as low as 40%. In our Indian diets, carbohydrates provide 60-70%
of the total calories. Diabetics need not to restrict the carbohydrate intake, but alter the
type of carbohydrate in their diet more complex carbohydrate in the form of cereals,
pulses, legumes. It is recommended that 60-70% of calories from the complex carbohydrate.
Low carbohydrate diet seems to be a logical approach to lowering postprandial glucose.
Carbohydrate containing foods are important sources of energy, fiber, vitamins and minerals
and are important in diet bioavailability. Although there are no data specifically in patients
with diabetes, diet containing total carbohydrate to <130 g/day are not recommended in
the management of diabetes due to risk of ketoacidocsis / hypoglycemia on other hand
an intake >300 g may elicit a hyperglycemic shock.
It is important to distribute the intake of carbohydrates in accordance with daily needs.
Since the blood sugar level depends mainly on the intake of carbohydrate. The total amount
of carbohydrate intake divided into 4-5 equal parts one third (33%) during lunch, one
third (33%) in dinner, 25% during breakfast and rest 9% during evening tea.
(i) Glycemic index / Glycemic load
Glycemic index is the numerical index given to a carbohydrate rich food that is based on
the average increase in blood glucose level occurring in blood after the food is eaten. The
higher the number, the greater the blood sugar response.
We can calculate the glycemic index of food by using this formula.

(Area under 2 hours response for equivalent glucose)
GI=------------------------------------------------------------------x 100

(Area under 2 hours blood response curve top test food)
A GI of >70 or more is high, a GI of 56 to 69 is medium and GI of 55 or less is low. The

glycemic index informs us how rapidly a particular, carbohydrate turn into sugar. It does
not tell us how much of carbohydrate is actually present in a serving of a particular food.
The glycemic load of a food is the glycemic index divided by hundred and multiplied by
its available carbohydrate contents (i.e. carbohydrate minus fibre) in grams. The glycemic
load is a relatively new way to assess the impact of carbohydrate consumption that takes
the glycemic index into account.
ii) Glycemic Load = Carbohydrate in Food Portion (gm x GI) / 100
The glycemic loads of foods, meals and diets are calculated by multiplying the glycemic
index of the constituent foods by the amounts of carbohydrate in each food and the totaling the value for all foods. Foods with low glycemic indexes includes oats, barley, bulgur,
beans, lentils, legumes, pasta, coarse, apples, oranges, milk, yogurt and ice-cream. Fiber,
fructose, lactose, and fat are dietary constituents that tend to lower glycemic response.
A recent meta-analysis of trial diet conducted in diabetes subjects showed that low glycemic index diets produced a 0-4 percent decrement A1C when compared to high glycemic
index diets. Food with a high glycemic index such as pasta and bread need not elicit a
postprandial spike in glucose and insulin, in such an effect is blunted by other food conNutritional Recommendations in T2DM
165
sumed concurrently. Food rich in soluble fiber are particulars effecting attenuating such a
response, high carbohydrate food such as most whole grains, legumes, beans, vegetable and
even fruits can contribute to low GL dietary patterns. Such foods also provide a diversity
of micronutrients of potential importance to overall health and cardiovascular health
specifically, antioxidants, flavonoids and carotenoids. Potential methodological problems
with the glycemic index have been noted.
The Glycaemic Index (GI) aims to quantify the blood sugar response after eating specific
foods. This has potential significance in diabetes where fluctuations or rapid increase
in blood sugar are undesirable. However, GI values vary considerably depending on the
exact nature of the food (e.g. method of processing or cooking, degree or ripeness etc.
and whether they are eaten alone or as accompanying a meal providing mixed macronutrients. At present, it is recommended that Glycaemic Index should act as a guide to a
foods overall glycaemic effect taken in conjunction with other dietary components but
it should be the sole criteria while advising food related issues in diabetic. It is using GI
value to provide a broad guide to a foods glyceamic effect may be a helpful adjunct to
other dietary issue, but that it should not be relied upon as the most important feature
of food-related advice.
Table 5: Glycaemic index of common foods
166
Item
Cereal products
Bread
Millets
Rice (white)
Wheat (Paratha)
Breakfast snacks
Pongal
Paratha
Upma
Idli
Chole
Sprout green gram
Sundal
Daily products
Milk
Ice-cream
Curd
Miscellaneous
Groundnut
Potato chip
Tomato soup
Glycemic index
70
71
72
70
55
60
75
80
65
60
80
33
36
36
13
51
38
Item
Fruits
Apple
Banana
Orange
Vegetables
Broun beans
Frozen beans
Potato
Sweet potato
Yam
Beetroot
Dried legumes
Soya bean
Rajmah
Bengal gram
Green gram
Black gram
Sugars
Fructose
Glucose
Maltose
Sucrose
Glycemic index
39
69
40
79
51
70
48
51
64
43
29
47
48
48
20
100
105
59-87
Sucrose 59-87: Source: Jenkins et al 1981; Am J Clin Nutr 34 : 362, 1981 ;

Raghuram et al. Diabetes Bull 7 : 64, 1977 ; Dilwari et al. Diet Digestion & Diabetes 1987
(iii) Sweetener
Substantial evidence from clinical studies demonstrated that dietary sucrose does not increase glycemia more than isocalories amounts of starch. Sucrose and sucrose containing
foods need not to be restricted because of concerns of aggravating hyperglycemia. It can
be substituted for other carbohydrate in the meal plan, adequately covered within insulin
or another glucose lowering medication, care should be taken to avoid excess energy
intake. Since the postprandial glucose response for fructose rich foods is lower than that
for food containing sucrose or starch, people with diabetes should prefer fruits, vegetables
and other natural foods which are rich in fructose. Fructose from these sources usually
accounts for only 3-4% of energy intake.
(iv) Sugar Substitutes
Non-nutritive sweeteners such as aspartame, sucrose and saccharin, confer sweetness without calories and do not raise serum glucose. These may be helpful in efforts to control
serum glucose and maintain weight loss, but evidence is lacking of sustainable benefit.
Stevia is a sweetener made by plant extracts from a group of herbs. It has been widely
used in foods; stevia provides 30 to 300 times the sweetness of sugar.
c. Protein
Proteins are essential for growth, development and tissue repair, when required it also
provide energy in the body. One gram of protein provides 4 kcal of energy. It is generally
recommended that 15-20% of total calories be derived from proteins. The Recommended
Dietary Allowance (RDA) for proteins is 1.0g/kg body weight and with high quality protein
intake recommended dietary intake 0.8 gm/kg body weight/day. Protein restriction may be
indicated if renal insufficiency develops. In patients with type 2 diabetes, ingested protein
does not raise plasma glucose concentration but does increase serum insulin response, and
thus protein should not be used to treat acute / prevent nighttime hypoglycemia. Short
term studies in diabetes suggest that diet with protein contents >20% of total energy
reduce glucose and insulin concentration, reduce appetite, and increase satiety. However,
the effect of high protein diet on long term regulation of energy intake and other factor
has not been adequately studied.
d. Fat
Fats are concentrated source of energy. One gram of fat provides 9 kcal. Fats contain essential fatty acids and are also source of fat soluble vitamins such as vitamins A, D, E and K.
With respect to dietary fats the primary goal in diabetics is to limit saturated fatty acids,
transfatty acids and cholesterol intake so as to reduce risk of CVD. Therefore, in diabetics,
saturated fats should contribute < 7% of total calories. Intake of transfat should be minimized. Dietary cholesterol should be <200 mg/day. High monosaturated fat diets have not
been shown to improve fasting plasma glucose or A1C value. Diets high in polyunsaturated
fatty acids appear to have effects similar to monounsaturated fatty acid on plasma lipid
concentration. Consumption omega-3 fatty acid from fish or from supplement has been
shown to reduce adverse CVD outcomes, but the evidence for a-linolenic acid is spare
and inconclusive.
e. Fiber
Dietary fiber is the part of food that is not digested by the gut and is considered as
unavailable carbohydrate. A daily intake of approximately 30 g of dietary fiber from a
167
variety of food sources is recommended in general population for health promotion and in
management of diabetes. There is evidence that soluble fiber in particular may be beneficial
in controlling both glucose and lipid levels in diabetes. In a study of men with type 2
diabetes, Anderson et al reported significant improvement in both lipids and glucose with
twice daily psyllium totaling 10 g, for a period of eight weeks. Fruits, oats, barley and
legumes are particulars good source of soluble fiber.
Table 6: Dietary Fibre Content of Some Common Indian Foods
168
Food
Cereals and Millets
Rice
Wheat
Sorghum
Bajra
Ragi
Pulses and Legumes
Green gram dhal
Black gram dhal
Red gram dhal
Bengal gram dhal
Nuts and Oilseeds
Groundnut
Coconut dry (copra)
Roots and Tubers
Sweet potato
Potato
Yam
Fruits
Banana
Mango
Vegetable
Amaranth
Palak
Brinjal
Ridge grourd
Snake gourd
Bottle gourd
Yellow pumpkin
Dietary fibre (g/100 g)

7.6
17.6
14.3
20.3
18.6
13.5
14.3
14.1
13.6
6.1
8.9
7.3
4.0
5.3
2.5
2.3
3.4
5.0
2.0
5.7
1.8
2.8
0.5
f. Alcohol
Abstention from alcohol should be advised for people with a history of alcohol abuse
or dependence, and with medical problems such as liver disease, pancreatitis, advanced
neuropathy or severe hypertriglyceridemia. Use of alcohol should be limited to moderate
amount (less than one drink / day for adult women and less than two drinks per day for
adult men). Excessive amounts of alcohol (3 or more drink per day) on consistent basis,
contributes to hyperglycemia.
g. Micronutrient Intake
Uncontrolled diabetes is often associated with micronutrient deficiencies. Individuals with
diabetes should be aware of the importance of acquiring daily vitamin and mineral requirement from nature / food source and a balance diet. There is no clear evidence of benefit
of vitamin and mineral supplements in people with diabetes.
h. Antioxidants Intake
Diabetes may be a state of increased oxidative stress, there has been interest in antioxidant therapy, but available data do not support the use of antioxidant supplement for
CVD risk reduction.
Healthy lifestyle nutrition recommendations for general population are also appropriate
for person with type 2 diabetes, as majority of type 2 diabetics are overweight and insulin resistant. So lifestyle modification that results in reduced calories intake and increase
physical activity level should be recommended. Increased physical activity in type 2 diabetes can lead to improved glycemia, decrease in insulin resistance, and a reduction in
cardiovascular risk factors. At least 150 min/week of moderate intensity aerobic physical
activity, distributed over at least 3 days are known to improve hyperglycaemia. Plasma
glucose monitoring can be used to determine whether adjustments in foods and meals
will be sufficient to achieve blood glucose goal.
Nutrition Recommendations for Controlling Diabetes Complications

Progression of potential diabetes complications like nephropathy and retinopathy can be
modified by improving glycemic control, lowering blood pressure and reducing protein
intake. In several studies conducted in diabetics having microalbuminuria, a reduction in
protein intake to 0.8-1.0 g/kg body weight / day favourably influenced the glomerular
filtration and urinary albumin excretion rate. Observation data also suggest that dyslipidemia may increase albumin excretion and the rate of progression of diabetic nephropathy.
Dietary modifications designed to reduce the risk for cardiovascular disease may therefore
limit the microvascular complications in diabetes.
Averting cardiovascular, cerebrovascular and peripheral vascular complications is a major
secondary goal in the management of type 2 diabetes mellitus. The following dietary approaches may prove beneficial:
Low calorie diet to achieve and maintain a modest weight loss in the overweight patients. This is likely to benefit the glycemic control as well as the blood pressure control.
Reduction in the salt intake, with a higher limit set at 5-6 g/day in all normotensive
and hypertensive patient. A diet rich in natural foods like fruits, vegetables, whole
grains, beans, nuts and low fat dairy products is extremely useful.
169
Reduction in dietary sodium intake to less than 2 g/day in those patients with diabetes
who suffer from moderate to severe chronic heart failure.
The contents and frequency of the meals should be planned in a manner that glycosylatedhemoglobin (HbA1C) remains as close to normal as possible without the patients
developing hypoglycemia at any time.
Role of functional foods

Some herbs and plant foods may exert a beneficial effect on the glycemic control in
people with diabetes. Ayurveda recognizes at least three such plant foods; the seeds of
fenugreek (Methi), the Jamun fruits and fresh juice of bitter gourd (Karela). The good effect of fenugreek seeds has been corroborated by several biochemical studies. The benefit
probably related to the active alkaloid trigonelline present in fenugreek seeds and the
high fibre contents. A pre-lunch and pre-dinner regimen of 25 g fenugreek seed taken
15 minutes before the principal meal may well improve the glycemic control in a patient.
The seeds should be consumed after overnight soaking with water or used as powder
dissolved in water or buttermilk. The seed powder may also be mixed with flour, rice,
legumes and vegetables.
Jamun also has a sugar lowering effect. An active principle, alpha-glucosidase inhibitor,
has been isolated from the fruits. This action of Jamun seems to be similar in nature to
that of the alpha-glucosidase inhibitor drug Acarbose.
The useful role of Momordica Charanita (bitter gourd) in improving the glycemic control
has also been a subject of study. It is said to contain a peptide much like vegetable insulin.
170
The best use of these plant foods is to take them as a recipe for an improved glycemic
control. However, they cannot be taken as substitutes for insulin or the other sugar lowering agents. The use of dietary supplements is common with almost one third of patients
using one or more than one supplements. Majority of the patients may not share such
information with their providers and secondly such drugs can cause side effects and interactions with prescriptions or over-the counter drugs.
Education
The diabetics should be educated on the nature of disease(s) they have and the possibility of development of acute and long term complications of disease, if blood sugar is
not kept under control. Adequate basic information on diabetes enables the diabetic to
comprehend and improve their psychological acceptance of the disease. In addition, the
importance of following the doctors instructions regarding diet, exercise, and drugs should
be explained. Lifestyle is influenced by culture and peers become role imperative models.
For a diabetic it may not be feasible to follow a perfectly normal life pattern and it is
imperative to make lifestyle more organized and disciplined. Some of the points to be
remember to prevent diabetes:

Maintain ideal body weight

Avoid high sugar, salt and fat foods
Take small bites and chew food thoroughly, eat and drink slowly
Eat protein rich food at each meal
Eat wisely at social gatherings and restaurants
Do physical activity, walk daily
Avoid aerated and excessive alcoholic drinks

Minimize use of tobacco and other harmful drugs
Use artificial sweeteners if you wish to have a sweet food
Read and educate yourself on various aspects of diabetes.
Avoid stress, enjoy good music, meditate and have positive attitude towards life.
Make lifestyle behavior change for better health.
Case Study
Example: Mr. Sharma is a busy office executive who was diagnosed to be suffering from
NIDDM about three years back. Over the past 3 years he has experienced several episodes
of hyper and hypoglycemia. He is 57 tall and weight 93 kgs calculate ideal body weight
and plan a diabetic diet chart.
Patients Profile
Name Mr. Sharma
Age 45 years male
Activity Sedentary
Dietary habits Non-vegetarian
Socio-economic status Upper MIG
Patients present weight 93 kg
*The ideal bodyweight can be calculated as per the following formula; Ideal body weight
= 48 kg for first 5 feet + 2.7 kg for each additional inch i.e. = 48 kg + 2.7 x 7= 66.9
kg (IBW).Therefore this obese and sedentary patient requires energy=20-25kcal/kgIBW/day.
Recommended Dietary Intake (RDI)
171
Energy 1505 kcal

Protein 94 gm (20% of total energy)
CHO 225 gm (60% of total energy)
Fat 25 gm (15 % of total energy)
Fibre 30-40 grams
Table 7: Exchanges Based upon the Patients RDI
Exchange
Amount
Skimmed milk
Lean meat
Pulse (whole)
Cereals
Roots / Tubers
Veg. A
Veg B
750ml
100gms
120gms
120gms
nil
300gms
300gms
No. of
exchanges
3
2
3
6
3
3
Energy
(kcal)
279
105
350
420
60
120
Protein
(gm)
24
17.5
24.5
12
3
6
Carbohydrate (gm)
44.1
59.5
90
10.5
210.0
Fat (gm)
1.0
-
Fruit
Fat (oil)
Total
160gms
15gms
2
3
80
125
1539
87
20
245.1
15
16
Table 8: Distribution of Carbohydrates According to Selected Exchanges
Exchange
No. of
exchanges
Early
morning
Breakfast
Lunch
Skimmed
milk
3.6
gm
cho
9
gm
cho
6gm
cho
Meat
(lean)
Pulses
1*/4
4.25
Cereals
7.5
15
Veg A
1.75
Veg B
Fruit
Fat
Total CHO
11.1
Dinner
Bedtime
6gm
cho
3.6g
cho
9gm
cho
17
12.75
17
37.5
15
30
3.5
1.75
3.5
3.5
3.5
10
10
43.5
71
Evening
tea
39
71.1
Carbohydrate (CHO)
172
Breakfast + evening tea 82.5gms

Early morning + lunch 82.1gms
Dinner + bedtime 80.1gms
Table 9: Sample Menu
Meal time
Early morning
Breakfast
Lunch
Evening tea
Menu
Milk
Whole wheat bran biscuit
Lassi (salted)
Sprouted channa
Veg upma with egg white
Pineapple
While urad dal
Mix veg (carrot + cauliflower)
Soya bean wheat chappati
Salad
Besan + Makki atta veg cheela
Coffee
Amount
1 cup
2 nos.
300 ml
katori
1 small plate
100 gm
1 katori
1 katori
2 nos.
As desired
1 medium
1 cup
Dinner
Post dinner

Egg
Fish curry
Began bhaja
Missi roti
Salad
custard
1 piece
1 katori
2 nos.
As desired
1 serving
References
1.
American Diabetes Association. Annual Review of Diabetes 2007. Diabetes Care 29: 2140-2157.
2.
American Diabetes Association. Nutrition Recommendations and Interventions for Diabetes (Position Statement). Diabetes Care 2007; 30:S48-S65.
3.
Anderson J, Allgood L, Turner J, et al. Effects of psyllium on glucose and serum lipid responses in men with
type 2 diabetes and hypercholesterolemia. Am J Clin Nutr 1999; 18: 6-12.
4.
David L Katz. Nutrition in clinical practice, Wolters Kluwer / Lippincott Williams & Wilkins Health, 2010.
5.
Jenkins D, Jenkin A. The glycemic index, fibre and the dietary treatment of hypertriglyceridemia and diabetes.
J Am Coll Nutr 1987; 6: 11-17.
6.
Jenkins D, Woener T, Jenkins A. Starchy foods and glycemic index. Diabetes Care 1988; 11: 149-159.
7.
Jenkins D. Wolkner J, Taylor R, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr 1981; 34: 302-366.
8.
Joanwebster-Gandy, Angela Madden, Michelle Holdsworth. Oxford Handbook of Nutrition and Dietetics;
2007: 423-430.
9.
Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, Clark NG; American Diabetes Association; North American Association for the Study of Obesity; American Society for Clinical Nutrition. Weight
management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for
the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 2004; 27(8):2067-73.
10. Michael J, Gibney, Marinos Ezia, Olle Ljungquist and Julie Dowsett. Clinical Nutrition: The Nutrition Society
Textbook Series, 2006.
11. Narsinga Rao BS. Dietary fibre in Indian diets and its nutritional significance. Nutrition Foundation of India
Bulletin 9 (4): 1988.
12. Norris SL, Zhang X, Avenell A, Gregg E, Schmid CH, Kim C, Lau J. Efficacy of pharmacotherapy for weight
loss in adults with type 2 diabetes mellitus: a meta-analysis. Arch Intern Med 2004; 164(13): 1395-404.
13. Raghuram TC, Parricha S, Sharma RD. Diet and diabetes. NIN 2005.
14. Raghuram TC, Swaran Parrica Upadhyay AC, Krishnaswamy K. Glycaemic index of Indian foods. Diabetes
Bull 7: 64: 1987.
15. Serrano-Rios M, Perez A, Saban Ruiz J. Cardiac complications in diabetes. In: World Book of Diabetes in
Practice. Prinection NJ: Elservier. 1986; 2: 169-78.
16. Srivastava RK, Tiwari BK, Agarwal Y. Current nutritional therapy guidelines, DGHS 2008; 182-190.
173
Yoga & Meditation in the

Prevention of Type 2 Diabetes
Dr B K Sahay
Former Prof. of Medicine
174
Osmania Medical College, Hyderabad

e-mail: sahaybk@gmail.com
&
Dr R K Sahay
Prof. of Endocrinology
Osmania Medical College & Hospital
Ph: 98495 97507
e-mail: sahayrk@gmail.com
Abstract
Diabetes has emerged as the major public health problem across the globe. At the turn of
millennium we had 3 million diabetics and it is projected that the prevalence would increase
to about 80 million by 2020. The problem is compounded further since diabetes starts at
much younger age and remains undetected in a large proportion. This would impose an
enormous economic burden. We have to adopt preventive strategies on a war footing.
We know that the factors contributing to this increase in prevalence are unhealthy dietary
habits and lack of physical exercise with rural to urban migration. Research in different populations has shown that emergence of diabetes in high risk populations can be
prevented by regular physical exercise and dietary modification. This knowledge can be
implemented in our day to day life on a universal basis.
Yogic practices have a favorable effect on correcting insulin resistance and perhaps in
preserving beta cell function, the two important pathogenic mechanisms causing type 2
diabetes. Yoga can be practiced by patients of all ages and in all seasons.
Diabetes has emerged as a major public health problem across the globe. The prevalence
is increasing every year at an alarming rate. In the year 2000 it was estimated that there
were 200 million diabetics in the world and it is projected that it would increase to 366
million by 2030, an increase of 70%. India has the dubious distinction of having the largest number of diabetics 30 million in 2000. It is projected this figure is likely to touch
80 million by 20251. The problem is further magnified by the fact that the age of onset
in our country is a decade earlier and the burden of undetected diabetes is very high.
The public health burden due to diabetes is apparent by the fact that diabetes is the leading cause of blindness, chronic renal disease and non traumatic limb amputations, more
importantly diabetes is the leading cause of coronary artery disease, stroke and peripheral
vascular disease. 75% of the mortality in diabetics is due to coronary artery disease and
stroke. Hence the economic burden imposed by diabetes is enormous. Once established
the disease is difficult to treat; there is a direct relationship to uncontrolled diabetes and
the development of its long term complications. It is often difficult to achieve optimal
glycaemic control. Hence it is important that we should strive hard to achieve primary
prevention of type 2 diabetes.
In order to prevent a chronic disease like type 2 diabetes it in necessary to have a knowledge about its natural history including the preclinical phase, modifiable risk factors,
effective and simple tools to identify high risk individuals and an effective intervention
that is affordable and acceptable.
Risk Factors for the Development of Type 2 Diabetes

It is accepted that genetic predisposition and environmental factors collude to favor the
development of diabetes. The environmental factors associated with increase occurrence of
type 2 diabetes include obesity, physical inactivity, previous history of gestational diabetes
in women, hypertension and dyslipidaemia. These risk factors interact with the genetic
predisposition indicated by a family history of diabetes or high risk ethnic heritage to
promote the development of diabetes such a phenomenon is clearly demonstrated in studies done in migrant Indian populations settled in South Africa, UK, USA, Fiji Islands, South
East Asia. These have shown a distinct similarity in terms of very high prevalence rates
Yoga & Meditation in the Prevention of Type 2 Diabetes
175
ranging between 15-20% in these populations, while the prevalence among the native
populations in these countries ranged between 2.5 4%. Hence this increased prevalence
among the migrant Indians was not due to environment factors alone, but it was proposed
that Indians were genetically more predisposed to develop diabetes. Studies also showed
that Indians were more insulin resistant. The life style changes that contributed in them
were decreased physical activity, increased food intake with fat dense calories and the
stress of working in an alien place2.
With industrialization and improved facilities available in our country in the past 3 decades
we have a similar scenario developing in our country leading to a very similar prevalence
rate of 15-20%. There is an increase in rural to urban migration, with changes in dietary
habits with diets rich in saturated fats and trans fatty acids with decreased physical activity. The increased longevity is another factor among our population.
Another major change has been the increasing prevalence of obesity in childhood and
adolescents. This is contributed by changing food habits due to availability of increasing
number of fast food counters, consumption of large quantities of aerated drinks, lack of
physical activity due to non-availability of play grounds in schools and colleges. Another
factor, i.e. an increase in, hours of TV viewing or computer use. Childhood obesity in turn
predisposes to the development of obesity in adulthood and early onset of type 2 diabetes,
hypertension and coronary artery disease.
Risk Factors for Developing Diabetes and Identification of High Risk Groups
176
1. Body Fat Distribution: It is important to recognize that type 2 diabetes is associated

not only with a high body mass index but also with a particular pattern of body fat
distribution. Individuals with central obesity i.e. with the android pattern of obesity are
far more likely to develop type 2 diabetes than those with gynaecoid obesity. Waist
hip ratio gives a good indication of central obesity and has been shown to correlate
with type 2 diabetes. Insulin resistance is probably the most important link between
obesity and diabetes. Hyperinsulinemia is correlated with increasing body mass index
and central obesity. In western societies, the combination of an unbalanced, excessive
diet and a sedentary lifestyle has increased the prevalence of central obesity. When,
populations with a low risk of type 2 diabetes adopt unhealthy westernized diets and
sedentary lifestyles, the risk of diabetes increases. The growing prevalence of obesity
highlights the importance of insulin resistance and type 2 diabetes.
2. Fat intake: There is evidence that dietary fat is the most likely component to have
aetiological relationship to development of diabetes. In rats fed with high fat diets,
insulin resistance tends to develop and it is possible that a similar phenomenon may
occur in humans especially, with a high intake of saturated fats.
3. Lack of physical activity: This is an important risk factor for the development of
type 2 diabetes. High levels of physical activity are correlated with lower levels of
plasma insulin and physical training can decrease insulin resistance. In one study the
prevalence of diabetes was three times higher in individuals indulging in light physical
activity compared to those involved in heavy work3.
4. Smoking: It has been found smoking is an independent risk factor for the development of type 2 diabetes mellitus. Data from the Osaka health survey have shown
that the risk for development of type 2 diabetes mellitus in current smokers is higher
than in non-smokers and that the number of cigarettes smoked and the number of
pack-years is positively related to the development of type 2 diabetes mellitus in a
dose dependent manner4.
5. Role of stress: During periods of stress the body responds by secreting excess of
catecholamnes, cortisol, growth hormone and glucagon. These hormones increase the
insulin resistance and over a period of time the increased stress may promote the
development of type 2 diabetes.
6. Genetic background: There is a strong genetic element in the development of type
2 diabetes and a genetic susceptibility probably predisposes individuals with changes
in their lifestyle, to develop diabetes. Certain ethnic groups such as native Americans
and Hispanics have a higher genetic predisposition for the development of diabetes.
The same is true with Asian Indians like us. An individuals risk of developing diabetes is doubled if one member of their family already has the disease. The risk gets
quadrupled if there are two family members with diabetes.
7. Previous Gestational Diabetes: Development of gestational diabetes mellitus during
pregnancy indicates a significantly higher risk of developing diabetes in future. In fact
the progression to type 2 diabetes is 5% per year with almost 50% of these women
with gestational diabetes developing diabetes over a 10 year follow up. Early detection of Gestational Diabetes Mellitus(GDM) by Universal screening and appropriate
management can not only prevent perinatal morbidity and mortality, but also prevent
the birth of either low body weight babies or large babies, both of which are associated with higher risk for development of type 2 diabetes. Exposure of the fetus
to higher glycemic levels in the mother has also been associated with a greater risk
of development of type 2 diabetes. Thus measures directed towards early detection
and effective management of GDM can therefore ensure long term benefit over three
generations and contribute to the prevention of diabetes.
Insulin Resistance
Insulin resistance has been demonstrated in first degree relatives of type 2 diabetic patients. Significant insulin resistance has also been reported in non diabetic, lean relatives
and offspring of type 2 diabetes patients. Overall up to 50% of 1st degree relatives are
insulin resistant for several years before they develop diabetes5,6. These data suggest that
insulin resistance as a metabolic precursor to type 2 diabetes and establish a rationale
for interventions that improve insulin sensitivity as one strategy for preventing diabetes.
Pancreatic beta cell dysfunction leads to progressive impairment of 1st phase of insulin
release. In a prospective study of Pima Indians this defect in the first phase of insulin
secretion proved to be a critical determinant of progression from normal to IGT to type
2 diabetes7. Progression from IGT to diabetes was associated with an approximately 75%
decline in the acute insulin secretory response to IV glucose. A high concordance rate for
impaired insulin secretion has also been reported among elderly identical twins discordant
for type 2 diabetes, which suggests a genetic basis for pancreatic beta cell dysfunction8.
The role of beta cell dysfunction in predicting progression to type 2 diabetes suggests that
interventions that prevent the progression of decline in insulin secretion can be expected
to prevent the development of type 2 diabetes.
177
Preventing Progression To Diabetes

Early intervention in high risk individuals with modification of lifestyle factors, such as
diet and exercise, have a major influence on the development and progression of impaired
glucose tolerance, dyslipidemia and insulin resistance, conditions that precede the onset
of type 2 diabetes. Although not all patients with such metabolic abnormalities progress
to diabetes, their risk of developing the disease is significantly increased.
Lifestyle intervention is an important clinical strategy that can help reduce obesity and
reduce the risk of developing type 2 diabetes. Major clinical studies like the Da Qing Study9,
The Finnish diabetes Prevention Study10, Diabetes Prevention Program11, have conclusively
brought out the benefit of life style changes in prevention or in delaying the progression of
pre-diabetes (impaired fasting glucose and impaired glucose tolerance) to type 2 diabetes.
The Indian Diabetes Prevention Program (IDPP) 12 a preventive study based on the Diabetes
Prevention Program has clearly demonstrated the importance of physical activity in the
prevention of diabetes in Indians.
178
531 (421 men 110 women) subjects with IGT (mean age 45.95.7 years, BMI 25.83.5 kg/
m2) were randomized into four groups. Group 1 was the control, Group 2 was given
advice on lifestyle modification (LSM), Group 3 was treated with Metformin (MET) and
Group 4 was given LSM plus MET. The primary outcome measure was type 2 diabetes as
diagnosed using World Health Organization criteria. After a median follow-up period of
30 months, the 3-year cumulative incidences of diabetes were 55.0%, 39.3%, 40.5% and
39.5% in Groups 14, respectively. The relative risk reduction was 28.5% with LSM (95%
CI 20.537.3, p=0.018), 26.4% with MET (95% CI 19.135.1, p=0.029) and 28.2% with
LSM + MET (95% CI 20.337.0, p=0.022), as compared with the control group. This study
therefore showed that although progression of IGT to diabetes is high in Indians, both
LSM and MET significantly reduced this progression and there was no added benefit from
combining them12.
Detecting and Managing those at High Risk for Type 2 Diabetes

In light of the impressive results of the Finnish Diabetes Prevention Study and the Diabetes
Prevention Program, the American Diabetes Association (ADA) and the National Institute
of Diabetes, Digestive and Kidney Disease (NIDDK) recommended that people over 45 years
with a BMI 25kg/m2 should be screened for IGT. Patients with evidence of IGT should be
given appropriate counseling on the importance of weight loss through a program of
dietary modification and exercise.
Identification of subjects at high risk of type 2 diabetes is relatively easy; no biochemical
or costly tests are required. From the prevention perspective, screening for type 2 diabetes
is not the same as measuring blood glucose. Risk can be determined using non-invasive
data, such as waist measurement and BMI. A diabetes Prediction Risk Score has recently
been developed based on the prospective study in Finland13. (Table 1)
Table 1: Risk Factors For Type 2 Diabetes
Family history of type 2 diabetes
Over weight / obesity
Physical inactivity
Gestational Diabetics
Delivery of a baby weighing more than 4 kg
Hypertension
Dyslipidemia
Ethnicity
Pre diabetic states IGT & IFG
An Indian Diabetes Risk score (IDRS) has recently been developed by Mohan et al., which
uses four simple variables namely age, family history, exercise frequency and intensity and
waist circumference to arrive at a risk score. (Table 2).
Table 2 : Indian Diabetes Risk Score
Particulars
Age (yrs)
Score
< 35
35-49
10
50
Abdominal Obesity
Waist < 80cm (female), < 90cm (male)
20
0
Waist 80-89cm(female), 90-99cm(male) 10

Waist 90 cm (female), 100 cm (male)
Physical Activity
Vigorous exercise or strenuous (manual)
Labour at home / work
20
0
Mild to moderate exercise or mild to

20
moderate physical activity at home / work
No exercise and sedentary activities at
home/work
Family History
No family history
30
0
Either parent
10
Both parents
20
179
Interpretation of Score
< 30 Low risk
30-50 Medium Risk
> 60 High risk for Diabetes & Cardiovascular disease
Those individuals with a score below 30 have a low risk, between 30-50 have an intermediate risk and those with a score >60 have a high risk of developing diabetes and
cardiovascular disease14.
Role of Yogic Practices in Diabetes Prevention

The science of yoga is an ancient one. It is a rich heritage of our culture. Several older
books make a mention of the usefulness of yoga in the treatment of certain diseases and
preservation of health in normal individuals.
We carried out several studies to assess the effect of yogic practices in normal healthy
volunteers, patients with diabetes, hypertension, asthma and obesity. These studies were
both short term and long term follow up. The following observations were made.
Effect of Yogic Practices on Body Composition
180
In normal healthy volunteers the skin fold thickness was significantly reduced with increase
in the lean body mass, without any significant change in the weight of the individuals.
One hundred eight patients with type 2 diabetes were studied for a period of 6 months.
All these patients developed a sense of well being and showed a significant fall in the
glycosylated hemoglobin and the drug requirements. In these patients there was a significant decrease in the body fat and increase in the lean body mass. The reduction in body
fat percentage and increase in the lean body mass helps to improve insulin sensitivity and
reduce insulin resistance15.
Effect of Yogic Practices on Insulin Kinetics

There was a reduction in the fasting insulin levels and a shift of the peak level of insulin
to the left. There was a normalization of the I/G ratio with a reduction in the free fatty
acid levels, suggesting a better peripheral utilization of insulin and reduction in insulin
resistance. This was confirmed by a study of yogic practices on insulin receptors, which
showed a significant rise in the insulin receptors even before glycemic control was achieved,
indicating a reduction in insulin resistance and improvement in insulin sensitivity 16.
Effect of Yogic Practices ln CMI in Type 2 Diabetes

Cell mediated Immunity (CMI) is defective in patients with type 2 diabetes, particularly
with poor glycaemic control. The defective cell mediated immunity predisposes the diabetics to various infections. Our studies have shown that yogic practices have a favorable
effect on the lymphocyte migration test, suggesting an improvement in the cell mediated
immunity. Yogic practices like Shavasana and Makarasana help in eliminating stress.
Effect on Co-Morbid Conditions

Hypertension is commonly encountered in patients with diabetes and it has significant role
in the development of both microvascular and macrovascular complications. Along with

hypertension dyslipidemia is also equally common.
Effect of Yogic Practices on Hypertension

Patients with hypertension were advised pranayama and shavasana. 20 non-diabetic patients with moderately elevated BP had reduction in both systolic and diastolic blood
pressure after 3 weeks of yogic practices and the blood pressure was maintained at normal
levels with significant reduction in the dosage requirement of anti-hypertensive drugs.
Similar reduction in the systolic and diastolic blood pressure and the fasting and postlunch blood sugar was observed in patients with diabetes and hypertension. The blood
pressure came under control in 15 days and the effect was sustained even in studies up
to 3 months. Patients were free from cerebrovascular, cardiovascular and renal problems
without any adverse effects on the lipid profile16.
Effect of Yogic Practices on Lipid Parameters

The impact on lipids was studied in the different groups of patients. The effect of yogasanas on lipoprotein profiles was studied. There was a significant decrease in the free fatty
acids, low density lipoprotein and very low density lipoprotein cholesterol, with increase
in high density lipoprotein cholesterol. These changes suggest improvement in the insulin
sensitivity following yogic practices16.
Studies like the UKPDS have shown that there is a progressive decline in beta cell function
leading to worsening of glycemic status. Our studies in a subset of elderly diabetics aged
over 65 years with yogic practices showed that they maintained good glycemic control
even as long as 7 years indicating that yogic practices help in preserving beta cell function.
The improved cell mediated immunity protects individuals from infections and stress is
eliminated with the practice of shavasana, which are additional factors identified as contribution to the development of type 2 diabetes. Therefore, by its influence on all these
factors yogic practices, help in the prevention of type 2 diabetes. In a pilot study 80 siblings born in diabetic families were followed for a period of 5 years. 24 subjects practiced
yoga regularly while the other 56 siblings did other forms of physical exercise. Only 1
out of the 24 subjects in the yoga group developed diabetes compared to 10 out of 56
in the non-yoga group.
By Following the Practice of Yoga the Following Changes Take Place

There is an increase in the lean body mass and decrease in the body fat percentage.
There is an improvement in insulin/ Glucose ratios, correction in the peak of insulin
secretion with a shift to the left.
There is an improvement in the insulin receptors, a decrease in the free fatty acid
levels and triglycerides.
All these lead to improved insulin sensitivity and decrease in insulin resistance which
is an important forerunner in the pathogenesis of type 2 diabetes16.
The effect on the glycaemic control and co-morbid conditions like dyslipidaemia and
hypertension protects the patients from complications of diabetes. Hence yogic practices have a role both in primary and secondary prevention in diabetes.
181
Summary and Conclusions

To conclude the war against Diabetes in our country should start focusing on school
going children, by educating them on the importance of healthy lifestyle with both diet
and exercise. The schools should provide facilities like playgrounds and introduce physical
training and yoga classes in the curriculum. Government should create public parks and
provide facilities for physical exercises. Growth of Fast food counters should be curtailed
by preventing the sale of junk food in the vicinity of the schools.
References
182
1.
Sicree R, Shaw J, Zimmet P. Diabetes and impaired glucose tolerance. In: Gan D, editor. Diabetes Atlas.
International Diabetes Federation. 3rd ed. Belgium: International Diabetes Federation; 2006. 15-103.
2.
Ahuja MMS. Epidemiological studies on diabetes mellitus in India In: Ahuja MMS, editor. Epidemiology of
diabetes in developing countries. New Delhi: Interpringt: 1979: 29-38
3.
Mohan, V, Shantirani ,C.S.,Deepa R .Glucose metabolism (DM & IGT) in a selected south Indian population with special reference to family history, obesity and life style factors. The Chennai urban population
study(CUPS) JAPI 2003:51:771-7.
4.
Uchimoto S, Tsumara K, Hayashi T, Suematsu C et al. Impact of cigarette smoking on the incidence of
Type 2 diabetes mellitus in middle-aged Japanese men: The Osaka Health Survey. Diabetic Medicine. 1999;
16: 951-955.
5.
Haffner SM, Hotman R, Califf R et al. Targeting post-prandial hyperglycaemia to prevent type 2 diabetes:
Rationale and design of the NAVIGATOR Trial, Diabetologia 2002:45 (Suppl 2) A106.
6.
Modan M, Halkin H, Almog S et al, Hyperinsulinemia link between hypertension, obesity and glucose intolerance J, Clin Invest 1985;75:809-817Mohan V, Deepa R, Deepa M, Somannavar S, Datta M. A simplified
Indian Diabetes Risk Score for screening for undiagnosed diabetic subjects. J Assoc Physicians India 2005;
53 : 759-63.
7.
Hanson L, Lindholm, LH, Niskanen L et al. effect of angiotensin-converting enzyme inhibition compared with
conventional therapy on cardiovascular morbidity and mortality in hypertension: The captropril prevention
project (CAPPP) randomized trial, Lancet 1999; 353:611-616.
8.
Yusuf S, Gerstein H, Hoogwerf B et al; Hope study investigators, ramipril and the development of diabetes,
JAMA 2001;286: 1882-1885.
9.
Pan XR, Li GW, Hu YH, Wang Jx, Yang WY, An Zx et al: effects of diet and exercise in preventing NIDDM in
people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537-544
10. Tuomilehto j, Lindstorm J, Eriksson JG, Valle TT, Hamalainen H, IIanne-Parikka P, et al: Prevention of type
2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N. Engl/Med
2001; 344: 1343 1350.
11. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al: Reduction in the
incidence of type 2 diabetes with lifestyle intervention or Metformin. N Engl / Med 2002; 346:393 403.
12. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes Prevention Programme shows that lifestyle modification and Metformin prevent type 2 diabetes in Asian Indian subjects
with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49:289-97
13. Lindstrom J, Louheranta A, Mannelin M, Rasta M, Salminen V, Eriksson J, et al: The Finnish Diabetes Prevention Study (DPS); Lifestyle intervention and 3-years results on diet and physical activity. Diabetes Care
2003; 26: 3230-3236.
14. Mohan V, Deepa R,Deepa M et al. A simplified Indian diabetes risk score for diagnosing diabetic subjects,
JAPI 2005:53:759-63.
15. Madhavi Sunita, Sahay B.K., Murty KJR et al. Effect of yogic exercise on lean body mass. JAPI, 1955:33:465-466.
16. Sahay B.K. Role of yoga in diabetes. JAPI 2007 55 121-6
Dr Pradeep G Talwalkar
Consultant Diabetologist,
S L Raheja Hospital, Mumbai.

Cell: 98202 81806
E-mail: pg_talwalkar@hotmail.com
183
What is Prediabetes?
Prediabetes is defined as a condition in which blood glucose levels are above the upper
limit of normal but below the lower limit required for diagnosis of diabetes. As defined
by American Diabetes Association [ADA], in prediabetes fasting plasma glucose [FPG] of
at least 100 mg/dl but less than 126 mg/dl, which is termed as Impaired Fasting Glucose
[IFG], or an abnormal two hours response to 75-g OGTT of at least 140 mg/dl and less
than 200 mg/dl, which is termed as Impaired Glucose Tolerance [IGT].1
The World Health organization defines IGT identically, but its definition of IFG differs. [FPG
at least 110 mg/dl and two hours post 75-g glucose load plasma glucose < 126 mg/dl] 2
The definition of prediabetes is based on assessment of disease risk and the distribution
pattern of plasma glucose in the population.
What is the Natural Course of Prediabetes?

The risk of progression from prediabetes to type 2 diabetes occurs over many years. The
risk is greater in those with both IFG and IGT as compared to those with isolated IFG or
IGT. The average annual risk of developing diabetes is 0.7% for those with normoglycemia
and 5-10% for those with IFG or IGT. 3 Over a life time, majority of people with prediabetes would develop diabetes.
Why Should Prediabetes be Treated?
184
Besides being a significant risk factor for the development of diabetes, prediabetes is a risk
factor for macrovascular disease and for retinopathy in particular and other microvascular
complications in general. A meta analysis of 38 prospective studies suggests that the post
challenge blood glucose levels in non diabetic range appear to have a linear relationship
with cardiovascular disease risk.4 7.9% of the participants with IGT had retinopathy in
Diabetes Prevention Program study.5 Based on the nerve conduction studies, 10-18% have
evidence of peripheral neuropathy at the time of diagnosis of diabetes suggesting that
peripheral neuropathy may commence at blood glucose levels in prediabetic range.6 The
crude analysis of data from Framingham Heart study showed 65% increased chances of
chronic kidney disease in people having IFG or IGT as compared to those having normoglycemia.7 Diabetes is as much a vascular disease as it is a metabolic disease. About 80%
of type 2 diabetics die from macrovascular disease, 66% among them from Coronary
Artery Disease [CAD]. Furthermore, about 50% of type 2 diabetics show evidence of CAD
at the time of diagnosis of diabetes when subjected to sophisticated diagnostic tests. In
order to reduce significant mortality and morbidity associated with type 2 diabetes, one
has to concentrate on primary prevention of CAD. In our endeavor to do so, we have
no alternative to prevention of diabetes. There is ample evidence that intensive lifestyle
intervention and various pharmacotherapeutic agents reduce the risk of progression to
diabetes in those with prediabetes. Thus it is clear from above discussion that it is vitally
important to identify and treat prediabetics as early as possible and to implement therapeutic measures to prevent onset of diabetes.
Who Should be Screened?

In order to detect prediabetic state as early as possible, following measures are recommended.
1. Every person should undergo fasting and post 75 g. glucose load blood glucose levels
at thirty years. These tests should be repeated every two years as long as the values
are well with in normal range.
2. Those with family history of diabetes and those with other cardiovascular risk factors
and those with history of gestational diabetes or delivering large sized baby should be
first screened earlier depending upon individual situation. [If a person is diagnosed to
have coronary artery disease at 25, he should be immediately screened for diabetes.]
In those with blood glucose values in IGT or IFG range, non pharmacological measures
to prevent diabetes should be immediately started. Depending on an individual case,
if required, one of the pharmacological agents should be added to life style measures.
Life Style Intervention in Individuals at High Risk for Developing Diabetes

The role of life style interventions in the form of weight reducing diets and moderate
intensity exercise in preventing diabetes in high risk individuals has been proved in a
number of studies. In Malmo study, men with IGT or type 2 diabetes were subjected to
life style interventions in the form of weight reducing diet and physical exercise. After a
mean follow up of 6 years glucose tolerance was normalized in > 50% with IGT.
In > 50% patients having type 2 diabetes at the start of the study, there was reversal to
normoglycemia.8 Similar observations were noted at the end of 6 years observation period
in Chinese Da Qing study designed to study the effect of diet and/or exercise in people
with impaired glucose tolerance. The study reported 36%, 39% and 47% reduction in risk
for diabetes in diet only group, diet plus exercise group; and exercise only group.9 The
results of these early studies were reconfirmed by subsequent well designed Finish Diabetes
Prevention Study10 and American Diabetes Prevention Program [DPP].11 Both these studies,
demonstrated there was about 58% risk reduction for diabetes after 3 years of follow up.
These two studies are briefly described below.
The Finish Diabetes Prevention Study: [FDPS]

In this study, 522 middle aged overweight people with IGT were randomized to intensive
life style intervention and control groups. Those in intervention group received individualized counseling aimed at reducing weight, total intake of fat, saturated fat and increasing intake of fiber and physical activity. The mean follow up period was 3.2 years. The
cumulative incidence of diabetes at the end of trial was 11% and 23% respectively in
intervention and control group respectively. Thus the risk of diabetes was reduced by 58%
in the intervention group.
Diabetes Prevention Program: [DPP]

The 3234, mostly obese American participants of this study consisted of those having IGT
or IFG, those with strong family history or associated risk factors, over weight and those
with history of gestational diabetes. The study period was of three and half years duration.
The participants were divided in four groups.
1. Intensive life style modifications [150 minutes of exercise per week and aim of reducing at least 7% of the baseline weight]
2. Metformin
3. Troglitazone,
4. Placebo.
185
Compared to placebo group, intensive life style management group and Metformin group
had 58% and 31% reduction in the risk for development of diabetes respectively. Within
10 months after initiation of study, Troglitazone was withdrawn from the market and thus
this arm was suspended.
The studies mentioned above convincingly prove the efficacy of life style intervention in
prevention of diabetes. However, a day to day real life situation is poles apart from the
situation in well designed and strongly supported clinical trial situation. During the study
period of many of the above mentioned trials, a large multi disciplinary team was constantly available to guide and monitor the patients. These teams included dietitians, physiotherapists, psychologists and dedicated nurses besides of course the clinicians. Moreover
many of the high risk individuals do not opt for intensive life style intervention in a day
to day clinical practice situation for various reasons. Thus in those high risk people who
do not reach glycemic goals with life style intervention or who are unwilling to implement
life style intervention of appropriate intensity in sustained manner, pharmacotherapy as an
alternative / additional mode of therapy can be considered. Some major pharmacological
intervention studies are described in brief below.
Study to prevent Non Insulin Dependant Diabetes Mellitus [STOP NIDDM]:

This was a three year study in which people having IGT were randomized to receive 100
mg of Acarbose three times a day or placebo. At the end of study period, there was 25%
risk reduction for development of diabetes in Acarbose group as compared to placebo
group.12 In addition there was reduction in cardiovascular risk in Acarbose group in respect
of development of hypertension and acute myocardial infarction.
186
Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications [DREAM]

In this study 5269 people with IGT, IFG, or both and no previous history of cardiovascular
disease participated. They were randomized to receive 15 mg of Ramipril/day or placebo,
or Rosiglitazone 8 mg/day or placebo, by using 2 x 2 factorial design and followed up
for 3 years. Use of Rosiglitazone led to impressive 62% risk reduction for development of
diabetes as compared to only 9% risk reduction in those on ramipril.13 However in 2010,
due to its cardiovascular side effects, Rosiglitazone was banned in many countries including USA, Western Europe and India.
Indian Diabetes Prevention Programme [IDPP]

In this study by A Ramachandrans group, 531 subjects with IGT were randomized in to four
groups, [controls, Life Style Modifications [LSM], Metformin, and Metformin plus LSM]. The
mean follow up period was 30 months. As compared to control, the relative risk reduction was 28.5% with LSM, 26.4% with Metformin, and 28.2% with LSM plus Metformin.14
Tripod
This study was conducted in 266 Hispanic women who had gestational diabetes in past.
It was 1:1 double blind study in which role of Troglitazone in prevention of diabetes was
compared with placebo. Risk of development of diabetes was reduced by 56% in Trogli-
tazone group as compared to control group. During the course of the study, Troglitazone
had to be discontinued due to its potential hepatotoxicity. Eight months after the discontinuation of Troglitazone, the protective effects had continued. Thus Troglitazone was
successful in true prevention of diabetes and not only in reduction of blood glucose.15
Xenical in Prevention of Diabetes [XENDOS]

In this 4 year double blind prospective study, 3305 obese patients were randomized to LSM
plus Orlistat 120 mg three times a day or LSM only. [79% had normal glucose tolerance
and 21% had IGT]. Orlistat group had 37.7% relative risk reduction for development of
diabetes as compared to control group at the end of 4 years. 16
Table1: Reduction of Diabetes Risk in Various Studies
Study
Intervention
FDPS
DPP
STOP NIDDM
DREAM
Da Qing
IDPP
Life style changes

Life style changes
Number of
subjects
522
3234
Diabetes risk
reduction in %
58
58
Metformin
Acarbose
Ramipril
1148
5269
31
25
9
Rosiglitazone
Life style changes
Life style changesMetformin
LSM + Metformin
Swedish Malmo Life style changes
Study
TRIPOD
Troglitazone
XENDOS
Orlistat
577
531
222
62
31-46
28.5
26.7
28.2
>50
266 women with 56

previous gestational diabetes
3305
37.7
Duration
3.2 yrs
2.8 yrs
3.3 yrs
3 yrs
6 yrs
2.5 yrs
187
6 yrs
2.5 yrs
4 yrs
Treating Prediabetes: Should we use pharmacological agents in those with failure or

non compliance of LSM?
The preferred mode of intervention in prediabetes is obviously LSM. However if LSM fails
or if it is not possible to implement, should we use the pharmacological agents? The question has no clear and universal answer. As on date very few regulatory authorities have
officially recognized prevention of diabetes as an indication for pharmacological agents
such as Metformin and Acarbose, the most widely studied and available among various
pharmacological agents studied for this indication. The issue of long term side effects
and their monitoring needs to be considered in details and the cost effectiveness of such
measures needs to be proved. Moreover are we really preventing diabetes or just treating
hyperglycemia by using pharmacological agents? Among all the agents tried so far, only
Troglitazone in TRIPOD study was able to really prevent diabetes for 8 months after its
discontinuation. Thus at present, the onus is on clinicians to study individual case and
take an appropriate decision.
References
1.
American Diabetes Association position statement: Diagnosis and classification of diabetes mellitus. Diabetes
Care. 2008; 31: S55-S60.
2.
World Health organization\International Diabetes Federation. Definition and diagnosis of diabetes mellitus
and intermediate hyperglycemia: report of a world health organization\ international diabetes foundation
consultation. Geneva, Switzerland, WHO document production services, 2006; p. 1-46.
3.
Gerstein HC,Santaguida P, Raina P, et all Annual Incidence and relative risk of : diabetes in people with
various categories of dysglycemia: a systemic overview and meta analysis of prospective studies. Diabetes
Res Clin Pract. 2007; 78: 305-312.
4.
Levitan EB, Song Y,Ford ES, Liu S. Is non diabetic hyperglycemia a risk factor for cardio vascular disease?
A Meta Analysis of prospective studies. Arch Intern Med.2004; 164: 2147-2155.
5.
Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance
and recent onset diabetes in Diabetes Prevention Program. Diabet Med.2007; 24: 137-144.
6.
Cohen JA, Jeffers BW, et all Risk of sensory motor peripheral neuropathy in non insulin dependant diabetes
mellitus. Muscle Nerve.1998; 21: 72-80.
7.
Fox CS, Larsen MG et all. Glycemic status and development of kidney disease; The Framingham Heart Study.
Diabetes Care, 2005; 28: 2436-2440.
8.
Eriksson KF, Lindgarde F. Prevention of type 2 diabetes mellitus by diet and exercise: The 6 years Malmo
feasibility study. Diabetologia 1991; 34:891-898.
9.
Pan Xr,Li Gw et all. Effects of diet and exercise in preventing NIDDM in people with impaired glucose
tolerance. The Da Qing IGT and Diabetes study. Diabetes Care 1997; 20:537-544.
10. Knowler WC,Barret-Connor E. et all. Reduction in incidence of type 2 diabetes with life style intervention
or Metformin. N Eng J Med2002;346;393-403.
188
11. Toumilehto J.,Linstorm J. et all. Prevention of type 2 diabetes mellitus by change in life style among subjects
with impaired glucose tolerance. N Eng J Med.2001; 344:1343-1350.
12. Chanson JL, Jos RG, Gomes R, Handfed M, Kurashiki A, Laasko M. Prevention of type 2 diabetes mellitus,
The STOP NIDDM randomized trial. Lancet: 2002; 359: 2072-2077.
13. The DREAM [Diabetes Reduction assessment with Ramipril and Rosiglitazone Medication] trial Investigators.
Effects of Rosiglitazone on the prevention of diabetes in patients with impaired glucose tolerance and
impaired fasting glucose: Randomized controlled trial. Lancet 2006; 368:1096-1105.
14. Indian Diabetes Prevention Programme shows that lifestyle modification and Metformin prevent type 2
diabetes in Asian Indian subjects with impaired glucose tolerance. Ramchandran A, Shehalata C,Mary S,
Mukesh B, Bhaskar A, Vijay V. Diabetologia. 2006; 49:289-297.
15. Buchanan AB, Xiang AH, Peters RK et all. Preservation of pancreatic beta cell function and prevention of
type 2 diabetes by pharmacological treatment of insulin resistance in high risk Hispanic women. Diabetes.
2020; 51:2796-2803.
16. Torgerson JA,Hauptman J, Boldrin MN,Sjostrom L. Xenical in Prevention of Diabetes in obese subjects [XENDOS]. Diabetes Care 2004; 27:155-161.
Dr A J Asirvatham
Professor & HOD Department of Diabetology,

Madurai Medical College,
Consultant Diabetologist, Arthur Asirvatham Hospital
& Apollo Speciality Hospital, Madurai.
Ph: 0452 2535266
e-mail: drajasirvatham@yahoo.co.in
189
Introduction
The word reappraisal as per the Oxford dictionary refers to a new or different assessment
of something. This 50 year old molecule is an apt molecule for such an appraisal in this
evidence based medicine era. The molecule with its discovery, dismissal and rediscovery
was possible only because of its worth.
Discovery
This drug has been isolated from a plant called Galega officinalis a summer-flowering
hardy perennial plant originated from southern Europe and western Asia and now spread
to all parts of the globe. The name is derived from a Greek word Gala meaning milk and
aigos meaning goat. The active principle in this plant was identified as a guanidine-like
alkaloid Galegine. The original plant was too toxic for agricultural use. It was the pioneering
work by Dr. Jean Sterne and his colleagues in France which made oral antidiabetic treatment with Metformin a clinical reality. The first synthesis of dimethylbiguanide Metformin
is attributed to Werner and Bell at Trinity College, Dublin, Ireland in 1922. The works of
Dr.Jean Sterne not only lead to the discovery of Metformin but also systematic studies with
the molecule. The finished product was launched by Aaron Laboratories Paris what is now
known as Merck Serono. Metformin was inducted for the treatment of Type 2 Diabetes
in 1957 in Europe and in the US in 1995. This grew from a small start promoted by the
word of mouth to the present state of a foundation therapy for Type 2 Diabetes with a
wide range of formulations, including prolonged release and combinations with all possible
oral hypoglycaemic medications from oldest sulphonylurea to the latest Gliptins.
Chemistry
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Biguanides are strong bases with pK values in the 11-12 region, and all biguanides are
essentially fully protonated at physiological pH. Only one amino group accepts a proton,
so that these agents are monocations in solution. Metformin has two methyl groups substituted at a terminal amino group. Metformin molecule consists of two planar regions,
one associated with each guanidine moiety which intersects at an angle of 68 degrees.
The positive charge is located on the amino group furthest from phenylethyl moiety while
the central amino group accepts the positive charge. The lipophilicity is concentrated at
the dimethyl-substituted terminal amino group. This is a small, low molecular weight,
chemically stable molecule that is freely soluble in water and does not undergo substantial metabolism in vivo. The concentration of Metformin in different tissues varies. The 3
dimensional structural differences between Metformin and Phenformin make Metformin
less prone for lactic acidosis.
Mechanism of Action
The mechanism of action was not known when the molecule was launched and was identified only recently. The physiological function of the plasma membrane depends on the
ability of its protein components to move freely within the phospholipid bilayer. In Diabetes
this fluidity is lost and this is re-established by Metformin. The effects of Metformin are
membrane related. It causes suppression of the mitochondrial respiratory chain, increased
insulin receptor kinase activity, stimulation of translocation of GLUT4 transporters to the
plasma membrane, activation of the enzyme AMP-activated protein kinase.
Figure 1: Metformin Mechanism of Action
Peripheral Glucose Utilization: There has been an 80% increase in the AMP-activated
protein kinase activity after Metformin therapy. Metformin does not consistently increase
the binding of insulin to insulin receptors. It increases the ability of insulin to induce
translocation of GLUT4 to plasma membrane. It also stimulates glycogen synthesis in oocytes. It enhances glucose metabolism by enzymatic pathways and by mitochondrial effects.
AMP-Activated Protein kinase (AMPK) is the regulator of metabolism and acts as an energy
sensor in the range of tissues central to energy homeostasis, including skeletal muscle,
liver, pancreas and adipose tissue. Normally this is stimulated by the increase of AMP:ATP
ratio and other factors leading to increased energy consumption via increased glucose
uptake and an increased rate of lipid oxidation as evidenced by the article in Journal of
molecular Endocrinology (2010)44, 87-97
Figure 2: AMPK- The Regulator of Metabolism
Activation for longer period could cause changes in the gene expression involved in metabolism & regulation of food intake. The metabolic effect of exercise has also been
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postulated as activation of AMPK. Recent research has highlighted a role for AMPK in the
mediation of increased translocation of GLUT 4 to the plasma membrane of the skeletal
muscle during contraction. Leptin and Adiponectin also activate AMPK suggesting a role
for AMPK in the integration of whole body energy homeostasis.
The AMPK pathway represents a point of overlap between the biochemical pathways mediating energy balance and those mediating suppression of tumour formation.
Thus the cellular entry and utilization of glucose is enhanced at the existing insulin levels
there by reducing insulin resistance at the liver and muscles. The term insulin sensitizer
was applied to this molecule.
Hepatic Glucose Output: There is lot of evidences to support the view that conversion
to glucose from non carbohydrate sources like lactate is suppressed by Metformin thereby
reducing the hepatic glucose output. Few studies also describe improved glycogen synthesis
in the liver and oocytes. Ultimately the fasting blood glucose levels are brought down.
Deletion of hepatic LKB1 by genetic manipulation in mice led to increased hepatic Glucose output and hyperglycaemia and loss of the effect of Metformin on blood glucose.
In a study Kolling institute, Sydney, Metformin in liver involves IR activation, followed by
selective IRS-2 activation and increase glucose uptake in the liver via increased GLUT-1
translocation (JCE&M Mar 88, 1323-1332)
Glucose absorption & Metabolism: Experimental studies showed that there is an increase
in the anaerobic metabolism of glucose in the intestine itself which reduces the load of
absorption. The excess lactate produced due to this is metabolized in the liver. This utilization of glucose reduces blood glucose in a significant extent.
Adipose Tissues: Lipolysis leading to excessive Free Fatty Acid levels has been shown to
aggravate insulin resistance and Beta cell function and may be instrumental in the progression of diabetes as well as the cardiac risk factors. Metformin in most of the studies
showed a reduction in lipolysis thereby reducing the FFA and thus preventing cardiac risks
and beta cell dysfunction. Reduction of FFA reduces the insulin resistance and improves
glucose uptake thereby reducing blood glucose.
Beta Cell Function: As described earlier the beta cell damage due to glucotoxicity and
lipotoxicity are reduced with Metformin therapy but there is no other evidence to prove
that it retains beta cell mass or its function for longer time in diabetic as well as non
diabetic individuals.
Figure 3: Metformin action on various tissues
Dosage & Formulations

The therapeutic efficacy of Metformin across various dosage regimens were studied by
Garber et al in a double blind, placebo controlled, dose-response trial published in The
American Journal of Medicine 103, 491-497 and found that the efficacy of Metformin was
found to plateau out after 2000 mg/day and so also the side effects and hence the dose
recommended is still 2000 mg only in the US whereas in Europe & other countries it is
3000 mg/day.
The Gastro intestinal side effects were much reduced by its improved preparations and
formulations. There are many patented technologies in this improved prolonged-release
Metformin. One, of them being a dual hydrophilic polymer matrixthe GelShield diffusion
system in which Metformin is contained within beads of one polymer surrounded by the
other which does not contain Metformin.
Picture 4: Prolonged Release Technology
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The tablet hydrates & swells after ingestion forming a gel layer around it. The advantages
of this technology are release of metered dose from the stomach to jejunum hence sustained action for 24 hours, less of gastric side effects and smoother onset of action. It
may be necessary to caution the patient that he would be passing the matrix of the tablet
in stools which would appear that the tablet has come out without getting absorbed.
The various prolonged release and its availability in various strength from 250 mg to
1000 mg alone as well as in combination with all generations of Sulphonylureas, Thiazolidinediones, Alpha Glucosidase inhibitors and DPP-IV inhibitors indicates its pivotal role,
efficacy, flexibility and importance apart from conveniences.
Indications

Type 2 Diabetes Mellitus

Type 1 Diabetes Mellitus
Impaired Glucose Tolerance
Obesity
Children & adolescent diabetics
Poly Cystic Ovarian Syndrome
Metabolic syndrome
Non-Alcoholic Steato Hepatitis
Type 2 Diabetes Mellitus: This was the first indication for this drug just after its discovery.
Even today, the largest volume of Metformin is used for this purpose. The insulin resistance
component of Diabetes is attended to by this drug. Ideal for the obese hyperinsulinaemic
group however it is being used in the normal weight population along with an insulin
secretagogue. In the lean group which is peculiar to the Asian population it may not be
an ideal monotherapy drug. It is our experience that these patients may not be truly Type
2 DM but may be even slow onset Type1 DM or LADA or the pancreatic diabetes and
differentiating them may be difficult at times due to inadequate facilities. Hence it would
be prudent to use an insulin secretagogue first and a TZD if needed.
Type 1 Diabetes: Insulin is the only drug which is available for this disease as of now.
In certain situations, where there has been associated insulin resistance, it could be used
in addition to insulin in which case there would be a reduction of insulin requirement.
Impaired Glucose Tolerance: It has been proved that Metformin could be used in IGT with
or without genetic syndrome wherein it could counter the important factor hyperinsulinemia and prevent progression to diabetes along with life style modification as evidenced
by Diabetes Prevention Program.
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Obesity: Obesity is a very common epidemic all over the world. Nearly 2/3rd of diabetics are obese and it should be considered that therapy should not create more problems
like increasing weight. Metformin in this context is a very ideal drug which would cause
weight loss which is very encouraging. A preliminary report suggests that Metformin may
induce redistribution of fat from the metabolically active abdominal depot to the relatively
inactive subcutaneous depot during a treatment period of 6-10 months. It also reduces
the weight gain caused by other drugs like Sulphonylurea, insulin or TZD when given in
combination with Metformin. Significant effects of Metformin on body weight or trends
towards a reduction in body weight with Metformin have been observed in obese nondiabetic population.
However a meta-analysis of controlled evaluations concluded that the magnitude of effects
on body weight did not support its therapeutic use for weight control per se.
Children & adolescent diabetics: Children & adolescent diabetes is on the increase not
only in the developed countries but also in the developing countries. Now T2DM is four
times commoner than T1DM in parts of Japan and China though not that much common
in India. The pathogenesis is triggered by obesity, high calorie food stuff consumption &
stress without adequate exercise (environmental factors) on the top of genetic factors,
family history & the surge of androgen during puberty. A survey of 1,00,000 children in
USA revealed that children with BMI >95th percentile doubled the incidence of diabetes.
The treatment is with life style modification, weight reduction and Metformin in a dose
of not more than 2gms/day. Care should be taken to exclude ketosis prone T1DM.
Poly Cystic Ovarian Syndrome: Polycystic Ovarian Syndrome (PCOS) comprises a constellation of factors which lead to variable clinical features, including menstrual irregularity,
acne, hirsutism, oligomenorrhoea and anovulatory infertility. PCOS can be diagnosed on
the basis of clinical or biochemical evidence of hyperandrogenism along with radiological
evidence of polycystic ovaries.
Peripheral insulin resistance with a compensatory hyperinsulinaemia is frequently seen in
PCOS, and the insulin excess leads to ovarian and adrenal androgen production
Picture 5: Pathogenesis of PCOS
PCOS is frequently, although not always, associated with obesity and glucose intolerance.
Treatment with Metformin can improve insulin sensitivity and lead to ovulatory cycles.
The dosage recommended is 500mg thrice daily for at least three months or till the cycles
are regular or till pregnancy. This could also be continued for at least first three months
during pregnancy which improves foetal outcome and reduced incidence of early miscarriage. The American college of Obstetricians and Gynaecologists 2002 states that all women
with PCOS should be screened for glucose intolerance & dyslipidemia and treated with
agents that improve insulin sensitivity, including Metformin may be of benefit. The American Association of Clinical Endocrinologists recommend to consider Metformin as initial
pharmacologic therapy for most women with PCOS particularly over weight and obese.
Glucose control in Gestational Diabetes with insulin / Metformin did not alter the foetal
outcome once there was a tight control. However the routine use of Metformin in diabetic
patient becoming pregnant is yet to be approved.
Metabolic Syndrome: Metabolic syndrome describes the co-occurrence of a constellation of metabolic disorders, which increase the risk of developing atherosclerotic vascular
disease and Type 2 diabetes. It affects 1 in 5 five people worldwide, and the prevalence
is rapidly rising as a consequence of the increase in the prevalence of obesity. This is of
major public health concern, due to the commensurate rise in prevalence of cardiovascular
disease that is occurring together with the rise in Type 2 diabetes.
Metformin would be an ideal agent to counter every component of metabolic syndrome.
Use of Metformin results in weight loss, cardiovascular risk reduction, favourable coagulation & lipid profile and the crux of the problem which is insulin resistance is corrected.
Non Alcoholic Steato Hepatitis (NASH) There is firm epidemiological evidence that NASH
is strongly associated with metabolic syndrome. Most cases of NAFLD occur in patients
with obesity (60-95%), Type 2 diabetes (28-55%) and hyperlipidemia (27-92%). In older
studies of patients with Type 2 diabetes, fatty liver was present at histological examination in 50% of cases. HOMA insulin resistance is nearly doubled in patients with NAFLD
195
compared to matched controls, and patients with NASH have more metabolic syndrome
compared to age, sex and severity of fibrosis matched patients with hepatitis. Reduced
insulin sensitivity is shown in many studies of patients with NAFLD or NASH, including
studies with hyperinsulinaemic, euglycaemic clamps, and oral / intravenous glucose tolerance tests . There appears to be a direct correlation with the degree of insulin resistance
with severity of liver disease from mild NAFLD to severe NASH and cirrhosis.
Both peripheral and hepatic insulin resistance is present in patients with non-alcoholic
fatty liver disease, irrespective of the coexistence of impaired glucose tolerance or obesity.
This observation, together with the frequent presence of hypertension, hypertriglyceridemia,
central adiposity and family history of diabetes, has led to NAFLD disease being considered
as the liver manifestation of metabolic syndrome.
Insulin resistance and increased non-esterified fatty acid (NEFA) are associated with increased intra-hepatic production of free fatty acids (FFA) from glucose not taken up by
peripheral adipocytes and myocytes.
Excess hepatic fatty acids are not oxidised and are converted to diacyl- and triacylglycerols,
and are stored in the hepatocyte cytoplasm, leading to steatosis. There are a combination
of genetic and acquired factors that are responsible for insulin resistance leading to the
development of steatosis, through increased lipolysis and delivery of free fatty acids to
the liver.
Treatment with sudden weight reduction has not shown regression of NASH however
lifestyle modification is the first form of treatment followed by drugs like Metformin and
Pioglitazone. These drugs reduce insulin resistance at the liver and muscle which corrects
the defect.
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Contraindications
The contraindications and precautions for the use of Metformin have been defined to
reduce the risk of drug accumulation in the plasma and /or to minimize the risk of
lactic acidosis. Elderly and patients with other comorbid illnesses have to be monitored
frequently to detect lactic acidosis. Metformin has been subjected for a study by Holstein
A & Stumvoli M which appeared in Diabetologia 48, 2454-2459 in such contraindications also
and was found that only one patient developed lactic acidosis.
Secondary failure of Metformin monotherapy in a trial was 42% and would be 17% per
year (Diabetes Care vol 33 no.3 march 2010)
It is prudent to take proper care not to use in contraindications. The following are the
contraindications.

Acute or chronic disease which may cause tissue hypoxia like cardiac or respiratory
failure, recent myocardial infarction, shock
Hepatic insufficiency, acute alcohol intoxication, alcoholism
Renal failure or renal dysfunction with creatinine clearance < 60ml/min
Acute conditions which could alter renal function such as dehydration, severe infection,
shock, diagnostic procedures involving IV iodinated contrast agents.
Lactation, Diabetic ketoacidosis, Diabetic pre-coma and in pregnancy

Hypersensitivity to Metformin
To follow up growth and development in children as data is not very huge. Though
the list is long it is reasonably a safe drug provided we take proper care in selection
of the patients.
Benefits
The hasty decision of banning Metformin did not affect this molecule whereas it actually resurrected from that assault only because of its efficacy, safety as well as the other
benefits it offered in addition to the anti-hyperglycaemic effects.
The basket of benefits it offers is as follows
Weight alterations
Lipid friendly
CV Risk reductions
Quality of life
Cost
Weight alterations: As already pointed out, this drug promotes weight reduction and
hence very ideal for obese diabetics and metabolic syndrome persons. It also reduces the
weight gain when it is given in combination with TZD, Insulin and sulphonylurea. It is also
beneficial in that it does not increase weight adding more problems in the therapeutic front.
Lipid Friendly: Treatment with Metformin results in the modest improvement in the lipid
profile, typically with reduction in total cholesterol, LDL-C and Triglycerides. HDL-C is usually unaffected. Though these are useful adjuvants, they are not sufficient to explain the
CV benefits due to the quantum of its action. Considering the sub-profiles, a study by
Lawrence,J.M et al Diabetes care, 27, 41-46 who showed that Metformin & Pioglitazone reduced
the amount of small, dense LDL particles(LDL-3 ) and increased the amount of large, more
buoyant LDL particles (LDL-1). The ratio of larger HDL2C to smaller HDL3-C was increased.
In few other studies there was no change in the size of these lipoproteins. Several non
randomized trials have demonstrated significant reductions in Free Fatty Acids following
treatment with Metformin. This is also considered by many others as secondary to glycaemic control. On the whole it is favourable but not the only factor for CV risk reduction.
Cardio Vascular Risk Reduction: Now it has been made mandatory by ADA that all antidiabetic and other drugs should prove its cardiac benefits before its launch. Metformin
though launched more than 50 years ago; it satisfies this latest requirement of ADA also.
UKPDS 33 was the first prospective long term study with oral antidiabetics as well as insulin
under two major divisions the intensive control arm and the conventional control arm and
brought to the world that intensive treatment arm scores over the other arm by a significant reductions in the complications of Diabetes and CV mortality. In the analysis between
the OHAs (UKPDS 34) it was found that in the Metformin group there was a marked & a
significant reduction in diabetes related death, myocardial infarction, any diabetes related
endpoint and all cause mortality than with diet treated as well as Glibenclamide/ insulin
group. This benefit was beyond glycaemic control which was a common denominator for
all the modality of treatment. Hence the concept was that Metformin is beneficial for all
diabetic patients beyond the number reduction in glycaemic value.
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Picture 6: Cardiovascular Benefits of Metformin
The measurement of Carotid Intima-Media Thickness (CIMT) after a 3 year follow up on

Metformin / Metformin + Glibenclamide / Glibenclamide. Metformin group showed lower
value. This also confirms its anti-atherogenic effect (Diabetologia 47, 1906-1913).
Metformin by activating AMPK, improves left Ventricular function and survival in heart
failure (Circulation research, ADA 2009; 104)
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Metformin reduces adiposity, insulin resistance, plaque lipid deposition, increases fibrinolysis
and improves lipid profile. These translate to a reduction in the macrovascular complications. The reduction in the oxidative stress, inflammation, Advanced Glycation End product
(AGE) which improves the endothelial function reduces macro & micro vascular complications. The reduction of blood glucose and improved capillary microcirculatory function
reduce the microvascular complications.
Picture 7: Vascular benefits of Metformin
Thus Metformin is not only a diabetologist friendly molecule but also a cardiologist friendly
molecule and ultimately a patient friendly molecule.
Economic Burden
Diabetes is increasing day by day and is a huge threat to the developing as well as the
developed nations as far as the cost incurred by the government in managing diabetes and
its complications. Metformin has proved itself in the UKPDS that the cost of therapy for
10 years is significantly lower than other group of drugs due to its low cost of medication
(< one rupee) as well as the reduction in the management of its complications. Moreover
the prevention strategy with Metformin has also become useful and economical supplying
more healthy manpower and more man days due to lack of complications which would
make any nation more productive and prosperous.
Quality of Life
Self-Administered Quality of Well-being Index (QWB-SA) and Euroqol (EQ-5D) are quality
of life questioners and valuation of diabetic patients was done and found that patients
without complications were better compared to patients with micro & macrovascular complications. The UKPDS population was also subjected to such a questioner and found that
patients on Metformin were better compared to other OHA and insulin users. It is understandable that a drug which reduces complications and without hypoglycaemia would do
better than other OHA like Sulphonylurea which was compared at that time. The extended
release preparation also has made a revolution in reducing the gastric side effects and
improving compliance.
Guidelines
Originally Metformin was initiated only in obese patients as per the randomization criteria
of UKPDS but now all organizations and associations like International Diabetes Federation
as in the clinical task force IDF Global guidelines, A joint position statement from the
European Association for the study of Diabetes and The American Diabetes Association as
per Diabetes Care 29, 1963-1972 and a position Paper from an expert group in the Asia pacific
region as in Diabetes Research and clinical practice 75, 255-266 support the initiation of oral
pharmacotherapy with Metformin along with lifestyle measures even from the time of
diagnosis in non obese patients also. This is based on the fact that the complications are
less with life style modifications along with Metformin.
Future
Though the future is not ours to see, this molecule appears to be the most ideal antihyperglycaemic drug of yesterday, today and tomorrow. The reason being, it has passed
through a stage of dismissal and won over the assault, able to satisfy all the rigorous
criteria of various associations as well as ADA and hence it is bound to stay for another
50 years to celebrate a centenary. There could be few more indications like Prevention,
HIV associated lipodystrophy, Neoplasia prevention.
Diabetes Prevention
This has to be taken in a war footing and in this drug therapy is definitely warranted
of which the commonest would be again Metformin as Acarbose and Orlistat are poorly
tolerated and TZDs are not free from side effects.
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The Diabetes Prevention Program showed a reduction of 32% with Metformin in the new
onset of diabetes in the high risk group.
The ADA recommendations in prevention are, as per the Diabetes care 27, 155-161, are
as given below.
Picture 8: Benefits of Metformin in Diabetes Prevention
In a case of IGT/IFG if there is any one problem like age<60, BMI >35, family history of
diabetes, High TGL, Low HDL-C, Hypertension, HbA1c >6% as in fig, it is an indication for
Metformin in a dose of 850mg b.i.d and if not even one is positive, then mere lifestyle
modifications are only needed.
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HIV Associated Lipodystrophy

Highly Active Antiretroviral Therapy (HAART) has revolutionized the management of HIV
however nearly 50% of them on this regimen more so with protease inhibitor develop
redistribution of fat similar to the type A insulin resistance state with loss of muscle and
subcutaneous fat and more deposition in the viscera leading to cardiometabolic syndrome.
They also have high insulin resistance and increased cardiac risk. These patients improve
well with Metformin. Seven randomized trials support this concept (Journal of Clinical
Endocrinology and metabolism 86, 939-943 and 87, 4611-4615)
Neoplasia Prevention
The metabolic effects of Metformin are mediated through AMP activated protein kinase.
A tumour suppressor, LKB1, has been identified as an upstream regulator of AMPK, thus
raising the hypothesis of a potential anti-neoplastic action of Metformin.
The AMPK pathway represents a point of overlap between the biochemical pathways mediating energy balance and those mediating suppression of tumour formation.
A rise in the AMP: ATP ratio caused by exercise or other depletion of cellular energy
stores/ hypoxia or ischemia induces binding of AMP to AMPK. This causes an allosteric
activation of AMPK involving phosphorylation of a threonine residue in the alpha subunit
of the enzyme. An upstream kinase, the tumour suppressor LKB1, is responsible for much
of the phosphorylation of Thr172 of AMPK. Activation of the overall AMPK pathway may
therefore be expected to inhibit the initiation of growth of tumours in addition to its

effects on metabolism.
Picture 9: Role of Metformin in Tumour Prevention
Activation of the AMPK pathways has been proposed as one of the mechanism by which
Metformin exerts its beneficial metabolic effects. Since LKB1 is upstream of the AMPK
pathway, it raises the possibility that Metformin may inhibit LKB1- dependent tumourigenesis.
The effect of Metformin on the growth of cancer cells were studied using cultured epithelial
cancer cells in vitro (Cancer research 66, 10269-10273) Stimulation of the MCF-7 breast cancer
cell line with IGF-1 or insulin, induced marked cell proliferation, which was essentially
abolished by co-incubation with Metformin. Similar reports were obtained in the prostate
(PC-3) and the ovary (OVCAR-3 and SKOV-3 cells). Metformin also inhibited proliferation
of the untransformed breast derived epithelial cell line.
Two large observational studies have reported a reduced incidence of neoplastic disease in
patients treated with Metformin relative to other therapies. The Diabetes Audit Research
in Tayside/Medicines Monitoring Unit (DARTS/MEMO) concluded that a trend towards a
greater protective effect was observed with increasing duration of exposure to Metformin
and the total number of Metformin prescription dispensed. The UKPDS also found that
in Metformin treated group, there was a reduction of risk of death from cancer of 29%
relative to diet treatment. The all cause mortality also was low with 36%.
Conclusion
Though Metformin is just the same at discovery and even now, several new facts have
been brought to light. The mechanism of action, the reason why Phenformin lost the
battle, the role of AMP kinase in the action at various levels even up to prevention of
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malignancy is reasonably studied. The concept of continuous improvement in Metformin

with new technology of extended release preparation and the ability to combine with
other molecules like SU/Meglitinide / DPP4 inhibitor/ AGI & Insulin and give better results
suppressing their drawbacks made the molecule comeback.
It is widely used in all spectrum of glucose intolerance in all diabetes as first choice with
LSM. It also has multidisciplinary action over NASH, PCOS, pregnancy; Malignancy, Obesity,
Metabolic syndrome and this made this molecule a versatile one.
The only drawback was lactic acidosis which was disproportionately beefed up those days
probably because of Phenformin causing it, but now it has been well documented that it
is rare & if proper care in taken to look for contraindication and avoid, it is not an issue.
The other benefits which were new finds with the old molecule are favourable weight
alteration, lipid friendly nature, cardio vascular risk reduction, better quality of life and a
very economical drug which made this drug to be a pleotrophic drug. The future prospects
also seem to be very bright with widening indications in the prevention of diabetes, its
role in HIV associated lipodystrophy and prevention of malignancy.
Thus the molecule which was dismissed by the European & American group was still continued in India by the efficient, careful, vigilant, Clinical giants because of their correct
clinical assessment of its values in spite of the rest of the world who were against it. It
definitely deserves this reappraised during its golden jubilee.
References
202
1.
Witters, L.A. (2001) The blooming of the french lilac. Journal of clinical Investigation, 108, 1105-1107
2.
Glucophage 1957-1997. Serving Diabetology for 40 years. Lyon : Group Lipha (Merk Serono), 24 Rue Saint
Romain, Lyon, France
3.
Keeler, R.F., (et al.,) (1988) Individual animal susceptibility and its relationship to induced adaptation or
tolerance in sheep to Galega officinalis L.Veterinary and Human Toxicology, 30, 420-423
4.
Alkaloid, (et al.,) in extracts of a rather noxious weed, Galega officinalis, dimethylbiquanide (Metformin)
5.
Now, new oral antidiabetic agents must be proven non-inferior to Metformin, and combination with
Metformin is advocated for many new drugs
6.
Pioneering work by Dr. Jean sterne (et al.,) and his colleagues in france made oral antidiabetic treatment
with Metformin a clinical reality
7.
The first synthesis of dimethyl biguanide (Metformin) is attributed to Werner and Bell at Trinity College,
Dublin, Ireland in 1922.
8.
All biguanides are strong bases, all biguanides are essentially fully protonated at physiological pH. Only one
amino group accepts a proton, 1-substitued biguanides, but whereas Metformin has two methyl groups
substituted at a terminal amino group,
9.
For example, diagnoses of type 2 diabetes in children are now four times as common as diagnoses of type
1 diabetes in parts of Japan and China (14,20)
10. The antihyperglycaemic efficacy of Metformin reached a plateau at doses of 2000 mg and above.
11. Metformin improves glycaemic control in type 2 diabetes without inducing increased insulin secretion (3),
agent therefore addresses insulin resistance.
12. A preliminary report suggests that Metformin may induce redistribution of fat from the metabolically active abdominal depot to the relatively inactive subcutaneous dept during a treatment period of 6 months.
13. Reductions in total cholesterol, LDL C and triglycerides.
14. Randomization to intensive glycaemic management with Metformin in this study was associated with
marked and significant reductions in diabetes-related death, myocardial infarction, any diabetes-related
endpoint, all-cause mortality, sulfonylurea or insulin, demonstrating the potential of Metformin to deliver
improvements outcomes beyond those attainable via tight control of blood glucose alone. 5102 patients
23 centres within the U.K,
15. Impair patients quality of life. Not further impair quality of life. (et.al.,)
16. Self administered quality of well being Index is a well validated quality of life.
17. Quality of life is rated on a score between zero (dead) and unity fully functioning)
18. About 0.7 slight reduction in the quality of life, with a greater reduction for insulin treatment
19. Quality of life (4.5) the second instrument, the Euroqol EQ-5D, was a generic quality of the questionnaire
which explored five dimensions.
20. Dual hydrophilic polymer matrix (the Gelshield(R) diffusion system), is contained within beads of one polymer
surrounded by the other,
21. When the tablet is swallowed it hydrates and swells, forming a gel layer on the outside of the tablet.
22. Formulation also enables a metered release of Metformin with the small intestine, by slowing diffusion
from the gel.
23. Bloodstream is slower and smoother than with the immediate release preparation 24 hour bioavailability
is similar and once-daily dosing.
24. J. Clin. Endocrinol. Metab. (et. al.,) 2003 88 : 1323-1332, doi : 10.1210/jc.2002-021394.
25. Circ. Res. 2009; 104; 403-411; originally published online Dec 18, 200;
26. Diabetes Care, Volume 33, Number-1, January 2010.
27. Journal of Molecular Endocrinology (2010) 44, 87-97.
28. Metformin The Gold Standard Clifford J.Bailey, (et.al.,)
203

Dr N R Rau
204
Professor, Department of Medicine,

Kasturba Medical College
Manipal - 576104
Tel Office: + 91 0820 - 2571201 - 22236
e-mail: nrrau@yahoo.co.in
&
Dr Shivashankara K N
Professor, Department of Medicine,

Kasturba Medical College, Manipal.
Manipal - 576104.
Abstract
Diabetes mellitus is now one of the most common non communicable diseases. Globally
it affects persons of all ages as well as their families, while also placing heavy economic
burdens on national economies and healthcare systems. Much of this money goes towards
treating the complications of diabetes. These complications are preventable if patients have
access to expert healthcare. Implementation of a comprehensive healthcare management
program for people with diabetes can lead to substantial improvements in costs and clinical outcomes in the short-term. Economic evaluation of therapy should be encouraged
to ensure improved cost effectiveness and efficiency in management. Regularly up-dated
drug formulary and evidence-based standard treatment guidelines would ensure better
choice of therapeutic options. More importantly, a concerted effort is needed to reduce
the incidence of diabetes mellitus in the society. It is expected that improvements will
increase over time, with continuing improvements in health status and a reduction in the
number of future diabetic complications.
Introduction
Diabetes is a common, serious, and chronic disease causing major long-term complications
and co-morbidities. Nearly 200 million people worldwide (or more than 5% of the global
adult population) have diabetes, and this number will increase to 333 million (or 6.3% of
the global adult population) by 2025 1. The world is facing an epidemic of type 2 diabetes
and an increasing incidence of type 1 diabetes 2, 3. The prevalence of diabetes worldwide
was estimated to be 2.8% in 2000 and projected to rise to 4.4% by 2030, with more than
three-quarters of people with diabetes living in developing countries 4. The World Health
Organization (WHO) estimates the number of people with diabetes in India in 2000 to be
31.7 million, which is likely to rise to 79.4 million by 2030 5.
The complications of diabetes may be acute or chronic. Acute complications are more
common in Type 1 diabetes and are due to low blood sugar (hypoglycaemia) or high blood
sugar that can lead to ketoacidosis both conditions causing death if untreated. Chronic
complications are due to vascular changes:

Macrovascular complications, where large blood vessels are damaged resulting in heart
disease, cerebrovascular disease, and peripheral vascular disease.
Microvascular complications, where the small blood vessels are damaged resulting in:
Diabetic kidney disease (nephropathy) takes about 5 to 15 years to develop and can
lead to end stage renal failure (ESRF) which is the most common reason for kidney
transplantation in Western Europe 6.
Diabetic eye disease (retinopathy) is present in up to 50% of persons at diagnosis with

T2DM and in 40 to 50% of persons with Type 1 at 10 years after diagnosis. Diabetes
is also associated with cataract formation at an earlier age and with less favorable
outcome of treatment than in people without diabetes.
Diabetic nerve disease (neuropathy) refers to damage to the nerves and is directly
related to
glycaemic control and duration of diabetes. Peripheral neuropathy contributes to the development of foot ulcers, gangrene and amputation.
205
It is generally accepted that the degenerative changes associated with diabetes mellitus
are to a large extent preventable through blood glucose control 7, 8. Environmental factors
that fuel the current epidemic include an ageing population, dietary changes, industrialization, improved transport, social changes, economic factors that feed into lifestyle changes,
reduced physical activity, obesity and other unhealthy lifestyle and behavioural patterns.
Epidemiological data supports the role of obesity, fat intake and physical inactivity as risk
factors for diabetes and have led to successful trials to prevent/delay the onset of T2DM
by lifestyle interventions.
The Diabetes Clinical Control Trial (DCCT) provided convincing scientific evidence about the
benefits of glycaemic control in the management of Type 1 diabetes. The UKPDS suggested
that improvements in glycaemic control are associated with reductions in microvascular
complications in patients with T2DM and tight blood pressure control reduced both microvascular and macrovascular endpoints.
This article focuses on the economic burden of diabetes at present and in future.
Burden of Diabetes
206
Diabetes mellitus is a major healthcare concern from both a treatment and a funding
perspective. Diabetes mellitus and its complications are the major causes of ill health and
premature death. From an economic perspective, it is the prevention of cardiovascular disease that is the key, as cardiovascular disease accounts for a large proportion of the excess
medical care costs attributed to diabetes. For T2DM, cardiovascular disease is known to be
the most costly single class of complications 9. Early detection and intensive interventions
will delay or prevent complications, reduce the burden in terms of cost and improve quality of life for the patient. This strategy will reduce the personal and economic burden of
diabetes. Atherosclerotic cardiovascular disease, including coronary artery disease, strokes
and diseases of blood vessels, are 2 to 5 times more common in people with diabetes.
People with diabetes are 17 times more prone to kidney disease. The high cost of diabetes
is caused largely by the treatment of complications of the disease, as they increase spending for the affected patient more than fivefold 10. Medical costs for a person with T2DM
are on average 1.5 times greater than those of a person without diabetes. The presence
of microvascular complications doubles the costs. The presence of macrovascular complications trebles the costs incurred, whilst the presence of both micro and macrovascular
complications increases costs by more than five times. These costs have tremendous impact
on the lives of individuals, their families, the healthcare sector, government and society.
Persons with diabetes have a five fold increased incidence of heart disease and a three fold
increased incidence of stroke. Diabetes is the leading cause of blindness in the working
population and end-stage kidney failure in the general population. Studies have shown a
prolonged prediagnosis state of on average seven years before clinical diagnosis of T2DM
is made, and hence a significant proportion of patients have complications of the condition at diagnosis. There is unequivocal evidence that early detection, management and
treatment of diabetes can reduce morbidity and costs.
Diabetes is a chronic, multisystem condition, which has a high risk of serious complications, is expensive to treat, and has profound effects on patients daily lives. However,
there is unequivocal scientific evidence that early detection, management and treatment
of diabetes can reduce morbidity and costs. To manage diabetes optimally it is necessary
to establish a platform for collaboration based on equality and the mutual respect of all
parties involved. The interests of all people concerned with diabetes, whether they live or
work with the condition, are best served by joining together, thus ensuring a uniform structure to fight this growing problem. The recent publication of the National Health Strategy
provides an opportunity for all parties to work together to combat this growing concern.
Pharmacoeconomics and Diabetes

The health care system is clearly in state of rapid revolution. Since the 1970s, much progress
has been made in applying economic analysis to diabetes and diabetes care. The number
of published studies increased from an average of 2 articles per year in 19791980 to an
average of 20 per year in 19992000 11. Traditional approaches to healthcare decisions
will no longer suffice; therefore, new tools will be needed 12. Medical, ethical and societal
concerns about costs, access and quality of care are causing healthcare practitioners to
consider a more comprehensive model for medical decision making 13 these trends led to
the evolution of Pharmacoeconomics 12. Cano and Crane 14, 15 defined Pharmacoeconomics
as the economic evaluation of drug therapy, pharmacy program or pharmacy technology.
Pharmacoeconomic evaluation of therapy is increasingly being advocated even in developed countries 15, 16 where per capital income is much higher. Traditionally, emphasis is
basically on clinical outcomes of therapy with little critical consideration for economic
and psychosocial (humanistic) outcomes of therapy 17. The research article is focusing on
economic outcome of therapy using Cost of Illness Analysis (CIA) 18. CIA shows the cost
of the condition in question (diabetes mellitus in this case) to the patient and the society
over a period of time 19. It is a pure cost analysis and health outcomes are not evaluated
unlike comparative cost analytical methods such as cost-cost analysis.
All costs caused by the condition over a defined period of time (one year in this case) are
evaluated and added up. It is the only type of analysis that gives a true picture of the
cost implication of a disease condition to the patient and the society.
Diabetes Mellitus is a major health problem 20. It is a chronic illness, which in most cases
is treated for life; hence the cost associated with it is enormous. Few data exists as regard
its cost to the patient and the society in developing countries. Such costs, if available,
are useful tools in policy formulations, decision taking and motivation for adherence to
preventive measures by the populace.
The overall costs of diabetes to the health care system and the society depends on its
prevalence, in addition to the severity, type of drug used, and compliance to medications
by the patients and development as well as progression of complications.
The prevalence of diabetes, in the developed countries is well established but less so in
developing ones. The World Health Organization stated in 1998 that a 122% rise in the
number of adults with diabetes is projected by 2005, to reach 300 million adults worldwide
76 % of this in developing countries 21.
Present Situation
Over the last 30 years, medical expenditure has increased throughout the world at a
considerably faster rate than other sectors of the economy 22, 23. Economic evaluations
of therapies to improve the management of diabetes mellitus have increasingly relied on
modelling of long-term outcomes and costs for the disease. Annual direct medical costs
207
increase from $1,400 to $4,600 as an individual progress from impaired glucose tolerance
to uncomplicated diabetes to diabetes requiring pharmacologic treatment to diabetes with
complications and co-morbidities 24. It is estimated that the care of people with diabetes
mellitus accounts for 4 to 5% of the total health budget of the United Kingdom 25. Study
done by the American Diabetes Association in 1997, showed diabetes accounted for $44.1
billion in direct healthcare expenditures, $37.1 billion in lost productivity due to disability
and $17.0 billion from lost productivity due to premature mortality 26. Of the diabetic
complications, cardiovascular disease by far was found to have the greatest proportion of
direct costs and more than half the mortality-related costs of the condition 27. In a recent
paper 28 it was shown that the per-person annual costs associated with Type II diabetes
increased by more than 50% when cardiovascular complications started to appear and
by 360% when a major cardiovascular event occurred. Abnormal renal function increased
diabetes treatment costs by 65% and end-stage renal disease by 771%. Due to the large
number of complications associated with diabetes, diabetic patients account for 1 in every
$7 spent on healthcare in the United States 29.
Developing countries like India will have to bear the major burden of diabetes. The low
socio-economic group will be disproportionately affected, as around 25% of the income
of low and middle-income Indian family with a person with diabetes is spent on diabetes
care 30. Indirect cost implications are also there due to loss of work-days and intangible
cost like pain, emotional and inter-personal strains.
208
IDF estimates that the annual direct healthcare costs of diabetes worldwide, for people
in the 2079 ages, to be at least 153 billion US dollars, and may be as much as 286 billion US dollars, or more 31. A study on the economic costs in the US in 2002 indicated
that people with diabetes had medical expenditures that were approximately 2.4 times
higher than those that would be incurred by the same group in the absence of diabetes
32
. Direct medical and indirect expenditures attributable to the condition were estimated
at 132 billion US dollars. Direct medical expenditures alone totaled 91.8 billion US dollars
of which 25% (23.2 billion US dollars) were attributed to direct care of uncomplicated
diabetes and diabetes-related supplies, 27% (24.6 billion US dollars) were attributed to
chronic complications related to the condition and 48% (over 44 billion US dollars) to
general medical conditions (such as visits or in-patient days where the primary diagnosis
is neither diabetes nor one of the usual chronic complications heart, eye, kidney disease, lower limb amputations, etc.,). Indirect medical expenditures to the amount of 40
billion US dollars referred to lost productivity due to disability and early mortality 32. In
addition, the study shows that 51.8% of direct medical expenditure is incurred by people
with diabetes over 65 years of age. For instance, sufferers over the age of 65 would
visit their physician twice as often as people with diabetes in the age range between 45
and 64 years. The use of the emergency department is also substantially higher for the
population over 65 years of age compared with the groups between 45 and 64 years, and
under 45 years. Although people with diagnosed diabetes only represent slightly more than
4% of the United States population, it is estimated that almost one in five US dollars is
spent on healthcare in the United States is for a person with diabetes. Also, because the
prevalence of T2DM increases with age, people with diabetes incur a substantial proportion of long-term healthcare services. For example, more than one dollar in four is spent
on nursing homes, home health services and hospice care providing for diabetes sufferers.
In Spain the CODE-2 Study of costs in T2DM indicated that hospital care accounted for
32% of healthcare costs 33, 34.
Diabetes related complications account for 60% of diabetes related health care costs
(direct costs) and almost 80-90% of indirect costs 35. For example, in 1986, the total cost
of type 2 diabetes in the US was estimated at 20 billion dollars but it had increased to
over a 100 billion US dollars in the mid1990s, for diabetes related health care problems 35.
This increase of over five times in a decade is astronomical, and amounts to a little lower
than one third of Indias GDP. Other studies on direct costs of T2DM have been carried
out in Argentina, France and Denmark. The direct cost per patient per year for T2DM in
Argentina was 330 US dollars, in France the cost was 675 US dollars and Denmark the cost
was 3535 US dollars 35. The BUD Study 36 estimated that the annual direct cost for routine
care in Bangalore, India in 1998 to be about 191 US dollars; the mean direct cost per
hospitalization for a diabetes-related episode was about 208 US dollars. From the available
information it is clear that diabetes will pose a severe burden on the already fragile and
under resourced health care system in India, in the future. The per capita expenditure on
health care in India is only 6.4% of the average world spending, while India accounts for
23.5% of the worlds disability adjusted life years lost due to diabetes (DALYs). Due to
scant resources and burgeoning costs, health care planners and providers are being forced
to cut resources worldwide. To be able to plan and allocate resources adequate background
data is required. This includes amongst other information, an estimates of current costs
The CODE-2 (Cost of Diabetes in Europe Type 2) study indicated that 30 to 65% (on
average 53%) of the total costs incurred by national health services on the care of persons
with diabetes are due to hospitalization; 18 to 39% are due to ambulatory care; 2 to 7%
on oral antidiabetic medication and 11 to 31% on other medication. This study also showed
that the presence of both microvascular and macrovascular complications increased patient
management costs more that 3.5 fold. Therefore, to reduce direct and indirect costs of
diabetes, it is recommended to try and reduce inpatient length of stay (LoS) and prevent
or delay the onset of complications.
Our study 37 of the direct cost incurred by T2DM patients for their treatment at our
hospital (a largely subsided care set up) revealed the following results

The median annual direct medical cost for patients with T2DM without complication
was Rs 14,507.
Patients with T2DM and Chronic Renal Failure CRF requiring dialysis spent 14 times
higher as compared to those without any associated complications.
About 80% patients self finance their treatment and spent about 50% on drugs and
21% on hospitalization.
Average length of hospital stay was 10.3 days and average daily expenditure as indoor
patient was Rs 871.85 (This included expenditure of food, drugs and cost of expenditure
of people accompanying the patients in the hospital).
Our study did not asses 1) Psychological cost e.g. loss of body integrity 2) Cost of
family life-lack of acceptance of disease by family 3) Social cost-feeling of isolation
and withdrawal.
A study by Dr Ramachanran et al 38 at Diabetic Research Centre Chennai estimated the

annual cost of care was Rs.12, 000 for patients taking insulin and Rs.2400 for those on
oral antidiabetics. Using the information then available, the estimated cost of treatment of
209
17.3 million diabetics in India would be Rs 7520 crores. This is about 3 times the national
health budget at that time. The present scenario must be too demoralizing even to imagine.
The T2ARDIS 39 report states that Type 2 diabetes costs Britains NHS 2 billion a year,
almost 5% of the total NHS expenditure and an additional 36 million is spent on related
social services. This report found that people with diabetes are 2 to 3 times more likely
to be admitted to hospital than their demographic peers and that on an average they
stay four times as long.
A recent UK study using hospital record linkage estimated that the cost of diabetes is
more realistically approaching 9% of the NHS budget. Although this figure includes the
costs for both Type 1 and Type 2 diabetes, it is well in excess of that estimated in the
T2ARDIS report.
Research from an as yet unpublished Irish study confirms that diabetes care costs 350.5
million per year, which is about 10% of the total healthcare budget. Of this, 59% is spent on
managing expensive and preventable complications, and only 16% on the management of
diabetes. The remaining 25% is spent on ambulatory care. There is now no doubt that the
onset of the complications of diabetes can be prevented and delayed by intensive treatment and education. By effective early intervention the total cost of diabetes care can be
reduced. Reducing the costs of diabetes may be achieved through:
210
Primary prevention
Prevention of complications
Earlier treatment of complications.
A recent evaluation of intensive blood glucose and blood pressure control showed that
reductions in future healthcare costs constituted a substantial subset of the intervention
costs (in the case of intensive blood glucose control with Metformin producing overall cost
savings 41. Each component of diabetes care has been found to be individually cost-effective
for society. For the general population of diabetes patients, treating diabetes, treating
hypertension, and treating hyperlipidemia are all cost-effective, based on the traditional
incremental cost-effectiveness ratio of $50 000/quality-adjusted life year (QALY). The annual medicine and consultation cost were significantly high in patients who are having
one or the other complication and patients with longer duration of illness. Less is known
about the cost-effectiveness of improving diabetes care comprehensively, which requires accounting for the costs related to simultaneously addressing glucose control, blood pressure
control, cholesterol control, and aspirin prophylaxis. Improvements in metabolic control are
generally achieved through optimized medication regimens, but costs specifically associated with such optimization have not been examined. The costs of routine diabetes care
are important determinants of diabetes cost-effectiveness analyses, and so understanding
how much more it costs to improve routine diabetes treatments is essential if we are
to understand the social value of multiple large-scale public investments in quality improvement. In this study, we assessed clinical characteristics, metabolic control, and actual
medication regimens of a large cohort of type 2 patients in an academic medical center.
We estimated incremental medication costs associated with changing medication regimens
from actual to idealized care in order to move patients metabolic control toward current
recommended treatment goals. Only 23% of the direct costs attributable to diabetes were
associated with diabetes management. Of direct costs attributable to diabetes, 12% were
related to diabetes medications and supplies and 9% to outpatient care.
Ulf G Gerdtham et al reported the results of a regression analysis, based on a large linked
administrative healthcare dataset from Sweden, to obtain empirical estimates of the annual
hospital inpatient costs associated with a wide range of diabetes related events. The results
indicate that events significantly elevate inpatient costs both in the year during which
they occur and in subsequent years. They also illustrate the importance of co-morbidities,
which more than double the short- and long-term inpatient costs compared with the same
event without co-morbidities 40, 41.
Programmes and treatments to prevent diabetes and its complications could result in tremendous savings to the healthcare system, even in the short term. However, these data
most likely underestimate the total cost burden, given that only direct medical costs were
taken into account in both studies; indirect costs such as work loss and family care were
not evaluated but can have significant impact on patients and their families. Several models
show that appropriate treatment of diabetic patients results in long-term savings. A model
using 1992-2002 data from over 734 000 patients with type 1 and 2 diabetes predicted
that the introduction of a diabetes management programme to reduce risk factors, including raised HbA1c and cholesterol levels, decreased macro-and microvascular complications,
resulted in a life-time incremental cost per QALY of $US5527 if the programme effects
lasted 1 year and $US4448 per QALY if they continued for 10years (payer perspective)
42, 43
. Another diabetes model found effective in targeting the financial resources toward
lowering HbA1c levels in line with guidelines could lead to savings in the range of $US35$US72 billion in direct healthcare costs over a decade 44.
By 2025....
The projected increase in the number of people with diabetes suggests that the annual
cost of diabetes could rise to estimate US dollars 156 billion by 2010 and to 192 billion
US dollars by 2020 (based on the 2002 value of the dollar). Hospital in-patient costs for
the treatment of complications are the largest single contributor to direct healthcare costs
of diabetes. Of these complications, cardiovascular disease represents the biggest burden.
The overall costs of diabetes to the health care system and the society depends on its
prevalence, in addition to the severity, type of drug used, and compliance to medications
by the patients and development as well as progression of complications. The number
of individuals on oral glucose lowering drugs was almost twice the number of users of
insulin and analogues. In terms of costs, the pattern was opposite in that the total cost
of insulin and analogues was twice the cost of oral glucose lowering drugs. This indicates
that treatment of type 2 diabetes becomes more costly with disease progression because
insulin is increasingly prescribed with progression.
Strategy for better diabetic care 2025. Only education and mass awareness of this disease
can contains the epidemic. This is the most cost effective measure suited for poor country
like India. In addition establishment comprehensive diabetic care at taluk levels will result
in comprehensive diabetic care at the periphery.
The problem must be tackled in the following four points
1.
2.
3.
4.
Life Style modification

Better antenatal care
Public Education and awareness
Establishment of comprehensive diabetic care clinics at Taluk level:
211
Life Style modification: The best way of preventing or treating diabetes mellitus is life
style modification along with increased physical activity. The Finish Diabetes Prevention
Study and Diabetes prevention Program (DPP) have shown that life style modification
causes grater reduction in the incidence of diabetes as compared to placebo and placebo
plus Metformin.
Physical activity results in improve insulin sensitivity through weight loss and many other
benefits independent of weight loss. In adults a modest weight loss of 5% improves cardiovascular health, with improvements in both CVD risk markers such as blood pressure,
dyslipidemia and hyperglycemia 45.
Diabetes prevention programme should start at school levels as children are nations future.
Catch them young should be the slogan. They should be encouraged to take part in
outdoor games, athletics (swimming if resources permit) for at least 30 to 45 minutes
daily. Adequate playground space should be made available in schools. Adults should be
encouraged 30 minutes brisk walk/cycling daily.
Exercise programme should be individualized and a search for micro and macrovascular
complications should be made prior to the beginning of the programme.
This is the most cost effective programme in reducing the incidence and complications
of diabetes.
Good Antenatal Care: IUGR and low birth weight makes the thrifty genotype more
robust, resulting in obesity, metabolic syndrome and diabetes in later years and timely
diagnosis and treatment of GDM is important. This will benefit both the present and
future generations.
212
Public Education and Awareness: Indians are a high risk group developing T2DM and
percentage of undiagnosed diabetes is high. Hence the importance of screening, even when
asymptomatic, should be highlighted and facilities for the same should be made easily accessible and affordable. Emphasizing the importance of proper treatment of hyperglycemia,
hypertension, dyslipidemia, neuropathy, nephropathy and retinopathy goes a long away in
reducing the economic burden.
Education should start at school level with inclusion of diabetes in the curriculum. At the
community level, elected representatives, Medical Association, NGOs and media both print
and audiovisual should take the lead. At the state and central government level a special
cell should be created for tackling the problem of Non communicable disease with special
emphasis on diabetes, hypertension and cardiovascular diseases.
Establishment of comprehensive diabetic care clinics at Taluk level: This clinic should
have the services of physician, surgeon and ophthalmologist. Regular screening for diabetic complications could be done here like peripheral neuropathy screening, taking care
of diabetic foot, frequent screening for microalbuminuria. This could be nodal centre for
training field workers of primary health centre for creating diabetic awareness in the rural
public and training them in insulin administration etc. Doctor in general should prefer
the more economic generic brand of drugs to more expensive brand names, thus assuring
better compliance by the patients.
Conclusion
In conclusion, Economic studies demonstrate that diabetes is a very costly disease. Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and
health care costs. Much of the economic burden of diabetes is related to its complications
and co-morbidities. The above data indicates that the options which may offer the most
potential are: retinal screening; foot care; control of blood pressure in primary care settings;
regular cardiac evaluation, screening for renal disease and lifestyle changes, focusing on
increasing physical activity and improving nutrition. Investment on these services should
prevent a significant proportion of expenditure on treating complications of more advanced
diabetes. As a result of its chronicity, of the seriousness of its complications and of the
resources that must be used to fight it.
Regularly up-dated drug formulary and evidence-based standard treatment guidelines
would ensure better choice of therapeutic options. More importantly, a concerted effort
is needed to reduce the incidence of diabetes mellitus in the society. Health providers and
policymakers should use this information in making clinical and policy decisions in order
to use resources efficiently. Good health is a prerequisite to successful human endeavor
and therefore it is very essential for economic growth. Clearly, those involved in diabetes
care delivery need to be aware of the factors that drive health costs. Effective treatment
of diabetes is not costly; however, in both human and economic terms, not treating the
condition is extremely costly.
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44. Minshall ME, Roze S, and Palmer AJ, et al. Treating diabetes to accepted standards of care: a 10-year projection of the estimated economic and health impact in patients with type 1 and type 2 diabetes mellitus
in the United States. Clin Ther 2005 Jun; 27 (6): 940-50.
45. Douen AG, Ramlal T, Rastogi SA ,et al. Exercise induced recruitment of the insulin responsiveness glucose
transporter. Evidence for distinct intracellular and exercise-recruitable transporter pools in skeletal muscle
Biol Chem.1900; 265:13427-30.
215
Education of T2DM for

School Children in their Curriculum
Dr K M Prasanna Kumar
Senior Professor & Head, Dept. of Endocrinology
216
M. S. Ramaiah Medical College

Bangalore - 560 054.
Phone: 98451 56811
e-mail: dr.kmpk@gmail.com
Dr Pramila Kalra
M. S. Ramaiah Medical College

Ph: 92417 39868
e-mail: pramilakalra@rediffmail.com
Introduction
A major public health problem facing the world and especially India today is epidemic of
type 2 diabetes mellitus (DM). India is going to be the diabetes capital of the world by
the year 20251. It is estimated that by the year 2025 about 300 million adults will have
diabetes. While there appears to be a host of potential genetic and environmental risk
factors for insulin resistance and limited -cell reserve, perhaps the most significant risk
factor is obesity. The rates of childhood obesity have doubled over the past 2 decades which
is one of the main factors behind the ongoing epidemic of type 2 DM2-8. The Bogalusa
Heart Study shows that fitness and absence of overweight at a young age can prevent
the occurrence of atherosclerosis, coronary artery disease and hypertension9. We need to
curtail the epidemic of type 2 DM by preventive measures.
Insufficient physical activity and poor nutrition and more of high calorie foods are the
primary causes of obesity 10-13. Intervening at an early age when modifiable factors for
the onset of type 2 diabetes can be controlled is the best strategy. It is clearly known in
literature that Indians are predisposed to onset of diabetes and stroke much earlier than
rest of the world. It is high time that our government realise the need to provide healthy
future to coming generations. The availability of all the resources now are causing the
children to be physically inactive consequently leading to much earlier onset of type 2
DM. People need to be made aware that onset of type 2 DM can be delayed by modifying risk factors. Proper nutrition and physical activity are the primary targets of health
promotion initiatives aimed at preventing childhood obesity and overweight and further
preventing onset of type 2 diabetes mellitus in adults. Ecological approaches that recognise
the interaction between individuals and the settings in which they spend their time are
currently at the forefront of public health action. Schools have been identified as one of
the key settings for health care promotion. Preventive measures should begin at a young
age as factors for development of type 2 diabetes are present in young children and adolescents 14, 15 Furthermore, health behaviours track across phases of life 16-19 cluster together
20
and adults have substantial difficulty adopting and adhering to healthy behaviours21. It
thus seems prudent to invest our resources in encouraging physical activity and healthy
behaviour education during the growing years and to sustain these efforts throughout
life. Recent approaches say that an individuals behaviour is a consequence of the environment and settings, in which they live, learn, work and play. Public health professionals
and physical activity researchers 22-26 have identified school as a critical setting for action.
Classroom learning is expected to benefit immediate families and community members as
students bring home what they learn. Education professionals will benefit from the curriculum as it brings new knowledge and teaching strategies into the classroom.
In India presently there is no definite curriculum in schools as regards to education about
type 2 DM. The education syllabi in India do not include any targeted education curriculum about use of lifestyle modification to prevent the ongoing epidemic of diabetes
and obesity. The education imparted at the school level may help the children more as
they are more receptive and this may help the immediate family of the child by indirectly
imparting the education to the family.
Do we have a study model in the world which has shown that physical
activity and type 2 diabetes mellitus education in schools can be effective?
Education of T2DM for School Children in their Curriculum
217
There have been few study models in the world which show that by imparting physical
education training and education about type 2 DM the epidemic of obesity and type 2
diabetes can be curtailed.
218
One good example of such curriculum is DETS (Diabetes Based Education in Tribal
Schools) Health Is Life in Balance K-12 Curricula targeted at American Indians (AI) and
Alaskan native (AN) children which is aimed at helping reduce the incidence of diabetes
in youth and improve the care of type 2 diabetes among the population. The DETS curriculum units are aligned with national science, health, and social studies education standards so that it is easy to blend them into the established curriculum. They also weave
together inquiry learning, exposure to science and health-related careers. At elementary
level the children are given conceptual training about life in balance. At middle school
level children are taught about lifestyle modifications in terms of dietary patterns, physical
activity levels, and personal choices. They are taught to identify environmental changes
that can be made to improve or maintain personal health and the health of families and
communities. Still further children learn through analyzing case studies how the physical,
mental, emotional, and spiritual aspects of a persons life are affected when someone has
diabetes and how to use those aspects of life plus input from the community to regain
balance and health. At grades 9 to 12 children are taught with the use of models about
the pathophysiology of type 2 DM. The DETS curricula take about four weeks to complete.
Typically, schools supplement their regular curriculum with DETS units. Because the DETS
units are aligned with national science, health, and social studies education standards, it
is easy to blend them into an established curriculum. An evaluation of the curriculum,
involving 1,519 students and 63 teachers across the country, showed pre-to-post student
achievement gains at all three grade-level bands (elementary, middle, and high school).
The teachers also commented that the curricula was easy to use, was more engaging than
similar curricula. Overall, students reported that the DETS curriculum was just right not
too hard but not too easy. One similar programme is being developed in some areas of Japan
which operate a school-based health promotion programme which is aimed at preventing
the development of risk factors for cardiovascular diseases and type 2 DM. Children are
screened for risk factors such as hyperlipidaemia, high blood pressure (hypertension) and
obesity. Lifestyle interventions against these risk factors are then implemented. 27, 28, and 29
SWITCH was another community-, school, and family-based intervention aimed at modifying key behaviours (physical activity, television viewing/screen time, and nutrition) related
to childhood obesity in third through fifth graders residing in two mid-western cities. The
primary objective of the study was to increase physical activity and to inculcate healthy
food habits and to decrease television viewing time.
SWITCH was organized into four sequential phases. During the first phase of the program,
the child with parental involvement established a baseline that identified current health
behaviour practices and evaluated attitudes and feelings towards making a change in the
three key components (Do, View, and Chew). Once families identified their current practices
they established long term and short-term goals that fit within their lifestyle. The second
phase of the program focused on making incremental changes reinforced by self- rewards.
Each change in behaviour towards reaching a self-identified goal was rewarded with goal
points or activity points. A weekly track of all these activities was kept and the child was
rewarded through the use of incentives.
The third phase of the program was designed to make it easier for families to plan meals,
include healthy snacks, and include healthy fruits and vegetables in shopping by providing
shopping and mealtime planners. This was aimed at making the families more health conscious and eager to make further changes. SWITCH provided families with the motivation,
and tools to make that process easier. The fourth phase of the SWITCH program focused on
maintenance of the health behaviours families established over the eight-month period. The
psychobiologic core of the model incorporates the genetic, physiologic, and socio-cultural
forces that shape our identity. This core is surrounded by cultural and social determinants
that directly influence a persons lifestyle behaviours. Behaviour settings are described in
the model as physical and social settings in which physical activity and eating behaviours.30
How to incorporate Type 2 DM in the curricula of school children in India?

Are there any models in India? At What age of it should be started? Which
class? What should be the Curricula?
Presently there are no definite curriculum guidelines for school children in India.
Few non-governmental organisations like Rotary club and Chetna (Children Health Education through nutrition and health awareness) are working to inculcate healthy lifestyles
and nutrition habits in school children. This is the first of its kind in India. This program
aims to impart health education through posters and lectures and group discussions with
parents, children and teachers.
Another MULTICENTRE project by Diabetes Federation of India being undertaken in schools
is project TEACHER (Trends in Childhood Nutrition and Lifestyle Factors in India) covering
4 major cities in India to obtain in depth understanding of nutrition and lifestyle behaviours that affect the health and well-being of urban Indians, particularly children, through
detailed knowledge attitude and practice survey questionnaire, group discussions and anthropometric measurement of children and mothers. These children are given dietary and
physical activity training. These programmes create awareness about obesity and diabetes.
Type 2 DM education needs to be started at the school level if we have to curtail this
epidemic. The role of school teachers is particularly important for proper implementation
of these curricula. The success of these programmes at the government school level can
be more as they can be directly supervised by the government and all teachers can be
given mandatory training for the same. Later on once these programmes are successful in
government schools private schools can be invited to participate.
In India schools especially government owned, are one of the major setting for implementation of these programmes. Schools in India do not have physical education curricula
designed to help optimize the health of children. This has to change. Though there is a
mandatory school health programme in most of the private and government schools, it
hardly addresses the issues of obesity and diabetes. Schools must re-institute vigorous
physical education programs for all children and in all grades. Though height and weight
of children are measured as a routine, the data analysis to identify obese children and
educate the child and parents hardly exists in our country.
We cannot simply transplant a model developed in the west. We should develop school
health programmes suitable to our social, cultural, financial and ethnic needs.
219
220
As there is no definite curricula presently these programmes can be incorporated in the

physical education programme where children can be taught about obesity and health risks
attributable to it and mainly about type 2 DM. These children can be assigned definite
activities as regards to type 2 DM like posters and charts and they can take assistance
from their teachers. In such activities participation of the parents should be ensured so
that indirectly they also are benefited and their knowledge about prevention and effective
management of type 2 DM is upgraded.
In India such type of programs can be implemented initially at government school level. The
government schools can be a better place for such interventions a government can directly
have control over all the activities while for private schools individual priorities may come
in the way of implementation of these programmes. The private schools may also be given
an option to take part in such activities and if they are interested they may be enrolled
into these programmes. The government approach for private schools should be flexible
and adaptable and easy to try and government can offer free training to teachers .31, 32
The school teachers can be given questionnaire to be filled during the time child is at
school regarding the amount of physical activity by the whole class and not by an individual student. All the school teachers will need some hours of training in nutrition and
physical education. The implementation of physical education and nutritional training will
be judged by a self reporting questionnaire. These programmes can be started as pilot
projects and after success of each phase they can be upgraded
Thus schools have to focus on increasing childrens physical activity and improving their
nutrition. Nutrition counselling needs to be available in school so that children understand
the importance of healthy eating. The selling of candy and sugar-containing drinks in
schools must be forbidden. Fast foods loaded with calories and fat must not be available in school settings. Every food item sold in school must meet a minimum nutritional
requirement that will ensure that it is good for children. We must put the health and
welfare of our children above the financial benefits accrued by selling junk food in school.
One of the practices followed in schools is to check the lunch box of children by teachers. Children should be encouraged to bring fruits and salads in their lunch pack instead
of chocolates and pastries. Parents are instructed to send healthy foods rather than junk
foods, for their children. This is one way is going to benefit the child but indirectly parents
will also realise the benefit of healthy eating behaviours.
Other community organizations must also help. Our communities need to develop safe
locations for children and their families to exercise. After-school care programs need to
include physical activities and provide good nutrition.
In addition to weight, activity level is also important. The epidemic of type 2 DM is a direct
result of the sedentary lifestyle we have. With the sharp rise in computer games and TVwatching and the trend toward abandoning physical education in schools, fewer children
are participating in sports. This increase in sedentary lifestyle has contributed to the type 2
DM epidemic. Every school should have adequate playground for children. Children should
be encouraged to play out door games rather than computer games. Adequate sports facilities and physical training should be provided in all schools. Thus incorporating healthy
lifestyle will benefit children as well as it will have an impact on the family members.
The potential target for preventive measures are children as the interventions should be
inculcated in lifestyle of the children The main target should be at school level and
participation of teachers and parents is needed for effective implementation of these
programmes .The nutrition and lifestyle counselling may help in prevention as well as
delaying the epidemic of type 2 DM.
Apart from physical education training specific curricula for education about type 2 DM
should me made such that it can be started at the entry level. The chapters should be
made such at each level the standard of chapters should become tougher. The initial education should be about the basics of type 2 DM and can be started at the elementary level
and as the children reach to higher classes they become more receptive to goal oriented
teaching. The participation of parents is equally important at each level because then only
the whole family will benefit from such curricula.
Our consistent and coordinated efforts across sectors and disciplines are needed to win
the battle against childhood physical inactivity which will finally curb the fast growing
epidemic of type 2 DM.
Are schools the appropriate setting for physical activity interventions for
prevention and education about type 2 DM?
Schools have been identified as major setting for public health intervention as they cater
to a large population of children across multiple ethnic groups and socioeconomic strata22
.Children spend majority of their waking hours in schools which provides a window of
opportunity for education about lifestyle changes including physical activity and nutrition
regardless of their family circumstances.
However schools are busy places and the problem with imparting health education at
school levels may be many. Schools my lack infrastructure for providing health education,
may have insufficient time and more competing priotirites.27-29
School based interventions can target elementary or secondary schools and interventions
can be different at every level. Elementary schools are mainly governed by generalist
teachers and secondary schools are mostly run by specialist teachers
Physical education can be optional at secondary school level so one size does not fit all
and interventions can be different at different levels.30-35
Secondly measurement tools must be age appropriate and self reporting instrument can
be particularly inappropriate for younger age groups. Lack of precise measures of physical
activity may affect outcome of paediatric studies 36-40
Schools are hierarchical clusters; classes are clustered within schools and children are
clustered within classes. Nesting must be managed within the research design or the
statistical approach to data. Finally, in-school models demand that all children be invited
to participate when 60% of children may already be undertaking sufficient daily physical
activitythis may create a ceiling effect and serve to dilute the effect of the intervention.
Out of the interventions to promote physical activity for both children and youth, 82% and
83% of studies of children and adolescents, respectively, were school based interventions37
A review of 21 papers reporting on 14 school-based interventions suggests that multifaceted, intra- and extra-curricular activities aimed to improve knowledge, behaviour and
risk factors can be useful. Most students consume 1 or 2 meals a day during school hours
and many typical school experiences offer potential opportunities for physical activity (e.g.
recess, lunch break). Since schools are first and foremost sites for learning, the studies
221
reviewed indicated that children may be more receptive to ideas presented at school and
be more willing to participate in planned activities with their peers. Changes to the surrounding environment involving food service, family and community also have the ability
to influence outcomes by improving accessibility to healthy foods and physical activity
opportunities. 41
A main limitation is that many studies have not built in the needed support from
Families or communities to allow behaviour change to be maintained over time. Thus, it
has been suggested that multi-level interventions that aim to influence healthy lifestyle
behaviours at the community, school and family levels may prove more successful in the
prevention of childhood obesity 42, 43, 44. Despite their intuitive appeal school based interventions the results of school based interventions have been mixed. Although some school
based interventions have a favourable effect on BMI 45-47 many have not.48, 49
Children who develop type 2 DM or at risk of developing type 2 diabetes mellitus or who
have a family member with type 2 DM may be targeted as a group and physical activity
and dietary interventions can be specifically targeted to this group. Curricula should be
developmentally focused to meet the educational needs of patients with type 2 diabetes.
According to the national standards for DSME,50 a multidisciplinary instructional team is
recommended for optimal educational intervention. Minimally, this team must consist of a
registered nurse and a registered dietitian. Because weight reduction is a treatment focus
in type 2 diabetes, the registered dietitian is an especially vital member of the instructional team. Other members of the multidisciplinary team may include family members,
medical practitioners, certified diabetes educators, social workers, psychologists, exercise
physiologists, and pharmacists.
222
Conclusions
Obese child will grow to become obese youth and obese adult. Obesity and lack of exercise
are the leading causes of Type 2 DM.
The education should not solely focus on nutrition aspect but should also concentrate
on other aspects of school environment like physical education training and environment
beyond the school like corner stores and homes. Preventive programmes should start at
a younger age so as to inculcate the behaviour through the growth phase. Presently
non-government organisations are more involved in such programmes but the participation of government schools is absolutely necessary. The participation of parents in such
programmes is equally important. Thus multifaceted interventions involving both family
and teachers may be more effective. Both governmental and non-governmental agencies
should work in close cooperation to modernise the school health programme to delay and
prevent type 2 DM in our population.
We are in the midst of an epidemic. There is a role for each of us in helping to put an
end to the rise of this devastating disease in our population.
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225
T2DM Education
for The Urban & Rural Population
Dr Apurba Mukherjee
226
Prof and Head of the Department of Medicine & In-charge Diabetic Clinic,
R.G Kar Medical College and Hospital, Kolkata.
Ph: 94330 14467
e-mail: drmukherjee@gmail.com
Dr Indira Maisnam
Assistant Professor of Medicine, WB University of Health Sciences, Kolkata
DM Resident, Department of Endocrinology & Metabolism,
IPGME & R, Kolkata.
e-mail- i.maisnam@gmail.com
Diabetes The New Epidemic

According to the 2009 IDF Diabetes Atlas, the global prevalence of diabetes will rise to
438 million by 20301. The regional prevalence of diabetes mellitus and IGT in the Southeast Asia region (where according to the IDF Atlas India has 85% of the regions adult
population) will be 101 million (8.4%) and 76.4 million (6.4%) respectively1. From 2000
to 2030, there will be a 151% increase in the number of people with diabetes in India,
whereas the total population will increase by just 40% 2. Indian studies have shown that
the prevalence of diabetes in India is higher than the global average, more so in urban
than in rural areas 3, 4 and a higher incidence of onset of diabetes in younger age group4.
Developing countries like India will have to bear the major burden of diabetes. The lower
socio-economic groups will be disproportionately affected, as around 25% of the income of
a low- and middle-income Indian family with a person with diabetes is spent on diabetes
care5. Indirect cost implications are also there due to loss of work-days and intangible
costs like pain, emotional and inter-personal strains.
What is Responsible for this Epidemic?

Lifestyle changes in the face of a vulnerable genetic make-up is mainly responsible. We
are endowed with a thrifty genotype. Our genes are programmed for a metabolic economy
to ensure growth and adaptation during periods of limited supply of nutrients6. When
exposed to a positive energy balance due to over-nutrition and under-activity, a catchup growth occurs with preferential catch-up of fat compared to lean tissue. Thus, the
metabolic adaptation turns maladaptive and we develop obesity, diabetes mellitus and
their complications6.
Though our genes are partly responsible, it is our lifestyle changed over the last few
decades that lie as the core of this problem. With rapid advances in technology we no
longer need to walk to a friends house, get-up to switch off the television or run to
receive a call. With globalization, international fast food joints have mushroomed not only
in big metropolis but also in small cities and smaller towns, have opened shops in Indias
highways and infiltrated into many rural areas. Imitations of these outlets with regional
modifications have arrived in smaller paras and bye-lanes; towns and villages alike. And
we have our own indigenous contribution to this epidemic in the form of samosas, tikkas,
bhatura and whole gamut of sweetmeats. Disturbing data show that rural India which was
spared of the assault till around two decades back have shown a marked increase in cases of
obesity, diabetes mellitus and cardiovascular diseases7. This has resulted from industrialization, improved transportation, urbanization of the rural areas and exposure to fast food 7.
Only Education can Contain this Epidemic

The population needs to be taught that a serious problem does exist and it can be minimized or prevented by awareness and lifestyle modifications. Education should be given
to the whole population on the following three points:
T2DM Education for The Urban & Rural Population
227
Lifestyle Intervention

Modifications in what we eat and the way we cook
Importance of increased physical activity and how to achieve it

Need For Good Antenatal Care

To prevent low birth weight
To treat diabetes in pregnancy and GDM

Creating Awareness

Screening for diabetes mellitus and atherosclerotic CVD is important even when
asymptomatic
Timely treatment can control disease and minimize, delay or prevent complications
1. Lifestyle Intervention
228
The most effective way to prevent or treat diabetes mellitus is lifestyle intervention in
the form of a healthful diet and increased physical activity. The Finnish Diabetes Prevention Study8 and the Diabetes Prevention Program (DPP) 9 showed greater reduction in the
incidence of diabetes with lifestyle intervention compared to placebo and placebo plus
Metformin respectively. Further analysis of the DPP showed that lifestyle intervention, and
not Metformin, restored Normal Glucose Regulation (NGR) in patients with pre-diabetes
through weight loss and even in the absence of weight loss, through healthy eating and
exercise9. Other factors that determined NGR was insulin secretion and other biological
factors that are retained in younger age.
Thus, lifestyle intervention not only results in prevention of diabetes mellitus but may
also restore normal glucose regulation. So, lifestyle intervention should be considered the
soul of diabetes care.
i) Dietary Regulation: A diet rich in whole grains, legumes, fibers, vegetables and fruits;
low in salt; low in saturated fats, with little or no trans-fat; with modest amounts of
PUFA and MUFA; without excess calories, should be considered ideal. A 2% absolute
increase in energy intake from trans-fat has been associated with a 23% increase
in cardiovascular risk10. Increased intake of omega-3 fatty acids, found in fatty fish,
improves CV profile11.
Mankinds ability to cook food has been one of its most significant survival advantages.
Cooking makes food digestible making nutrients available for absorption. It improves
palatability thereby increasing intake. But, the way food is cooked may destroy nutrients and make it more harmful also. In many urban Indian families, following the breakdown of the joint family system, and both partners working in nuclear families, eating
out and packaged fruit juice and other food items have become a convenient way
of eating. Studies in US show that there is a clear time-course association between
childhood obesity and the increased availability of calorie-dense processed foods12.
Food item
Per 100 gm
Parboiled rice
Atta
Maida
Maize
Bengal gram
Red gram
Cabbage
Drumstick
Fenugreek
Spinach
Potato
Colocasia
Brinjal
Bottle gourd
Almond
Apple
Mango
Bhekti
Hilsa
Mutton
Egg (hen)
Curd
Cows milk
Protein
(gm)
8.5
12.1
11
11.1
17.1
22.3
1.8
6.7
4.4
2.0
1.6
3
1.4
0.2
20.8
0.2
0.6
14.9
21.8
18.5
13.3
3.1
3.2
Fat
(gm)
0.6
1.7
0.9
3.6
5.3
1.7
0.1
1.7
0.9
0.7
0.1
0.1
0.3
o.1
58.9
0.5
0.4
0.8
19.4
13.3
13.3
4.0
4.1
Carbohydrate
(gm)
77.4
69.4
73.9
1.5
60.9
57.6
4.6
12.5
6.0
2.9
22.6
21.1
4
2.5
10.5
1
16.9
3.0
2.9
3.0
4.4
Kcal
349
341
348
342
360
335
27
92
49
26
97
97
24
12
655
59
74
79
273
194
173
60
67
Fibers
(gm)
0.2
1.9
0.3
2.7
3.9
1.5
1.0
0.9
1.1
0.6
0.4
1
1.3
0.6
1.7
1.0
0.7
-
Calcium
(mg)
10
48
23
10
202
73
39
440
395
73
10
40
18
20
230
10
14
480
180
150
60
149
120
Iron
(mg)
2.8
4.9
2.7
2.3
4.6
2.7
0.8
0.85
1.93
1.14
0.48
0.42
0.38
0.46
5.09
0.660
1.3
3.1
2.1
2.5
2.1
0.2
0.2
Table. 2 Calories in fast-foods and some common snacks13, 14
Food Items
Samosa
Malpua
Malai Kulfi
Medium french fries
Crispy Chicken
Double Cheeseburger
Portion
1 pc.
40gm
75gm
147gm
219gm
173gm
Kcalories
369
342
210
450
500
480
So, we see that Indian foods have high nutritive value and that the calories in one serving
of fast food provide almost 50% of the days energy needs.
229
The following healthy habits in cooking and food intake maybe recommended for the
urban and rural population:
230
Steaming food instead of frying. Stir fry instead of deep fry.
Avoiding trans-fat, like vanaspati and trans-fat containing food items like cookies,
doughnuts. Oil should not be exposed to extreme heating.
Avoiding use of butter, oil, ghee while making dough for chapattis, parathas
Absorbing visible fat in fries with paper napkins
Having two to three servings of fish per week for non-vegetarians
Adding little lesser salt than normally used in dishes will not alter taste
Adding more vegetables in dishes whenever possible
Having salad prepared from green vegetables and sprouts
Using whole grain products more often than refined grain products e.g., atta instead
of maida
Fruits, low-fat yogurt instead of sweets or fries for desserts and snacks. Fresh fruit
juice instead of packaged fruit juice
Taking small amount of sweets, if it has to be consumed at all, as a small amount

of sweet gives almost the same sense of satisfaction as a larger amount for a sweettooth individual.
Avoiding calorie dense food, like fast foods from international and local outlets
Reducing the potentially harmful effects of fast foods by choosing healthier items
in the menu, avoiding sugar-sweetened beverages and eating small or medium sized
items instead of king sized ones15.
ii) Increased Physical Activity: Physical activity results in improved insulin sensitivity
through weight loss and many other effects independent of weight loss. In adults, a
modest weight loss of up to 5% improves cardiovascular health, with improvements in
both traditional CVD risk markers such as blood pressure, dyslipidemia and hyperglycemia
and non-traditional risk markers like C-reactive protein, lipoprotein (a) and homocysteine
levels16, 17. The advantages of exercise are manifold. To mention a few, exercise increases
insulin sensitivity. It increases translocation of GLUT4 transporters to the cell surface,
increasing peripheral uptake of glucose18. Exercise activates adenosine monophosphatedependent Kinase (AMPK) and increases insulin signal transduction18, 19. Exercise alters the
distribution of fat by decreasing visceral obesity18, 19. Many of the effects of exercise can
be seen independent of weight loss18, 19.
Traditionally, physical activity in rural India has always been more, and is still more, than
in the urban areas. Children still walk in groups to school and adults still cycle to work.
This should be encouraged and people be made aware that the health benefits and mental well-being of these activities far outweigh the comforts of motorized travel. Though
mechanized farming is an integral part for the nations productivity, whenever possible and
feasible manual field work like planting, sowing, shafting should be encouraged.
In urban areas people should be advised to use stairs instead of escalators or elevators,
to park cars or get down from bus ahead before the destination.
In both areas there should be an extra increase in daily activities like cleaning ones own
home, walking while talking on phone, getting up to switch off the television, taking walking break in office instead of coffee break20. People should walk for at least 30 minutes
per day. Walking should be made enjoyable and not considered a punishment. It can be
made pleasant by providing good and clean sidewalks, free of crime and pollution. One
can make walking partner(s) too.
Children are the nations future. Healthy children ensure a healthy and productive nation.
Inactive people who view more than 15 hours of television per week have a three times
higher risk of diabetes21. It is crucial to increase childrens physical activity by decreasing
television watching to less than one hour per day, decreasing time spent on video games
and computers. Adequate playground space which is clean and safe should be provided
at schools, at the community level and if possible, at home. Children often imitate their
parents and peers, and so parents and teachers should set an example by being active
themselves
Exercise program should be individualized and a search for macro- and micro-vascular
complications should be screened before beginning an exercise program24. Patients with
intermittent claudication should have a supervised exercise program and advised to stop
smoking24. Patients with active proliferative diabetic retinopathy (PDR) should avoid anaerobic and strenuous exercises, as they may precipitate vitreous hemorrhage or retinal
detachment24. Patients with overt nephropathy often have a reduced capacity for exercise,
which leads to self limitation in activity level24. Patients with peripheral neuropathy should
undergo non-weight bearing exercises, like swimming, rowing and arm-exercise etc24.
Studies in US have shown that children from poor socio-economic status are less physically
active and less fit22. This is also applicable for Indias urban poor children who get access
to the calorie dense street food laden with trans-fat. Lack of physical activity arises from
lack of space, infrastructure and finances22. A solution to this problem must be sought, as
slum population will touch 93 million in 2011 23
2. Good Antenatal Care

Intra Uterine Growth Rate (IUGR) and low birth weight makes the thrifty genotype more
robust resulting in obesity, metabolic syndrome and diabetes mellitus in later years. Hence,
good antenatal care should be made available in the form of facilities for ante-natal
check-up, improved nutrition, treatment of infections and prevention and treatment of
complications like pre-eclampsia / eclampsia.
Diabetes begets diabetes. Children of women with diabetes mellitus and GDM have increased chance of diabetes mellitus, besides other complications like macrosomia, malformations, hypoglycemia etc25, 26. So, adequate treatment of pre-existing diabetes and
timely diagnosis and treatment of GDM is essential. This will benefit not only the present
generation, but future generations too.
3. Awareness about the Importance of Timely Screening and Treatment

The onset of type 2 diabetes usually precedes by seven years of clinical diagnosis (even
more than 12 years in some studies) 27. The percentage of undiagnosed diabetes in developing countries like India is high with half to three-fourths of all cases of diabetes
remaining undiagnosed28. The percentage of micro- and macro-vascular complications at
231
the time of diagnosis may be very high29, 30. Hence, the importance of screening, even
when asymptomatic, should be highlighted and the facilities for the same should be made
easily accessible and affordable.
Many studies like the UKPDS and DCCT showed that good glycemic control resulted in
decreased microvascular complications31, 32, 33. Follow up of the UKPDS and DCCT have shown
that good glycemic control in the early years after diagnosis leads to long-term reduction in
macrovascular complications34. There was also a legacy effect where the beneficial effects
of good glycemic control was seen even when glycemia was no longer well controlled35.
The UKPDS group showed a 32% reduction in diabetes-related deaths in patients randomized to tight blood pressure control36. The Steno-2 Study demonstrated that treatment of
diabetes focused on control of hypertension, high cholesterol and dietary risk factors can
produce significant reductions in cardiovascular morbidity and mortality37. Awareness of the
importance of timely treatment of hyperglycemia, hypertension, dyslipidemia, nephropathy,
neuropathy, and retinopathy should be created, with lifestyle intervention at every stage.
How to Educate the Population?

At school level

Education about diabetes should be a part of the school curriculum in textbooks and
school activities
At individual level

Education through interaction with doctors and other health care providers.
At community level
232
Panchayats, municipal corporations, clubs and NGOs should be involved in providing

awareness and delivery of services in collaboration with health care providers.
A responsible media has a great role in providing education through television, radio
and other forms of electronic and print media
At government level

Health centers should provide awareness, diagnosis and treatment facilities through
involvement of doctors, nurses, technicians, and paramedical staff and health workers.
Referral hospitals should provide specialized and advance treatment, along with providing basic care and awareness.
Teaching hospital should organize more social-awareness and public-interaction programs, and produce more specialists, sub-specialists and paramedical personnel.
A robust Non-communicable Disease Program should be created with the Centre and
States taking responsibility for providing research, knowledge and delivering services.
Conclusion
The threat of diabetes mellitus in its sheer numbers and complications looms large for India.
Education has the biggest role to play in containing this epidemic. Responsibility should
be at every level, from individuals to big organizations to governments, from childhood
to old age. Whereas in other big economies like USA, Japan and many European countries
the population is aging, we in India are blessed with a young population. We need to take
stock of this advantageous situation and do our utmost for our health. We should never
turn this blessing of a vibrant young nation to a curse of an unhealthy young nation.
References
1.
2009 International Diabetes Federation - atlas@idf.org
2.
Sarah Wild et al: Global prevalence for diabetes: Estimates for the year 2000 and projections for the year
2030. Diabetes Care 2004;27:10471053
3.
Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V, Das AK, et al. Diabetes Epidemiology Study
Group in India (DESI). High prevalence of diabetes and impaired glucose tolerance in India: National Urban
Diabetes Survey. Diabetologia 2001;44:1094-101
4.
Mohan V, Deepa M, Deepa R, Shantirani CS, Farooq S, Ganesa A et al. Secular trends in the prevalence
of diabetes and glucose tolerance in urban South India- the Chennai Urban Rural Epidemiological study
(CURES- 17). Diabetologia 2006;49:1175-8
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Health Administrator Vol: XXII Number 1& 2 - 2009:110-112
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Neel JV. Diabetes mellitus: a thrifty genotype rendered detrimental by progress? American Journal of
Human Genetics. 1962;14:353-362
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Ramachandran A, Snehalata C, Bhaskar ADS, et al. Temporal changes in the prevalence of diabetes and
impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India.
Diabetologia 2004;47;860-5
8.
Tuomileto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle
among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343-50
9.
Knowler WC, Barett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med 2002;346(6):393-403
10. Remig V, Franklin B, Margolis S, Kostas G, Nece T, Street JC Trans fats in America: a review of their use,
consumption, health implications, and regulation. J Am Diet Assoc. 2010 Apr;110(4):585-92
11. Grundt H et al. Improvement of serum lipids and blood pressure during intervention with n-3 fatty acids
was not associated with changes in insulin level in subjects with combined hyperlipidemia. J Intern Med.
1995;237:249-259
12. McCrory MA et al. Dietary variety within food groups: association with energy intake and body fatness in
men and women. Am J Clin Nutr. 1999;69(3):440-7
13. C. Gopalan, B.V. Rama Sastri, S.C. Balusubramanian Nutritive value of Indian foods. National Institute of
Nutrition. ICMR. Hyderabad
14. www.mcdonalds.com
15. Emily Brindal et al. Obesity and the effects of choice at a fast-food restaurant. Obesity and Clinical Practice.
July 2008; volume 2:issue 2
16. Blackburn G. Effect of degree of weight loss on health benefits. Obes Res. 1995; September (3 Suppl.2):211s6s
17. OBrien, et al. Diet induced weight loss is associated with decrease in plasma serum amyloid a and Creactive protein independent of dietary macronutrient composition in obese subjects. J Clin Endocrinol
Metab. 2005;90(April(4)):2244-9
18. Douen AG, Ramlal T, Rastogi SA, et al. Exercise induces recruitment of the insulin responsiveness glucose
transporter. Evidence for distinct intracellular and exercise-recruitable transporter pools in skeletal muscle.
J Biol Chem. 1990;265:13427-30
19. Long YC, et al. AMP-activated protein kinase signaling in metabolic regulation. J Clin Inves. 2006;11:1776-83
20. www.diabetes.niddk.nih.gov/intro
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21. Hu FB, Li Ty, Colditz, et al. Television watching and other sedentary behaviors in relation to risk of obesity
and type 2 diabetes mellitus in women. JAMA;2003;289(14):1785-91
22. Nelson MC, Gordon-Larsen P, Song Y, et al. Built and social environments: association with overweight and
activity. Am J Prev Med. 2006;31(2):109-17
23. The Economic Times; 4th September 2010
24. Exercise and NIDDM (Technical Review) Diabetes Care 13:785789, 1990, and Exercise in individuals with
IDDM (Technical Review) Diabetes Care 17:924937,1994
25. England LJ et al. Am J Obstet Gynecol 2009;365.e1365.e8
26. Dornhorst A, Rossi M. Risk and prevention of type 2 diabetes in women with gestational diabetes mellitus.
Diabetes Care. 1998 Aug;21(suppl 2):B43-49
27. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 years before clinical
diagnosis. Diabetes Care 1992; 15:815819
28.
Chow CK, Raju PK, Raju R, Reddy KS, Cardona M, Celermajer DS, Neal BC. The prevalence and management
of diabetes in rural India. Diabetes Care 2006; 29:17171718
29. Lehtinen JM et al. prevalence of neuropathy in newly diagnosed NIDDM and nondiabetic control subjects.
Diabetes. 1989;38:1307-13
30. UK Prospective Diabetes Study group UK Prospective Diabetes Study XII: Difference between Asian, AfroCarribean and Caucasian type 2 diabetes patients at diagnosis. Diabetic Med. 1994; 11:670-7
31. The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.
N Engl J Med. 1993;329:977-986
32. Effect of intensive blood-glucose control with Metformin on complications in overweight patients with type
2 diabetes. (UKPDS 34): UK Prospective Diabetes Study Group. Lancet. 1998;352:854-865
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33. Intensive blood-glucose control with Sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes. (UKPDS 33): UK Prospective Diabetes Study Group.
Lancet. 1998;352:837-853
34. Standards of Medical Care, American Diabetic Association 2010; S19
35. Holman RR, et al. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med
2008;359:1577-1589
36. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:
UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317: 70313.
37. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in
type 2 diabetes. N Engl J Med 2008; 358: 58091.
Education in Diabetic Foot Care

Dr Asish Kumar Basu
Assistant Professor,
Department of Endocrinology,
Medical College, Kolkata.
Ph: 98300 59952
e-mail: asish_basu@rediffmail.com
&
Dr. Pankaj Singhania

Post Graduate Student
Department of Endocrinology,
Medical College, Kolkata
235
Diabetes: A Global Burden

Diabetes mellitus is a global problem and the phenomenal increase in the incidence at an
alarming rate is really mind-boggling and thought-provoking. In a recent WHO study, it
was found that the rate of increase is mostly in the developing countries. India was found
to be the worst affected country just behind china. The magnitude of the problem in India
can be assessed by the fact that the estimate of the disease in 1995 was 19.3 million,
currently touched 40 million and the projected figure for 2030 is 80 million 1. According
to one estimate India is just behind China in the estimate of diabetic population2. Actually
the figures pertaining to India are an under estimate due to inadequate reporting and
care seeking. The real figures may turn the table upside down.
Diabetes mellitus is not just about hyperglycemia, but the chronic hyperglycemia is associated with long term complications affecting various organs, especially eyes, kidneys, nerves,
blood vessels & heart (micro & macroangiopathy). While in the past these complications
have been considered part of the diabetic syndrome, today we understand that these are
not inevitable, in fact prevention of these complications is now the main objective behind
treatment of diabetes as intervention within proper therapeutic window of opportunity
can potentially reverse complications. This message should be emulated and inculcated on
the part of every diabetic care provider.
Diabetic Foot Disease
236
One extremely dreaded and morbid complication associated with diabetes is the foot complication which can range from an ulcer to any extent of amputation if not taken care of.
Previous studies have indicated that diabetic patients have up to a 25% lifetime risk of
developing a foot ulcer 3. The annual incidence of diabetic foot ulcers is 3% and diabetes
is the most common cause of non-traumatic amputations. the enormity of the global
burden of diabetic foot diseasethis much neglected, but potentially devastating, complication of a disease that is reaching epidemic proportionsSomeone, somewhere, loses
a leg because of diabetes every 30 seconds of everyday4 If you commit one mistake
by not knowing anything then you commit ten mistakes by not looking into it. These
golden lines by Winston Churchill are very relevant in case of diabetic foot as the very
concept of making a total clinical assessment of diabetic foot is not in the back of mind
of most diabetic care providers and meticulous foot examination is often overlooked or so
to say the mindset of caregivers is not tuned with the concept of looking into the foot
of diabetic patients with utmost sincerity and devotion. This is the cause of catastrophes
later like a diabetic foot on the verge of amputation.
Pathophysiology of Diabetic Foot Disease

In order to prevent and treat this ordeal it is necessary to briefly understand the pathogenesis and popular classification system of the disease. 60% of diabetic feet are neuropathic
in origin, 30% are ischemic and 20% are infectious. In India also neuropathic origin is
the commonest. The spectrum of foot infections in diabetes ranges from simple superficial
cellulites tochronic osteomyelitis. Infections in patients with diabetes are difficult to treat
because these patients have impaired microvascular circulation, which limits the access of
phagocytic cells to the infected area and results in a poor concentration of antibiotics in
the infected tissues. For this reason, cellulites is the most easily treatable and reversible
form of foot infections in patients with diabetes. Deep skin and soft tissue infections are also
usually curable, but they can be life threatening and result in substantial long-term morbidity 5.
Diabetes mellitus is a disorder that primarily affects the microvascular circulation. In the
extremities, microvascular disease due to sugar-coated capillaries limits the blood supply
to the superficial and deep structures. Pressure due to ill-fitting shoes or trauma further
compromises the local blood supply at the microvascular level, predisposing the patient
to infection. The infection may involve the skin, soft tissues, bone, or all of these tissues.
Diabetes also accelerates macrovascular disease, which is evident clinically as accelerating
atherosclerosis and/or peripheral vascular disease. Most diabetic foot infections occur in
the setting of good dorsalis pedis pulses; this finding indicates that the primary problem
in diabetic foot infections is microvascular compromise. Impaired microvascular circulation
hinders white cell migration into the area of infection and limits the ability of antibiotics to
reach the site of infection in an effective concentration. Diabetic neuropathy encountered
in conjunction with vasculopathy may allow for incidental trauma that goes unrecognized
(e.g., blistering, penetrating foreign body).
In chronic osteomyelitis, a sequestrum and involucrum form; these represent islands of
infected bone. Bone fragments that are isolated have no blood supply. Administered antibiotics do not penetrate the devascularized infected bone fragments; they can enter the
area of osteomyelitis only via the remaining blood supply. Therefore, antibiotic therapy
alone cannot cure patients with chronic osteomyelitis without surgical debridement to
remove these isolated infected elements. Surgical debridement is essential to remove the
infected bony fragments that the antibiotics cannot reach so that affected areas can be
treated with antimicrobial therapy.
Classification
There are many classification systems used to depict ulcers that can aid in developing
standardized method of description. The two mot popular classification systems are the
Wagner classification system 6 and the University of Texas system 7
Wagner Grading System
1.
Grade 1: Superficial Diabetic Ulcer
2.
Grade 2: Ulcer extension

Involves ligament, tendon, joint capsule or fascia
No abscess or Osteomyelitis
3.
Grade 3: Deep ulcer with abscess or Osteomyelitis
Grade 4: Gangrene to portion of forefoot
Grade 5: Extensive gangrene of foot.
University of Texas Wound Classification System

1. Stages

1. Stage A: No infection or ischemia
2. Stage B: Infection present
3. Stage C: Ischemia present
4. Stage D: Infection and ischemia present

237
2. Grading
1. Grade 0: Epithelialized wound
2. Grade 1: Superficial wound
3. Grade 2: Wound penetrates to tendon or capsule
4. Grade 3: Wound penetrates to bone or joint
Prevention is Better Than Cure

Going by the age old saying that advocates disease prevention before its occurrence, it is
the prudent and holy duty of the diabetic care team to prevent this dreaded complication
of diabetic foot disease. The diabetic foot care team which consists of the treating physician
or diabetologist, the orthopedician, the podiatrist, the physical medicine and rehabilitation
specialist, the dermatologist, the vascular surgeon, the infectious disease consultant, the
microbiologist and the diabetes tutor must ensure that diabetic foot disease is prevented
and the immense economic burden due to the disease in the form of hospitalization, amputation surgeries, rehabilitation, loss of man-years is arrested. The St Vincent declaration
of 1989 had affirmed the need to cut down the rate of amputation for diabetic foot by
half as one of its major goals for slashing the hiking costs.
All this is not possible with the active and regular participation of the real beneficiary
the diabetic patient. Here comes the role of educating the diabetic patient regarding the
advantages and methods of preventing diabetic foot disease.
In order to tackle the problem simplified risk stratification has been proposed for these
patients ranging from a risk level of 0 - 3. 8
238
Risk Level
Foot Ulcer %/yr
3:
2:
or
1:
0:
28.1%
6.3%
Prior amputation Prior ulcer

Insensate and foot deformity
absent pedal pulses
Insensate
All normal
4.8%
1.7%
18.6%
% Office Patients
(diabetes clinics)
7%
10%
17%-30%
66%
Low Risk
Low risk, Category 0 patients have intact protective sensation to the 10-gram monofilament, no major foot deformities, pedal pulses are present, and there is no prior history
of foot ulcer or amputation. Category 0 patients require an annual comprehensive foot
examination. This examination can be facilitated by a questionnaire that patients complete
in the waiting room and a decision-supported diabetic foot examination form Category 0
patients at higher risk of foot ulcer-persons from racial minority groups or persons who
are homeless or suffer from alcoholism should additionally have a visual inspection of
their feet at every visit. Category 0 patients should have basic foot care education about
self-management of their feet and appropriate footwear. This can be accomplished with
brief counseling and a short, written patient education handout.
High risk
High risk category 1-3 patients, who have sensory neuropathy and one or more of the
other key risk factors of major skeletal deformity, peripheral arterial disease, and/or prior
foot ulcer or amputation, require a more aggressive approach to prevention. In addition
to an annual comprehensive foot examination, the feet should be carefully inspected at
every office visit, and patients should be referred to podiatry at a frequency necessitated
by their risk level. Intensive patient education is essential, and any barriers preventing
optimal foot care should be detected and managed. Finally, select patients may benefit
from the use of therapeutic footwear.
High Risk Nursing Care9

Nurses and medical assistants can facilitate the performance of foot examinations in the
office setting, first by identifying high risk patients with a chart sticker .They can remove
the patients shoes and socks prior to the clinician entering the room; in a randomized
clinical trial this simple maneuver was shown to significantly increase the number of foot
exams performed on diabetic patients. They should determine that the patient can both
reach and see the soles of their feet. They should keep each exam room well-stocked with
10-gram monofilaments, and it may be reasonable to train them to accurately perform the
monofilament examination. Finally, they should provide the patient with written education
materials appropriate to their level of literacy and language needs.
High Risk Podiatry Care

High risk category 1-3 patients should be referred to podiatry for regular prophylactic
care of their skin and nails and for assessment of their footwear needs. A randomized
clinical trial demonstrated a 48% relative risk reduction for recurrent foot ulceration in
patients who had regular podiatric care 10. The optimal frequency of visits to podiatry has
not been determined. Some investigators suggest that category 1 patients be seen every
3-6 months while category 2 and especially category 3 patients be seen more frequently.
High Risk Patient Education

High risk category 1-3 patients should receive intensive education from primary care clinicians, podiatrists, and diabetes educators. This education should be reinforced frequently as
clinical studies have demonstrated low retention of this information. In particular, patients
should be asked to demonstrate their self-care knowledge, and this can be efficiently accomplished using available questionnaires. A systematic overview of clinical trials suggests
that patient education may reduce the rate of foot ulcer and amputation although the
quality of available studies is low.
1. Basic Foot Care Concepts

A central concept of basic foot care is daily inspection of the feet. This may require use
of a mirror by patients who cannot reach their feet or a magnification glass by patients
who cannot see their feet. In some patients the exam may need to be done by a caregiver.
Patients should be educated to recognize important foot lesions and report them immediately including areas of persistent erythema following shoe removal, enlarging callus, and
pre-ulcers (callus with hemorrhage).
239
Diabetic patients must make a commitment to self-care of the feet including daily cleansing with care to avoid excessively hot water and to dry thoroughly between the toes. The
feet should be lubricated daily but not between the toes, a site for excessive moisture
and maceration. Debridement of callus with a callus file, Emory board, or pumice stone
may reduce plantar pressure by 25%, but debridement should not be accomplished with
sharp instruments like razor blades or over-the-counter corn plasters that can cause a
chemical burn. Patients should not cut their own nails if they have significant sensory
neuropathy, peripheral arterial disease, or poor vision. Services of a podiatrist should be
sought for when needed.
2. Basic Foot Protective Behavior

Patient foot care education should include cautions to avoid temperature extremes (walking barefoot in hot water or on hot sand, pavement or in snow) as well as to never walk
barefoot or stocking-footed, a source of many traumatic injuries. Appropriate exercise is
important for patients with diabetes, but patients with significant sensory neuropathy
and loss of protective sensation may be better served by bicycling or swimming than by
walking or treadmill exercise. Patients with significant neuropathy should inspect their
shoes for foreign objects before they put them on. Optimal footwear is effective only if
it is worn at all times; dangerous blisters may form when inappropriate footwear is used
for special occasions.
3. Basic Foot-Wear Education: Dos & Donts

Avoid:
240
Pointed toes
Slip-ons
Open toes
High heels
Plastic
Black color
Too small
Favor:

Broad-round toes/ wide toe box
Adjustable (laces, buckles, Velcro)
Athletic shoes, walking shoes
Leather, canvas
White/light colors
between longest toe and end of shoe
Preferably one size bigger with extra insole
4. Barriers to Diabetic Foot Care

It is essential to detect and manage any barriers that might prevent optimal foot care.
The prevalence of depression may be as high as 15-25% in persons with diabetes, and it
may reduce patient motivation to care for their feet 11. The Patient Health Questionnaire-9
(PHQ-9) is a validated tool to screen for major depression in primary care and may be
administered annually or as needed. Similarly, alcoholism should be detected and appropriately managed. Social isolation is a significant issue in diabetic patients who are unable
to reach and/or see their feet if they are unsuccessful with mirrors and/or magnifying
glasses; home health aides may be a solution for some patients. Diabetes is an expensive
disease, and financial barriers can interfere with optimal foot care. As will be discussed,
Medicare will certify certain diabetic patients for therapeutic shoe benefits.
Therapeutic Footwear 12
1. Concept
Therapeutic footwear may benefit selected diabetic patients. Inappropriate footwear is estimated to contribute to 21-76% of foot ulcers and subsequent lower extremity amputations.
Optimal footwear should meet several criteria:

Protect the feet from external injury
Reduce plantar pressure and the shock and shear forces that contribute to callus and
ulcer formation
Accommodate, stabilize, and support any skeletal deformities of the foot, and
Be suitable for use in occupational, home, and leisure settings.
2. Components
Padded socks are one component of therapeutic footwear, and several brands are available.
Their role is to cushion the metatarsal heads and heels and reduce callus formation. Ideally,
the socks should be white to facilitate detection of blood or pus from unrecognized foot
ulcer, seamless to minimize pressure points, and absorbent to reduce excessive moisture.
Shoe inserts and insoles are designed to reduce plantar pressure. Composed of closed-cell
foam or viscoelastic materials, they can be purchased off-the-shelf for some patients,
but they may have to be custom-molded for others. Therapeutic shoes can be purchased
off-the-shelf with extra-depth to accommodate insoles and/or skeletal deformities, and/
or with extra-width for skeletal deformities. Rigid-rocker outsoles can be added to reduce
mid-foot pressure. Some patients will require custom-molded shoes.
3. Efficacy
The efficacy of therapeutic footwear is controversial. While therapeutic footwear clearly
reduces plantar pressure 50-70%, its ability to reduce ulcer rates is less well established.
No data are available concerning primary prevention of foot ulcer. For secondary prevention, analytic and descriptive studies have found 50-70% reductions in ulcer rates with
therapeutic footwear. Two small randomized clinical trials have demonstrated no benefit.
It is likely that benefits are greatest in patients with severe foot deformities or prior amputations who wear their therapeutic footwear consistently.
241
Figure 1: Therapeutic Foot wear
Serial consequences of Diabetic foot disease to

be communicated to every diabetic patient by videos or slides
242
Figure 2: Hammer and Claw-Toe Deformity
Figure 3: Callus
Figure 4: Charcots Foot
243
Figure 5: Neuropathic Ulcer
Figure 6: Ischemic Ulcer
Figure 7: Gangrene in Diabetic foot
244
Figure 8: Amputated Fore foot
Conclusion
Diabetic foot disease is common and it has devastating consequences both in terms of
patient morbidity and economic consequences. Screening is simple and prevention should
be the target. Diabetic care providers should be thoroughly trained that dont be in haste
while examining diabetic patients. Look feet and footwear first then go upwards in examining these patients. Simple clinical examination can unleash a lot of clues to categorize the
status of foot problems. A team care approach with the patient at the core and patient
education as the preamble can reduce diabetic foot ulcers and amputations.
The diabetic who knows most will live the longest million dollar citation from the legend
of diabetic care Prof. EP Joslin some 70 years ago highlights the need for comprehensive
education regarding diabetic care to be catered on a compulsive basis to each and every
diabetic patient. This is very much pertinent in our efforts to curtail the incidence of
diabetic foot complications. A nasty diabetic foot down the line lands up in amputationinvolvement of huge financial burden, psychosocial problem and rehabilitation issues. To
address the whole gamut of diabetic foot problems, education and counseling of the patient & the caregivers is of paramount importance. Both government and non-government
resources should be focused in unison for providing services. To conclude, education in
diabetic foot care will not only add years to life but life to years of our diabetic patients.
References
1.
Wild S, Roglic G, Green A, Sicree R, King H, Global prevalence of diabetes: estimates for the year 2000 and
projections for 2030. Diabetes care 2004, 27,1047-1053
2.
N Engl J Med, March 2010
3.
Singh N, Armstrong DG, Lipsky BA: Preventing foot ulcers in patients with diabetes. JAMA 293:217-228,2005
4.
Lancet. 2005;366:1674
5.
Bridges RM Jr, Deitch EA. Diabetic foot infections. Pathophysiology and treatment. Surg Clin North
Am. Jun 1994;74(3):537-55
6.
Wagner FW Jr: The Diabetic foot. Orthopedics 10 :163-172,1987
7.
Oyibo SO et at. A comparison of two diabetic foot ulcer classification systems. Diabetes Care. 24 :84-88, 2001
8.
Diabetes Care. 2001;24:1442
9.
J Gen Intern Med. 2003;18:258
245
10. Diabetes Care. 2003;26:1691

11. Diab Metab Res Rev. 2004;20 (Suppl 1):S13
12. Diabetes Care. 2004;27:1832
Future Strategies for Improving

246
Dr Ashok Kumar Das
Director, Professor of Medicine & Medical Superintendent

JIPMER, Puducherry - 605 006.
Ph: 97894 57887
e-mail: ashokdas82@gmail.com
1. Diabetes - How Big is the Problem Going to be for Our Country?

Diabetes is now one of the most common non-communicable diseases globally and in our
country. It is the fourth or fifth leading cause of death in most developed countries and
there is substantial evidence that it is epidemic in many developing and newly industrialized nations.
Complications from diabetes, such as coronary artery and peripheral vascular disease, stroke,
diabetic neuropathy, amputations, renal failure and blindness are resulting in increasing
disability, reduced life expectancy and enormous health costs for our society. Diabetes is
certain to be one of the most contemporary challenging health problems in our country
in 2025. It is now recognized that it is the developing countries that presently face the
greatest burden of diabetes. We discuss the future projections of diabetes in India and
the strategies to deal with this epidemic in the following sections.
The number of studies describing the epidemiology of diabetes over the last 20 years has
been extraordinary, both in India and other countries all over the world. This has allowed
for accurate projection of diabetes prevalence in these countries. The estimates are based
on demographic changes alone with the conservative assumption that other risk factor
levels such as obesity and physical activity remain constant (in developed countries) or
are accounted for by urbanization (in less developed countries).
In 2010, the total world population was estimated at 7.0 billion. Out of this, the adult
population (20-79 yrs) constituted 4.3 billion. The current world prevalence of diabetes
among the adult population was estimated at 6.6%, amounting to 285 million persons
with diabetes. The top 10 countries with respect to diabetes prevalence and the number
of people with diabetes is given in table 1.
Table 1. Top 10 countries with respect to number of People
with Diabetes and Prevalence of Diabetes (2010)
Sl.
No
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Country /
Territory
India
China
U.S.A.
Russian Federation
Brazil
Germany
Pakistan
Japan
Indonesia
Mexico
2010
Millions
50.8
43.2 / 90.4*
26.8
9.6
7.6
7.5
7.1
7.1
7.0
6.8
Sl. Country /
No Territory
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
2010
Prevalence (%)
Nauru
United Arab Emirates
Saudi Arabia
Mauritius
Bahrain
Reunion
Kuwait
Oman
Tonga
Malaysia
247
30.9
18.7
16.8
16.2
15.4
15.3
14.6
13.4
13.4
11.6
(Currently, according to The Estimates of International Diabetes Federation (IDF),

China has taken over India with a whooping prevalence of 90.4 Millions.)
By 2025, the worldwide estimate of persons with diabetes is expected to increase to 380
million, or 7.1% of the adult population. The larger increases will take place in the regions
dominated by developing economies.
Future Strategies for Improving Diabetes Care in India
Figure 1. Prevalence estimates of diabetes (2025)

2010
248
2030
2010 /
2030
Populations
(20-79
Years)
No. of
people
with
diabetes
Comparative
diabetes
prevalence
Populations
(20-79
Years)
No. of
people
with
diabetes
Comparative Increase
diabetes
in the No.
prevalence
of people
with
diabetes
Region Millions
Millions
Millions
Millions
NAC
320
37.4
10.2
390
53.2
12.1
42.4
MENA
344
36.6
9.3
833
51.7
10.8
93.9
SEA
838
58.7
7.6
1.200
101.0
9.1
72.1
EUR
646
55.5
6.9
659
66.2
8.1
20.0
SACA
287
18.0
6.6
382
29.6
7.8
65.1
WP
1.531
76.7
4.7
1772
112.8
5.7
47.0
AFR
379
12.1
3.8
653
23.9
4.7
98.1
Total
4,345
284.6
6.4
5589
438.4
7.7
54.0
Table 2. Regional estimates for diabetes (20-79 years), 2010 and 2030
By 2025, India is expected to have 6.98 crore diabetics, with a national prevalence of 8.2%,
rising from a prevalence of 7.1% (7.13 crore) in 2010. This increase is mainly expected to
occur in the age group of 40 59 yrs.
Figure 2. The Estimated Age Distribution of Diabetes in India by 2025.
The sex distribution is expected to be almost equal with males showing a slight preponderance.
249
Figure 3. The Estimated Sex Distribution of Diabetes in India by 2025
The increase in diabetes is not going to be restricted to the urban areas, but is expected
to be seen equally in the rural areas also. This could be due to population growth, aging,
urbanization, and increasing prevalence of obesity and physical inactivity.
Figure 4. The Estimated Urban / Rural Distribution of Diabetes in India by 2025.
Quantifying the prevalence of diabetes and the number of people affected by diabetes,
now and in the future, is important to allow rational planning and allocation of resources.
This is especially important in a country like India where the population is large and the
resources including financial, natural resources and manpower are limited.
2. Need for Strategies for Improving Diabetes Care in our Country

The epidemiological data and predicted numbers given above prove that we are definitely
headed towards an epidemic of diabetes. In a country like India where the population is
diverse in so many respects, a single strategy is doomed to failure. So, a multi-pronged approach is the need of the hour if we aspire to come close to even containing this epidemic.
3. Existing and being Launched Strategies by the Government of India

A) National Programme for Prevention and Control of Diabetes, Cardiovascular
Diseases and Stroke (NCDs)
i) Why this Programme?
India is witnessing a rising incidence of non-communicable diseases (NCDs) and old age
diseases. This rise is occurring in a setting where health expenditures are growing rapidly
led by an unregulated private sector and where health insurance and pension coverage are
still limited. These financial concerns are further exacerbated by the emerging evidence that
the Indias poor are at heightened risk of acquiring NCDs owing to high rates of smoking
and tobacco use, occupational risks, and living conditions. According to a World Bank
report, it is estimated that Indians spent nearly Rs. 84,600 crores out of pocket on health
care expenses (year 2004), amounting to 3.3 per cent of Indias GDP for that year. If we
consider only those who are working, the annual income loss to households associated
with NCDs is estimated to be Rs. 28,000 crores.
250
Until now we have had no policy for intervention with regard to non-communicable
diseases barring giving some limited financial assistance for purchasing of equipment or
undertaking pilot projects or studies.
Recently, a National Programme for the Control of Cancer, Vascular Diseases and Diabetes,
Health Care of Elderly (Geriatrics Care) and Mental Health have been approved to be taken
up in 100 districts during the next two years (2010-11 and 2011-12).
Major NCD programmes under approval for the remaining two years of the Eleventh Five
Year Plan are:
National Cancer Control Program with an outlay of Rs. 731.52 crores.
National Programme for Prevention and Control of Diabetes, Cardiovascular Diseases
and Strokes with an outlay of Rs. 499.38 crores.
National Mental Health Programme (district component) with an outlay of Rs. 600 crores.
National Programme for Health Care of the Elderly with an outlay of Rs. 288 crores.
Under this key initiative, dedicated staff will be positioned in community health care centres and district hospitals and training being given to frontline health workers as well as
medical and paramedical staff at different health facilities for diagnosis and early referral
and appropriate health care facilities.
ii) Pilot Phase of the National Programme for Prevention and Control of Diabetes,
Cardiovascular Diseases and Stroke
In order to evaluate the efficacy and reliability of the National Programme for Prevention
and Control of Diabetes, Cardiovascular diseases and Stroke, a Pilot Phase of the programme
was launched on 4th January 2008 by the Deputy Chairman, Planning Commission, in the
august presence of Honble Minister for Health and Family Welfare and Honble Minister
of State. The objectives of the Pilot Phase are risk reduction for prevention of NCDs
(Diabetes, CVD and Stroke) and early diagnosis and appropriate management of Diabetes,
Cardiovascular Diseases and Stroke. One district in each of the following States is covered
for Pilot Phase:
SL No
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
District
Assam
Punjab
Rajasthan
Karnataka
Tamil Nadu
Kerala
Andhra Pradesh
Madhya Pradesh
Sikkim
Gujarat
State
Kamrup
Jalandhar
Bhilwara
Shimoga
Kancheepuram
Thiruvananthapuram
Nellore
Jabalpur
East Sikkim
Gandhi Nagar
Table: 3 List of states and districts for the pilot project of NCDs
The strategies of the pilot phase are

(1) Health Promotion for the General Population
(2) Disease Prevention for the High Risk Groups.
Health Promotion for the General Population: Targeted to healthy, risk free population
and involves development of an effective communication strategy to modify individual,
group and community behaviour through media. It also focuses on community mobilization and participation and mainstreaming the health promotion agenda to reach till
the village level. The interventions involve at various settings of Community, School and
Work Place.
Community Based Interventions: Involves health education regarding benefits of physical activities, dietary changes , mainstreaming the agenda of Health Promotion into the
activities of Village Health and Sanitation Committees (VHSCs), Gram Panchayats, Self Help
Groups and faith based organisations will be part of the strategy for health promotion.
Workplace Interventions: To introduce health promotion for their respective organisations
by identifying peer educators and providing initial training.
School Based Interventions: Evaluation of the existing school health programme components viz. physical education, nutrition and food services, health promotion for school
personnel, health education and health services followed by activities to make health
promotion a defined agenda in the school curriculum.
251
Disease Prevention for the High Risk Groups: Interventions aimed at early diagnosis
and appropriate management for reducing morbidity and mortality targeting people who
suffer from elevated risks demonstrated through hypertension, obesity, high blood lipid and
glucose levels and those who have suffered from a previous cerebral or coronary event
and are at the high risk.
Reorienting the Public Health Delivery System: System strengthening: At primary, secondary and tertiary levels. Health care providers at all levels will be mobilized and trained
to involve in risk detection and screening, viz., blood pressure checks, recommending lifestyle modifications, dissemination of information and referring for further management.
Setting up Special Clinics: Special clinic for Diabetes/Cardiovascular disease /Stroke will
be established at the District Hospital. Services of Private Practitioners may be taken for
this clinic as a visiting consultant. The clinic will do the screening and will also provide
the management. Difficult and complicated will be referred to tertiary care centre or the
nearby Medical College.
Harnessing the Private Sector: To correct the imbalance towards care using high cost, low
yield technologies and use of more cost effective interventions.
Specific interventions at the tertiary level to enhance capacity to respond to the
needs of NCD: It has been established that prompt intervention to manage a cardiac
event can reduce mortality to a large extent. Identification of a referral centre and
strengthening the linkage to the nearest referral centre at the tertiary/secondary level and
strengthening of the centre through provision of necessary infrastructure and manpower.
252
Specific intervention for Rheumatic fever / Rheumatic heart disease: Rheumatic fever/
Rheumatic heart disease affects children and if early intervention is made is curable or
else will require chronic care and in developed cases will require surgical interventions.
Specific activities for creation of public awareness, reorientation of primary health care
providers for early detection and referral will be taken up.
iii) Outcome of the Pilot Phase

Awareness generated on Healthy Life Styles
Health promotion at School, Community & Work places
Decrease in the incidence of Non Communicable Diseases

Cardiovascular Diseases and Stroke
particularly, Diabetes,
iv) Launch of the Main Programme

In the current five year plan, the full NCPDS has been launched with an outlay of 490
Crores. In 15 States 138 Districts have been targeted. It will be in 20,000 subcenters and
770 Community centers.
B) Population Strategies being adopted in India

The population strategy involves at lowering the risk for the whole population. This strategy is more meaningful for India, as the entire population of India may be considered
high risk for diabetes, hypertension and atherosclerotic heart diseases. Ethnically we are
more prone for this metabolic disease. By lowering the risk of whole population through
increasing physical activity, improving the diet, reducing obesity, there is a chance of
preventing high risk individuals developing diabetes. Further, the programs reduce the
chance of individuals with low risk, transferring into high risk.
Since India is facing an epidemic of diabetes and it is time to actively consider preventive measures. The first step in the preventive program is awareness of diabetes. There
is a necessity for community oriented, mass scale education programs. Mass media, movie
theatres pamphlets, posters, booklets and CDS should be utilized freely both in urban
and rural areas.
1. The strategies adopted can be broadly divided into
2. Those that are aimed at prevention of development of diabetes (primary prevention).
Those that are aimed at early diagnosis, optimal treatment and prevention of complications
of diabetes (secondary and tertiary prevention).
Primary Prevention
(Normal and Prediabetes)
Lifestyle changes through
mass education, group
education
Pharmacological intervention
Secondary Prevention
Tertiary Prevention
(Clinical DM)
(DM with complications)
Early diagnosis by screening To limit complications and
impairment
Adequate treatment to
reverse the disease / complication
Control suffering and rehabilitate
Table 4. Strategies for Prevention of Diabetes

i)Primary Prevention (Normal and Prediabetes)
Primary prevention involves lifestyle changes through mass education, group education
and pharmacological intervention. Burden of diabetes in the community can be reduced
by primary preventive measures which delays or prevent the occurrence of diabetes. These
measures essentially lie in life-style modifications targeting high risk population or entire
population.
High Risk Groups: The high risk subjects in the population are, individuals, with family
history of diabetes, prediabetes, obese, ageing and sedentary individuals and certain ethnic
groups. The number of prospective studies conducted in subjects with IGT, have shown
reduced progression or prevention of diabetes by lifestyle changes or pharmacological
interventions. The Indian Diabetes Prevention Programme (IDPP-1) showed a very high
progression rate to diabetes of 55% over 3 yr in subjects with Impaired Glucose Tolerance.
There were 4 groups in the study: Group 1 was the control, Group 2 was given advice on
Life Style Modification (LSM), Group 3 was treated with Metformin (MET) and Group 4
was given LSM plus MET. The median follow-up period was 30 months, and the 3-year
cumulative incidences of diabetes were 55.0%, 39.3%, 40.5% and 39.5% in Groups 14,
respectively. Hence this study clearly demonstrated that there was a significant decrease
in the development of diabetes when these preventive measures were applied. So, it is
the need of the hour to identify these high risk groups and start preventive measures
in them. Other similar studies have been briefly listed in tables 5 and 6. The high risk
253
approach, though efficient, is limited to small group, and may not alter the risk for the
whole population.
Study
Population
Study Protocol
Effect on Diabetes
Incidence
Da Qing IGT and

Diabetes Study
Patients with IGT

(n = 577)
Diet; exercise; or diet Reductions : 31%, 46%

plus exercise
and 42% respectively.
Diabetes Prevention Program
Patients with IGT

(n = 3234)
Intensive lifestyle
intervention; or standard lifestyle intervention plus placebo
or Metformin
Finnish Diabetes
Prevention Study
Overweight patients
with IGT (n = 522)
Lifestyle intervention; Reduction: lifestyle

or control group
intervention 58% vs.
control group
Reductions: intensive lifestyle 58%

vs. placebo, 39% vs.
Metformin
Table 5. Lifestyle Interventions to Prevent Diabetes in Patients with Prediabetes
254
Study
Population
Intervention
Effect
DPP
Patients with IGT (n

= 3234)
Metformin 850 mg
BID or placebo
Reduced risk of diabetes:

31% with Metformin vs.
placebo
TRIPOD
Hispanic women
with gestational
diabetes (n = 266)
Troglitazone or
placebo
Reduced incidence of
diabetes: 55% with Troglitazone vs. placebo
DREAM
Patients with IPG or

IGT (n = 5269)
Rosiglitazone 8 mg/d Reduced risk of diabetes:

60% with Rosiglitazone;
or placebo, plus
ramipril 15 mg/d or 9% with Ramipril.
placebo
STOP- NIDDM
Patients with IGT (n

= 1429)
Acarbose 100 mg TID Reduced relative risk of

or placebo
diabetes: 25% with Acarbose vs. placebo. Reduced
risk of CV events: 49%
with Acarbose vs. placebo
Chinese Acarbose Study
Chinese patients
with IGT (n = 261)
Acarbose 50 mg TID
or placebo
Reduced conversion to
diabetes: 7 vs. 12 with
Acarbose vs. placebo.
XENDOS
Obese patients with

or without IGT (n =
3305)
Orlistat 120 mg TID

or placebo, plus lifestyle intervention
Reduced risk of diabetes:

37.3% with Orlistat for all
patients, 45% for patients
with IGT vs. placebo
Table 6. Pharmacological Interventions to Prevent Diabetes or

Cardiovascular Events in Patients with Prediabetes
From the health system point of view the strategy prevents or delays direct medical costs,
which includes cost of education, counselling, glucose monitoring, treatment and man-
agement of complications. From societal point of view delaying or preventing diabetes

reduces medical costs, out` of pocket costs, and time lost from work. It may also improve
the quality and length of life.
The direct medical cost of treating diabetes is enormous. The cost increases with increasing HbA1c level, and presence of complications and co-morbidities. The costs are 2.1
times higher in patients with new clinically diagnosed diabetes compared with individuals
without diabetes. The results of within trial cost-utility analysis of DPP suggest the
value of lifestyle and Metformin intervention is $ 9000- 29,000 for lifestyle intervention
and $ 35,000 for Metformin intervention for, QALY (quality adjusted life year) gained.
The CDC cost effective group estimates the intensive glycemic control in newly diagnosed
type 2 diabetes, in US costs approximately $ 41,000. Hence the cost per case of diabetes
prevented seems to be cost-effective especially when implemented in a group format. The
cost per QALY gained also tended to be lower.
There are no comprehensive, cost effective studies on life style and pharmacological interventions for primary prevention of type 2 diabetes from India. However, estimates of the
economic burden of diabetes (both direct and indirect) apportioned at individual, family
and societal level show that the total direct costs amounts to Rs. 16, 765.50 and indirect
cost to Rs. 35,714.30 per annum per patient which includes expenses at all levels. In
Cost of Diabetes in India study (CODI) the mean direct annual cost for outpatient case
for diabetes individual was Rs. 4,724. The total indirect cost for non earning diabetic
patient is Rs. 9,748, whereas for earning member it is Rs. 16,831. The cost of management
of diabetes, apparently far higher than preventive strategies
ii) Secondary Prevention (Clinical DM)
Secondary prevention involves early diagnosis by screening and adequate treatment to
reverse the disease/complication.
Screening for diabetes: Early detection of prediabetes and diabetes is the cornerstone
for prevention of diabetes and its complications. The Indian Diabetes Risk Score (IDRS)
can be used as it helps in selective screening instead of universal screening of the population and thereby reduce the cost of screening. The screening system has been developed
using four simple parameters, like age, abdominal obesity and family history of diabetes
and leisure time physical activity. The IDRS is simple, safe, and cost effective especially
with our explosive diabetes population and of which an estimated 40% are undiagnosed.
iii) Tertiary Prevention (DM with complications)
Tertiary prevention programs aim to improve the quality of life for people with various
diseases by limiting complications and disabilities, reducing the severity and progression of
disease, and providing rehabilitation (therapy to restore functionality and self-sufficiency).
Unlike primary and secondary prevention, tertiary prevention involves actual treatment
for the disease and is conducted primarily by health care practitioners, rather than public
health agencies.
Tertiary prevention efforts have demonstrated that it is possible to slow the natural course
of some progressive diseases and prevent or delay many of the complications associated with
chronic diseases such as arthritis (inflammation of the joints that causes pain, swelling, and
stiffness), asthma (inflammation and obstruction of the airways that makes breathing difficult),
heart disease, and diabetes.
255
iv) Primodial Prevention (by Gestational Diabetes Control and Breaking the Transgenerational Transmission)
Approximately 7% of all pregnancies are complicated by GDM, resulting in more than
200,000 cases annually. The prevalence may range from 1 to 14% of all pregnancies, depending on the population studied and the diagnostic tests employed. Indian women have
an eleven fold increased risk of developing glucose intolerance during pregnancy compared
to Caucasian women. Among ethnic groups in South Asian countries, the Indian women
have the highest frequency of GDM. The recent data shows 16.55% prevalence of GDM
in our country.
As ongoing epidemics of obesity and diabetes result in more type 2 diabetes in young
women, the number who are undiagnosed (before pregnancy) is increasing. The need to
identify these women and address perinatal risks that may be particular to their greater
degree of hyperglycemia is becoming more important.
The presence of fasting hyperglycemia is associated with an increase in the risk of intrauterine fetal death during the last 48 weeks of gestation. Although uncomplicated GDM
with less severe fasting hyperglycemia has not been associated with increased perinatal
mortality, GDM of any severity increases the risk of fetal macrosomia. Neonatal hypoglycemia, jaundice, polycythemia, and hypocalcemia may complicate GDM as well. GDM is
associated with an increased frequency of maternal hypertensive disorders and the need
for caesarean delivery.
256
Women with GDM are at increased risk for the development of diabetes, usually type
2, after pregnancy. Obesity and other factors that promote insulin resistance appear to
enhance the risk of type 2 diabetes after GDM, while markers of islet celldirected autoimmunity are associated with an increase in the risk of type 1 diabetes.
Offspring of women with GDM are at increased risk of obesity, glucose intolerance, and
diabetes in late adolescence and young adulthood.
Thus there are consequences of GDM for two generations. This urges the need for directed
and intensive strategies for diagnosis and subsequent interventions.
A policy of universal testing of all pregnant women irrespective of risk factors should be
undertaken. Although the ADA recommendations suggest risk assessment and subsequent
testing with the glucose challenge tests for pregnant women at high risk, in the Indian
context this is not ideal. Indian women have 11 fold increased risk of developing glucose intolerance during pregnancy compared to Caucasian women. Additionally, metabolic testing
in this age-group is not commonly performed outside of pregnancy. Well-designed studies
should however be conducted to determine whether this is beneficial and cost-effective.
The second is to have a simplified and easily applicable one step procedure which serves
both as a screening and a diagnostic tool at the same time and which is acceptable,
economical and feasible to perform in the Indian context. As a pregnant woman walks
into the antenatal clinic in the fasting state, she has to be given a 75g oral glucose load
and at 2 hrs a venous blood sample is collected for estimating plasma glucose. This has
also been recommended by the Diagnosis in Pregnancy Study group India and is one
step procedure of challenging women with 75 gm glucose diagnosing GDM. It is simple,
economical and feasible.
When
1st prenatal visit
Diagnosis
Overt diabetes
24-28 weeks
Gestational
diabetes
Test
FPG
HbA1C
Randoma
FPG
75g OGTT-1 hr
75g OGTT-2 hr
Cut-off for diagnosis

126 mg/dL (7.0 mmol/L)
6.5%
200 mg/dL (11.1 mmol/L)
180 mg/dL (10.0 mmol/L)
a
Confirmation required.
Table 7 Proposed Screening for GDM
Women who exceed the threshold for GDM on FPG (92 mg/dl or 5.1 mmol/L) at the first
prenatal visit are diagnosed as having gestational diabetes. Women whose FPG at first
prenatal visit is below 92 mg/dl (5.1 mmol/L) are tested with a 2-hour OGTT at 24-28
weeks to rule out GDM.
Certain new recommendations have been suggested:
1. To go from a 2-step screening procedure (50-g challenge, then 100-g 3-hour OGTT if
challenge test is positive) to a 1-step procedure;
2. The glucose load used for the OGTT decreases from 100 g to 75 g, which may improve
patient acceptance;
3. The 75-g, 2-hour test is the same as that used in nonpregnant adults, although
diagnostic thresholds will be different, so less likelihood of error with the lab doing
the wrong test;
4. A single elevated value (out of the 3 blood samples -- FPG, 1-hour, and 2-hour) will
be sufficient to diagnose GDM, rather than the current requirement for 2 elevated
values (out of 4) . . . this will eliminate the borderline state of one abnormal value
and the quandary as to how to treat these patients.
Prompt treatment of newly diagnosed women with GDM is important. Most fetal weight
accretion occurs in the third trimester, so treatment should begin as soon as the diagnosis
is made.
Treatment strategies for GDM include dietary modifications, regulated exercise, and pharmacologic agents. Most women can be managed with diet and exercise, and will not
require insulin.
As for any pregnancy, women with GDM should be advised to return to their health care
provider for a 6-week postpartum check-up. The ADA recommends evaluation for the
development of diabetes by completing a 75-g, 2-hour oral glucose tolerance test (OGTT)
in the 6- to 12-week period after the birth of the child. It is also recommended that the
fasting blood glucose level be checked at least every 3 years thereafter.
Women with chronic medical conditions such as diabetes might not have the opportunity
to take steps to optimize management of their diabetes before becoming pregnant. Adverse
outcomes are more likely to occur in women with GDM who do not receive preconception
counseling. This is a potential target in the strategy of better diabetes care in pregnant
women.
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Lifestyle interventions have been shown to prevent the progression of prediabetes to

diabetes in a randomized trial. With help, women may be able to avoid the risks of a
diabetic pregnancy.
Every healthcare provider who takes care of a woman of reproductive age has something
to contribute to preconception care, by diagnosing prediabetes and helping that individual
avoid progression to diabetes and its attendant risks during pregnancy.
4.Future Strategies to be adopted in India

A) Screening Programmes for detecting Diabetes
Is there a need for Universal Screening?
Currently the Union Government is contemplating a universal screening programme to
enable detection of all diabetic patients at a very early stage so that the secondary prevention measures can be instituted at an early phase. Although economically it might
be difficult to implement and sustain, serious steps must be taken towards this so that
the maximum benefit of the programme can be accrued now when the epidemic is
ongoing - rather than when the epidemic has already peaked. Also, since the prevalence
rates of diabetes in the young and children is constantly rising, this strategy of universal
screening can be of particular benefit in picking these cases which would be missed if
only high risk screening is done and preventing complications in them.
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The National Programmes for Control and Prevention of Diabetes, Cardiovascular Disease
and Stroke (NPDCS) is in place, aiming at early diagnosis and appropriate management of
these non communicable diseases and is being expanded from pilot phase involving ten
places to cover 20,000 sub-centres and 700 Community Health Centres. Such programmes
should be well funded and supported so that the benefits of the early diagnosis and prevention of complications can be maximised.
B) Information, Education and Counselling about Diabetes in India
Strategically it should be aimed at:
Health care givers GPs, Physicians
Paramedical workersNurses, Educators, would be Podiatrist.
Creation of a Multipurpose Diabetes Paramedical worker cadre
Diabetes Patient Education
Education of the family and general public
The incidence and prevalence of type 2 diabetes mellitus are increasing in epidemic proportions and impacting the 30 to 69-year age bracket. The increasing morbidity and
mortality in this population group and the complexity of diabetes treatment, including
dietary restrictions, use of medication and associated chronic complications (retinopathy,
nephropathy, neuropathy, cardiovascular complications, diabetic foot and others) emphasize
the need for effective educational programs and training for health professionals, in order
for them to meet this demand adequately. This is one of the current challenges for public
health, especially in primary care.
Main aims of Diabetes Education: Education is not just a part of diabetes treatment;
it is the treatment1. According to World Health Organization (WHO), Education is the
corner stone of diabetic therapy and vital to the diabetic in the society. Unfortunately,
due to their clinical preoccupation with diagnosis and management of diabetes and its
associated disorders, physicians do not have the luxury of spending adequate time with
patients to sufficiently educate them. Hence there is a major role of a diabetes educator
who could be a nurse, a dietician, a social worker or in a more sophisticated centre, a
qualified diabetes educator to fill this important void. This article will briefly review the
goals and targets of a diabetes educator and explain how diabetes education has helped
to improve the lives of diabetic patients.
The key aims of diabetes education are to change behaviour of people and promote selfmanagement. The objective for continuing education is meant to increase the participants
knowledge, skills and flexibility. Self management implies that the person with diabetes
will understand the impact of factors such as food intake, exercise, stress and medication
on blood glucose, and will be able to make appropriate adjustments to maintain glucose
levels within a target level. Diabetes education consists of providing tools and the necessary support to patients as they learn to manage their disease.
Role of a Diabetes Educator: Diabetes Mellitus, being a chronic life-long disease with
varied acute and chronic complications, its treatment, unlike any other acute illness, is
not just a matter of taking a few pills or injections till the patient becomes symptom
free. Since no cure of the disease is in sight, the patient has to accept to live with the
disease life long, eliminating its symptoms and trying to avoid or reduce its complications
with regular treatment, medications, along with changes in life style. To achieve these difficult goals, a considerable amount of time has to be spent in patient education so that
the patient can actively participate in daily self-care to maintain good metabolic control.
The need for more diabetes educators to serve the numbers of people with the disease is
the first major challenge in our country. In urban areas, at least in some metros, up to
30-40% of people can be reached through a diabetes education facility. However, in rural
or less developed communities, this number may drop to zero. People in rural areas may
have to travel for hours or even days to access specialist services.
The sheer number of people with diabetes may overwhelm the resources available for
treatment and education. Similarly, the demand for normoglycemia may place impossible
expectations on healthcare professionals and patients alike. Since individuals are unique,
their educational need will also vary - with age, stage of the disease, culture and life style
of the people. Effective instruction can only be accomplished by a collaborative effort
between educators and patients to identify individualized educational needs. Thus it is
essential for the educators to get educated before they educate others.
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Figure 5: The Central Role of Diabetes Educator in the Management of Diabetes
Factors Preventing Implementation Of Education Programme In Diabetes
260
Lack of time
Professional motivation lacking
Lack of financial incentives
Low wages
Professionals inadequate knowledge
Lack of space for educational activities in primary care centres
Limited access
The principal barrier to the effectiveness of diabetes care is the professionals inadequate
knowledge on how to manage diabetes and group education. The health education professionals should be prepared to conduct educational practices for people with diabetes,
pointing to gaps in their knowledge on the disease, the importance of diabetes management, and problems in pedagogical methodologies as aspects that hinder more effective
results in patient education for diabetes self-management.
There is a need to establish partnerships to use places other than the health centre such
as temples, homes for the elderly, and neighbourhood associations in order to ensure
comfortable areas with the necessary privacy for the patient education activities.
The health professionals motivation is an important factor. Motivation was viewed as a
catch-all term for issues related to professional interests, intentions, and awareness.
Health care professionals involved in the diabetes education programme must be boosted
with regular incentives and rewards based upon their performance in the field. There are
several economic, cultural, and social patient-related factors that impact the continuity
of patient education activities in diabetes. Problems in provider-patient communication
included health professionals lack of understanding of the social context, inattention to
specific knowledge, language differences, and insufficient consultation time for patients
to be heard and express their doubts, knowledge, and difficulties in understanding medical terminology.
These can be overcome by selecting health care professionals from once own community
who has a firsthand information about the social and cultural aspects of the population
under his control and also has a caring attitude towards his fellow men.
It is important to improve individual patient education by working on cultural and social
issues and developing reflexive listening to foster education in self-care and help patients
realize that their own actions can make the difference in diabetes treatment. There must
be health care professional-patient integration on cultural, social, cognitive and linguistic
grounds.
C) Training of Health Care Givers
Training is as mentioned above the most important strategy for control of diabetes in
general and all non-communicable diseases in particular. It has been stressed that four
risk factors, namely, tobacco, physical inactivity, unhealthy diet, and obesity are responsible
for diabetes, cardiovascular disease, hyperlipidemia and hypertension. These risk factors and
their amelioration must be the focus of an intensive training programme.
The Government of India in the recent past for the control for diabetes has organised
numerous training programmes under the title of Training of the Trainers, Development
of Handbook of Training, etc. One such programme has been organised by the National
Institute of Family Welfare and Health Education in Delhi and the other one by LNJP and
Associated Hospitals, New Delhi. Various regional programmes and local programmes have
also been organised.
i) Training of Physicians: There is inadequate time given for diabetes education in the
undergraduate or in the postgraduate curriculum. Hence there is a great need of continuous medical education programmes, structured courses, TOT programmes, guideline
education and familiarization programme amongst the GPs and Physicians.
ii) Training of Paramedics: It has been the common experience that whether it is smallpox, guinea worm or polio, it is the paramedics who deliver the goods. For a chronic lifelong disease like diabetes, the paramedical training is of paramount importance. Whether
to empower existing ASHAs or developing a new cadre is a point of discussion. Suffice
to mention, the training in the following categories must find a place in our agenda to
combat diabetes by 2025.

Podiatric training
Diabetes Educator training
Diabetes Specialist Nurse training
Diabetes Dietician training
D) Creation of Multipurpose Diabetic Paramedical Workers

There is also a need to urgently develop the strategy of creating a multipurpose diabetes
261
worker with training in all the four aspects together. This will solve the problem of cost,
manpower and will be easy to execute. This multipurpose diabetes worker can deliver the
goods till all the four above cadres are developed.
E) Treatment Strategies
a) Oral Drugs
i) Metformin 54 years old and still going strong: In a country like India where affordability of drugs and therapeutic procedures is a major consideration in the management
of patients, Metformin seems to be a boon. It is cheap, easily available and has minimal
adverse effects. Other than just improving glycemic control, it has other pleotrophic effects including favourable effects on lipid profile and cardiovascular risk. Hence Metformin
will be a crucial drug in our strategy of tackling diabetes in India in the future. Needless
to mention India has the maximum experience with Metformin compared to any other
country in the world.
1.
2.
3.
4.
5.
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6.
7.
8.
9.
10.
Weight loss : favourable weight profile

Glycemic durability higher
Anti hyperglycaemic effect : freedom from hypoglycaemia
Sub maximal dosing for therapeutic effects
Vascular drug : favourable cardiovascular effects, microvascular and macrovascular
benefits
Lipid friendly : favourable modulation of deranged lipid parameters
Equivalent benefits demonstrated in obese and non-obese diabetics
Gestational DM : Trials underway show therapeutic role
Low cost of therapy: Extremely important for countries like India
Can be used in prediabetes also and is of proven benefit in preventing progression
to diabetes
Table 8. Factors How Metformin scores over other oral anti-diabetic drugs
ii) Sulfonylureas: In recent years, especially after the discovery of incretin analogues
and DPP-IV inhibitors and the invention of long acting basal insulins, sulfonylureas have
been pushed further and further down in the antidiabetic drug list. However in
India, sulfonylureas will continue to have significant role to play in view of their low cost
and easy availability. It is likely that the cost of drugs like Incretin analogues and DPP-IV
inhibitors will fall by 2025 and hence can be afforded by many Indians. However, sulfonylureas will still probably remain as the 2nd or 3rd line drug for treatment of diabetes.
iii) Incretin analogues and DPP-IV inhibitors: These novel classes of oral anti-diabetic
drugs have distinct advantages over other hypoglycaemic drugs which have made them
attain almost the 2nd choice spot in the treatment of diabetes. However, high cost is a
real constraint. In India, it is likely that the use of these agents will rise in the future
and by 2025 may play a crucial role in diabetes treatment and complications prevention.
For this to happen, the cost of these drugs should be reduced by appropriate government
intervention including subsidized supplies and free supply to people with poor economic
background.
B) Insulin
In todays scenario in India, Insulin as a potent ant-diabetic drug is underutilized. It could
be partially due to the relatively high cost involved, fear of injections, irrational beliefs
and the overemphasized fear of hypoglycaemia. By 2025, India needs to promote use of
Insulin such that every patient needy of insulin should get it irrespective of his financial
condition. This can be achieved if the following steps are taken:
Subsidising insulin and insulin delivery devices such that a larger proportion of the
population can afford them.
Tax rebates on the processes involved in production, storage and marketing of insulin
products.
Funding for research into new insulin delivery devices such as insulin pens which
target the fear of injections, systems like insulin pumps and their individualization to
our population and their lifestyles
Research into orally bioavailable insulins which can tremendously increase acceptance
of insulin by patients and also is likely to be more physiological.
Licensing and research into long acting insulins, depot preparations which can reduce
the burden of daily injections.
The maternal health and foetal outcome depends upon the care by the committed team
of diabetologists, obstetricians and neonatologists. A short term intensive care gives a long
term pay off in the primary prevention of obesity, IGT and diabetes in the offspring, as
the preventive medicine starts before birth.
F) Inter-sectoral Approach
i) Public-Private Partnership Role of NGOs: This is one of the important strategies
in controlling diabetes. In fact, in the pilot phase, as in the full programme, this NGO
partnership has been enlisted. The various societies, professional associations, people action
groups and patient groups have a lot of stake in diabetes control and must be included
in the programme execution in future.
Similarly, the Pharma companies also have their corporate social responsibility and their
role in operational research in executing national control programmes. Further, their
partnership will bring funding and also will be of mutual help.
ii) Role of Various Ministries: The diabetes control in our country cuts across many
Ministries and it is mandatory that in future, all the following Ministries must be working
in unison to control diabetes and other non-communicable diseases. They are:
Ministry of Education
Ministry of Culture, Sports and Youth Affairs
Ministry of Urban Development
Ministry of Food and Agriculture
Ministry of Food Processing and Food Labelling
Ministry of Transport
The need of the day is Inter-sectoral partnership, as a whole society, whole life course,
whole family approach to reduce the incidence, harm and costs of Type 2 diabetes. The
263
program should be aimed at long-term structural changes by involving many sectors within
the community, especially involvement at the family level.
The inter-sectoral approach should include local government; the transport sector; the food
industry; religious leaders; schools and sports organizations, and many public and private
health sector organizations. At its core, the program takes a whole society/whole family/
whole life approach that recognizes that an individual is part of a family/community which
has a direct influence on environmental risks, choices and decisions. Therefore, wherever
possible, working with families is central to the program.
The program should focus on ten Action Areas which reflect a variety of intervention
strategies to reduce risk and improvement management of diabetes.
The possible Action Areas should include:
264
Supporting community leadership and action

Promoting behaviour change through social marketing
Changing urban design to support healthy active lifestyles
Supporting a health environment through food industry accord
Strengthening health promotion co-ordination and activity
Enhancing child health and school health services to reduce childhood obesity
Developing a schools accord to ensure children are fit, healthy and ready
Supporting primary case-based prevention and early intervention
Enabling vulnerable families to make healthier choices
Improving service integration and care for advanced disease.
Few more steps to be taken in order to ensure a sustained and efficient inter sectoral
approach in preventing diabetes include:

Encourage healthy work environments through exercise programs, healthy food policy
for workplace, etc.
Schools/Early Childhood Nutrition Program which should fund projects such as school
gardens, school play area.
Improving School Lunches and mid day meal programmes which can promote healthy
eating in schools.
Organising a social marketing program at regular intervals with radio, print, billboard
and other media campaigns designed to get individuals involved in dialogue about
changing behaviours to prevent or delay diabetes.
Development of a Healthy Recipes Cookbook for families in the community.
Support of regular walking excursions and exercise groups in collaboration with other
organizations such as the Parenting Network.
School health
approach
Prevent
childhood
obesity and
childhood
diabetes
Promoting baby
friendly hospital
initiative
Urban planning
and
reorganisation
Diabetes care
Interaction with
food providing
authorities/
food ministry
Better maternal
and child care
Human
resources
development
Make work
places health
friendly
265
Figure 6: Team Work: For Comprehensive Diabetes Care
1. Implement Healthy Eating, Healthy Action and strengthen health promotion activities:
Develop a plan of action for implementation of Healthy Eating, Healthy Action
Devise a plan of action for strengthening health promotion coordination and activity
by concentrating on the recommendations based on earlier studies
2. Children and Diabetes
Develop a consistent, coordinated approach to reducing the prevalence of factors which
predispose children to type 2 diabetes by concentrating on:
Breastfeeding
Childhood obesity
Intersectoral approaches
3. A patient-centred clinical care pathway.
Develop a patient-centred clinical care pathway.
Continue to support and enhance a structured evidence-based approach to early diagnosis and treatment of diabetes through annual free checks, Diabetes and CVD risk
assessment, and Chronic Care Management Programmes.
Carry out regular audits of practice to monitor compliance with the pathway and patient
satisfaction.
4. Review existing services for those with diabetes

5. Develop and support an effective coordinated workforce.

Develop a workforce action plan that is aligned to the needs of people with diabetes.
Develop a district-wide coordinated approach.
6. Employ a Diabetes Strategy Coordinator Service Development and Funding team to assist
with strategy implementation
7. Work with food producers and vendors e.g. supermarkets, to produce and market healthier foods; and work with national food accord initiatives
8. Make workplace a healthy lifestyles role model by

Conducting a healthy lifestyles programme for employees and gathering baseline

data on diet and activity levels
Evaluating cafeteria food choices and snack and drink vending machines to ensure
that the healthy options are promoted above less healthy alternatives
Preparing a healthy food policy
Encouraging use of stairs, walking and cycling
9. Reduce the number of children at risk of diabetes

Working closely with all lead maternity centres to ensure all hospital maternity/
obstetric facilities meet Baby Friendly Hospital Initiative standards and provide
ongoing resources to maintain the standard.
Demonstrating leadership as an employer by having an effective breastfeeding

policy and facilities to support staff and contractors who are breastfeeding their
own children.
Enhancing existing and/or prioritising new services that focus on improving breastfeeding rates among vulnerable.
Ensure early identification and optimal management of gestational diabetes, preconception counselling and optimal management of young women with diabetes.
Strengthen the capabilities of well baby clinic/school health clinics to assess children
with developing obesity risks and ensure early and appropriate referral.
266
10. Work closely with urban development authorities for introducing separate cycling
lanes by the sides of all thoroughfares in the cities for more people to take up cycling.
To develop walkers lanes in many parts of the cities for encouraging people to walk to
their place of work
5. Conclusions
We need an integrated strategy to control diabetes by 2025. Diabetes with its complications will be the most important cause of morbidity and mortality unless we wake up to
the occasion. The National Programme for Prevention and Control of Diabetes, CVD and
Stroke is a very ambitious programme and the success of the 10 pilot programmes bear
testimony to the fact that the full programme is going to be a success. The allocation
of 495 crores and the execution of the programme in 20,000 subcentres and 700 community health centres during this Five Year Plan will pave the way for the success of the
full control programme by 2025. In addition, the crux of the control programme will lie
in its population strategy of primary prevention. This should be based on an universal
screening programme and appropriate measures to prevent prediabetes becoming diabetes.
Further, detection of GDM by universal screening by using simple criteria will result in
primodial prevention of diabetes. This strategy should also include information, education and counselling of both the health care providers and persons with diabetes. Even
the general public will have a role to play. The treatment strategies will depend upon
the cost effective diabetes management for a resource constrained country like ours with
multitude of other health problems. Needless to mention, the intersectoral approach with
inputs from all other stakeholders like NGOs, Pharmas, and various other Ministries such as
Ministry of Education, Ministry of Culture and Sports, Ministry of agriculture, etc., working
with Health Ministry will be the mainstay in the control programme.
References
1.
International Diabetes Federation. Global Burden of Diabetes: Prevalence and Projections, 2010 and 2030
(http://www.diabetesatlas.org/content/diabetes-and-impaired-glucose-tolerance)
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International Diabetes Federation. Global Burden of Diabetes: Prevalence and Projections, 2010 and 2030
(http://www.diabetesatlas.com/content/prevalence-estimates-diabetes-mellitus-dm-2010).
3.
Diabetes Atlas, Third Edition, International Diabetes Federation, 2006.
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Diabetes Atlas, 4th edition, International Diabetes Federation, 2009.
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Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes. Estimates for the year 2000
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King H, Aubert RE, Herman WH. Global Burden of Diabetes, 19952025. Prevalence, numerical estimates,
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MMS, Tripathy BB, Moses SGP, Chandalia HB, Das AK, Rao PV, Madhu SV. Research Society for the Study
of Diabetes in India. Hyderabad. 2002, pp. 307-10.
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Sarma A: Diabetes education need of the hour. In: Type 2 diabetes - The Indian scenario. 1st edition,
Micro labs Ltd., Bangalore. 2002, pp 22829
10. American Diabetes Association. Diabetes Education Goals (3rd Edition), EDS Siminerio L, McLauglin S, Polonsky W. Canada, 2002.
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17. World Health Organization, ECOSOC High Level Segment, Non-communicable diseases, 2009.
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19. Steinbrook R. HIV in India The Challenges Ahead. The New England Journal of Medicine 2007; 356(12):11971201.
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268

Dr Shashank R. Joshi
Dept. of Endocrinology, Grant Medical College & Sir JJ Group Hospital

Consultant. Endocrinologist, Lilavati & Bhatia Hospital
Hon. Emeritus Editor, JAPI, Mumbai

269
Introduction
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The huge burden for people with diabetes in India falls on diabetes centers, of excellence,
endocrinologists, internists and general practitioners (GPs) without necessarily a close or
regular cooperation existing between all theses specialties. In the last few years there has
been a tendency to expand diabetes centers, more recently economic and social pressures
have been pushing towards a different solution with diabetic patients being managed as
much as possible in general or consulting physician practice. Information Technology (IT)
is poised to revolutionize healthcare trade through new thresholds in human connectivity.
Information and Communication Technologies (IT1) could revolutionize healthcare. With
the right policy choices, IT is able to promote new thresholds of human connectivity and
is a powerful tool of global convergence through cross-border supply of services. Firstly, IT
enables new opportunities for production of knowledge, the only factor of production not
subject to the economic laws of diminishing returns, and to trade in it for direct economic
benefits. Secondly, international diffusion of new knowledge and best practice opens new
ways of improving the performance of health systems. Disease management is defined as a
system of coordinated health care interventions and communications for populations with
conditions in which patient self-care efforts are significant. It is rooted in the assumptions that care for chronic diseases can be greatly improved without the organizational
changes required by the chronic care model. Most disease management programs are built
around four specific processes concerning patientsidentification, enrollment, engagement,
and retentionwhich work in concert to improve quality of care and outcomes. In fact,
payers, recognizing that disease management may help avoid or delay costly complications
of chronic diseases, have been investing in disease-management programs, many of which
only indirectly involve physician practices. Such programs emphasize the empowerment of
patients to manage their own care and to use evidence-based guidelines to help them
stay as healthy as possible.
A growing body of literature suggests that diabetes-management programs in particular
need an Information Technology (IT) backbone in order to be effective. For instance, the
Health Care Delivery Work Group from the National Institutes of Healths Behavioral
Research and Diabetes Conference of America concluded in 1999 that in order for a
diabetes-management program to be successful it is necessary to have a clinical infor
mation system to support it.
The advantages of IT tools include: promoting better provider-guideline compliance by
presenting recommendations at the point of care; helping to identify patients overdue for
care and assisting providers to proactively reach out to them; enabling patients to manage
their own care through education and communication tools that allow them to receive
direct feedback; and providing numerous other benefits as well. IT allows health care
providers to collect, store, retrieve, and transfer information electronically. However, more
specific discussion of IT in health care is challenging due to the lack of precise definitions,
the volume of applications, and a rapid pace of change in technology.
IT-enabled diabetes management is believed to create value by improving processes of
care, which reduces the rate of diabetic complications, which in turn produces both cost
savings and enhanced quality of life. For instance, IT in Diabetes Mellitus promotes strict
dietary compliance, which improves blood-sugar levels and lessens damage to small blood
vessels throughout the body. This reduction in microvascular disease lowers rates of diabetes
complications such as blindness, lower-extremity amputations, and end-stage renal disease.
Such outcomes not only improve patients quality of life but also reduce utilization of
health care resources, potentially leading to cost savings.
Available Technologies
Technologies used by insurers and providers
- Disease registries
- Clinical decision-support systems
Technologies used by patients
- Self-management
- Remote monitoring
Integrated provider-patient systems
Technologies Used by Health Care Providers and Insurers

Insurer systems interface with electronic-claims systems to track patients with diabetes and
monitor diabetic-specific information. Payer systems compare patient data with recommended guidelines in order to identify opportunities for improved management; provide
feedback to patients and providers by telephone, email, or postal mail; and can focus on
behavioural change, using health coaches to convey educational and motivational information to patients. The systems, which may be based at the payer organizations themselves or
at separate disease-management companies, involve only those two entities and patients.
There is typically no point-of-care component, though many programs do follow up with
providers during or after an intervention.
Diabetes Registries: Track patients with diabetes and store information specific to their
care. At the point of care, registries may generate concise patient reports for clinicians
that highlight areas for attention during the office visit. Registries may also aggregate
information across the population to generate report cards, which show, for example,
the proportion of patients with diabetes who had foot exams during the prior six months
or a list of patients with hemoglobin A1c (HbA1c) levels above 7 percent, which indicates
that the patients blood-sugar level is too high. Registries may also use these report cards
to facilitate a providers communication with patientsfor instance, to generate lists for
announcements about available diabetes-education sessions or to facilitate appointment
scheduling.
Clinical Decision-Support Systems: Generate alerts and reminders for clinicians during a
patient visit. Such communications may caution providers about potential errors or remind
them of recommended guidelines for improving quality of care. In addition, it may offer
information that helps providers navigate the complex array of treatment options by suggesting regimens based upon a patients condition. Unlike diabetes registries, it is built on
Electronic Medical Records (EMRs), which maintain comprehensive health data about each
patient. Though EMRs are not generally designed for population-level reporting, providers
and their office staff may query them to generate such information.
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Electronic Health Record (EHR): EHRs were originally envisioned as an electronic file
cabinet for patient data from various sources (eventually integrating text, voice, images,
handwritten notes, etc.). Now they are generally viewed as part of an automated orderentry and patient-tracking system providing real-time access to patient data, as well as a
continuous longitudinal record of their care.
Computerized Provider Order Entry (CPOE): CPOE in its basic form is typically a medication ordering and fulfillment system. More advanced CPOE will also include lab orders,
radiology studies, procedures, discharges, transfers, and referrals.
Bar Coding: Bar coding in a health care environment is similar to bar-code scanning in
other environments: An optical scanner is used to electronically capture information encoded on a product. Initially, it will be used for medication (for example, matching drugs
to patients by using bar codes on both the medications and patients arm bracelets), but
other applications may be pursued, such as medical devices, lab, and radiology.
Radio Frequency Identification (RFID): This technology tracks patients throughout the
hospital, and links lab and medication tracking through a wireless communications system.
It is neither mature nor widely available, but may be an alternative to bar coding.
Automated Dispensing Machines (ADMs): This technology distributes medication doses.
Electronic Materials Management (EMM): Health care organizations use EMM to track
and manage inventory of medical supplies, pharmaceuticals, and other materials. This
technology is similar to enterprise resource planning systems used outside of health care.
272
Interoperability: This concept refers to electronic communication among organizations so

that the data in one IT system can be incorporated into another. Discussions of interoperability focus on development of standards for content and messaging, among other areas
and development of adequate security and privacy safeguards.
Technologies Used by Patients

Self-Management: technologies provide patients with educational resources and datagathering mechanisms for managing their own care between provider visits. These technologies include automated phone systems that generate reminders or offer educational
content; electronic diary tools that collect information to be taken to a visit; interactive
educational programs on computers; and online resources, such as peer support groups,
sponsored by providers.
Remote-Monitoring technologies capture and send providers information that is needed to facilitate diabetes management between office visits; patients periodically submit
structured electronic data about their condition via a telephones touchtone keypad, for
example and they receive feedback and instructions. Newer remote-monitoring programs
use web sites that accept data uploaded directly from glucometers and other home devices. Although the focus of remote-monitoring technologies is on the data sent from
the patients homes to providers offices, some systems also deliver educational content to
patients, content such as self-care advice in recorded phone messages, when they submit
their data. These systems may also connect patients to resources such as EMRs, endorsed
educational materials, interactive self-care tools, and provider e-mail.
Integrated Provider-Patient Systems

It is a fully integrated chronic care platform that would coordinate the delivery of evidence
based care across multiple care settings, including outpatient clinics and patients homes.
This system would include a disease registry to manage chronically ill populations, patient
education tools to support self-management, and remote-monitoring devices to measure
and report patient symptoms and clinical progress to providers between visits.
Glucose Monitoring, Glycemic Variability and Biomathematics: Clinical

Relevance
We need to know Glycemic variability as we need to know in vivo understanding of the
dynamics of glucose regulation in our patients. Current technology only allows us to estimate average glucose and a few points of glycemic time points (Table 1).
Monitoring of Glycaemic variability
Temporal Resolution, Spacing and Data Analysis
Monitoring
Method
HbA1c
Self monitoring
data
Continuous
monitoring
data
Spacing in
time
Episodic, once
every few
months
Episodic, several
readings / day
Temporal
Resolution
Months / Years
Reflects
Days / Weeks
Daily variation;
Weekly trends
Regular every
few minutes
Minutes / Hours System dynamics fluctuation,

periodicity
Slowly changing average
Data Analysis
Methods
Standard statistical methods
Standard
statistics; Risk
analysis
Time series;
Deterministic
methods
Table 1: Current Technology for Estimation of Glycaemic Variability
We need to understand and know indices of glycemic variability now as we need to understand hyperglycemia induced oxidative stress and mechanism of glucose mediated vascular
damage. The pathways for hyperglycemia induced vascular damage leads to overproduction
of super oxide by mitochondrial electron transport chain. This is due to each of these four
pathways viz. enhanced polyol activity, advanced glycation end products, activation of
protein kinase C and nuclear factor kappa B and increased hexosamine pathway flux. The
glycemic variability correlates with magnitude of oxidative stress, may underlie hyperglycemic memory in EDIC cohort, it is more important than chronic hyperglycemia and does
explain DCCT results from the 7 point glucose data. It is also relevant for hypoglycemic
associated autonomic failure hypoglycemic associated coma/death, cognitive dysfunction
and depression. The need of GV is best explained in Fig 1 where two patients with same
glycosylated Hb have different GV.

273
Figure 1: Glycemic Variability as seen in Two Patients
274
To assess Glycemic Variability we need tools of IT and the measures of GV are standard
deviation (Standard statistical approaches to measuring the dispersion of symmetric data
around the mean), MAGE, M value, lability index and risk analysis. The MAGE and M Value
are insensitive to hypoglycemia while the Liability Index is sensitive to hypoglycemia. The
MAGE and M Value are classic measures of glucose variability introduced in 1965 (Schlichtkrull et al, Acta Med Scand 177) and 1970 (Service et al, Diabetes 19), respectively.
While lability index, was designed to identify candidates for islet transplantation, particularly sensitive to hypoglycemia (Ryan et al, Diabetes, 53, 2004). But these measures rely
on statistical independence (or weak dependence) between the data points; do not take
into account the temporal order of the data and do not estimate risk. To estimate risk in
the blood glucose equation we need to understand the normal blood glucose distribution.
Normal Glucose Distribution: Using IT to symmetrize clinical and

Numerical Center
Fig 2 highlights a very important physiological fact that distribution of normal blood
glucose values does not follow the Gaussian or normal curve. Therefore the clinical and
numerical center is not symmetrised and we need help of modern IT and Biomath tools
to do the same.
Figure 2: Distribution of Normal Blood Glucose Values
Symetrization of the scale is done by transformation of equations. The simple non-linear

transformation creates symmetry to the BG scale which is relatively easy for a mathematician but more challenging for beleagured clinicians is useful in enhancing prediction of
hypoglycemia (fig 3).
275
Figure 3: Symetrization of Blood Glucose Scale

Figure 4: The Concept of Risk in the Blood Glucose Function

The asymmetry of the BG scale, or why standard deviation would not work is because
SD is symmetric and is relative to the mean; while Risk increase is asymmetric and is
related to absolute BG level. The low blood glucose index (LBGI) Predicts risk of severe
hypoglycemia (fig 6, 7 and 8).
276
HBGI Associated with postprandial hyperglycemia and HbA1c. The real utility of risk
analysis is the variance carried by hypoglycemic and hyperglycemic readings is equalized;
Excursions into extreme hypoglycemia and hyperglycemia get progressively increasing risk
values and the variance within the safe euglycemic range is attenuated, which reduces
noise during data analysis. Therefore ADRR was described by Kovatchev. Average Daily
Risk Range (ADRR)is a risk measure using SMBG to assess and predict the likelihood of
extreme hypoglycemia and hyperglycemia (Kovatchev et al, Diabetes Care, 29, 2006). The
ADRR is similar to LBGI and HBGI vizthe Risk of Extremes namely ADRR <20 - low risk,
ADRR 20-40 moderate risk and ADRR >40 high risk. It is simple as is based on only
3 Blood glucose readings in a day. The method of ADRR calculation is in fig no and all
modern monitoring softwares of glucose monitors can estimate it. Risk analysis can be
used for evaluation of glucose patterns, in particular for assessment of the risk-reducing
effect of various treatments.
Risk analysis can be used for evaluation of glucose patterns , in particular for assessment
of the risk - reducing effect of various treatments
Figure 5: Defining The Low and High Blood Glucose Indices
Role of Continuous Glucose Monitoring (CGM)

CGM provides us the rate of change and direction of change of glucose. It has System
dynamics, fluctuation, and periodicity of the blood glucose function. Its interstitial fluid
glucose estimation. It allows Time series analysis is most suitable for real-time prediction
of imminent glucose fluctuations.
Figure 6: Prediction of Imminent Severe Hypoglycemia

Time series analysis is most suitable for real-time prediction of imminent glucose fluctuations
The combination of risk and time series allows for analysis of system dynamics enabling
closed-loop control. The suggested temporal variability measures are Variance (SD) of the
BG rate of change, Dispersion of Point of care plot and Time-series methods (power spectrum, approximate entropy). The Use of standard statistics is relatively OK on readings that
are more than 1 hour apart; One-hour block aggregation produces a Markov chain. This risk
analysis reveals treatment effects inaccessible by standard statistical techniques: a marked
reduction in risks for hypo- and hyperglycemia taking place during the first 10 days of
unmasked real-time continuous glucose monitoring, and sustained afterwards; Reduced
risks reflect reduced glucose variability; This effect is independent from average glycemia,
which does not change. Thus we can therefore speculate that eventually improved average glycemia (and thereby HbA1c) would be secondary to reduced risk for hypoglycemia,
which would allow for intensified treatment.
Figure 7: Prediction of Long-Term Severe Hypoglycemia

277
Closed Loop Technology: Glucose profiling, can influence both treatment decision and
treatment delivery which in turn shall influence the outcome. The currently available closed
loop technology of SMBG, CGM and Insulin delivery pumps can reduce number of hypoglycemia episodes, reduced duration of hypoglycemia, reduced number of hyperglycemia
episodes, reduced hba1c and reduced glucose variability.
Thus Glycemic Variability can be may contribute to short and long term complications, can
be assessed using risk analysis and can be reduced with standard management techniques,
new medications, continuous monitoring, transplantation, and/or closed loop control. With
modern technology we can now study and apply IT methods to use GV in modern day
diabetes practice.
References
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Committee on Engaging the Computer Science Research Community in Health Care Informatics (2009).
Computational Technology for Effective Health Care: Immediate Steps and Strategic Directions. Washington,
D.C., The National Academies Press.
2.
Hayes, B. and W. Aspray, Eds. (2010). Health Informatics: A Patient-Centered Approach to Diabetes.
Cambridge,Massachusetts, MIT Press.
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Berger, J. (2007). Economic and clinical impact of innovative pharmacy, benefit designs in the management
of diabetes pharmacotherapy. American Journal of Managed Care 13 (Suppl2), S55-S58.
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Villagra VG, Ahmed T. Effectiveness of a disease management program for patients with diabetes. Health
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management program in managed care. J Clin Endocrinol Metab. 1998;83:2635-2642.
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Meigs JB, Cagliero E, Dubey A, et al. A controlled trial of web-based diabetes disease management: the
MGH diabetes primary care improvement project. Diabetes Care. 2003; 26:750-757.
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Lobach DF, Hammond WE. Computerized decision support based on a clinical practice guideline improves
compliance with care standards. Am J Med. 1997; 102:89-98.
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McMahon GT, Gomes HE, Hickson Hohne S, Hu TM, Levine BA, Conlin PR. Web-based care management in
patients with poorly controlled diabetes. Diabetes Care. 2005; 28:1624-1629.
10. Glasgow RE, Boles SM, McKay HG, Feil EG, Barrera M,Jr. The D-Net diabetes self-management program:
long-term implementation, outcomes, and generalization results. Prev Med. 2003; 36:410-419.
11. Hoerger TJ, Richter A, Bethke AD, Gibbons CB. A markov model of disease progression and cost-effectiveness
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12. Hummel J. Building a computerized disease registry for chronic illness management of diabetes. Clinical
Diabetes. 2000; 18:107-113.
13. Feil EG, Glasgow RE, Boles S, McKay HG. Who participates in internet-based self-management programs? A
study among novice computer users in a primary care setting. Diabetes Educ. 2000; 26:806-811.
14. Turnin MC, Beddok RH, Clottes JP, et al. Telematic expert system Diabeto. New tool for diet self-monitoring
for diabetic patients. Diabetes Care. 1992;15:204-212.
15. Smith SA, Murphy ME, Huschka TR, et al. Impact of a diabetes electronic management system on the care
of patients seen in a subspecialty diabetes clinic. Diabetes Care. 1998; 21:972-976.
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Immunization in T2DM
Dr B M Jayaram
Formerly, Head of the Department of Medicine,

Bangalore Medical Collage.
Superintendent, Bowring & Lady Curzon Hospital
Bangalore-560 001.
Mobile: 98452 87261
&
Dr Kashinath Dixit
Senior Physician
High Court of Karnataka

Mobile: 94484 46678
e-mail: doctorhck@yahoo.co.in
279
Introduction
Patients with diabetes have co-morbid factors such as age and other chronic diseases which
increase morbidity and mortality from infection. Influenza and Pneumococcal infection associated with high death rates in those with diabetes. For those with diabetes, influenza
vaccination associated with 54% reduction in hospitalizations and 58% reduction in deaths.
Annual influenza vaccination may decrease cardiovascular disease morbidity and mortality.
Prevalence of pneumococcal vaccination among patients with diabetes may be as low as
38% in the United States and national estimates of influenza vaccination in the general
population (> 65 years of age) range from 33 to 75%. But in India, these two vaccines are
not used as extensively as in US due to lack of awareness among Medical Professionals
and lack of studies in Indian Diabetic Population.

Patients with diabetes may have abnormalities in immune function and presumed
increased morbidity and mortality from infection.
Epidemiological studies support the fact that patients with diabetes (in particular
those with end-organ complications of cardiac and renal disease) are at high risk for
complications, hospitalization, and death from influenza and Pneumococcal disease.
There is sufficient evidence that people with diabetes generally have appropriate humoral immune responses to vaccination.
Subgroup analysis of patients with diabetes reported in clinical narrative and case
control studies support the fact that vaccination against influenza has been effective
in reducing hospital admissions during influenza epidemics.
Although the question of the efficacy of Pneumococcal vaccination in preventing non

bacteremic disease remains unresolved, many studies have shown that the vaccine is
effective in reducing life threatening bacteremic disease.
Immunization against influenza and pneumococcal disease is an important part of preventive services for many chronic diseases such as diabetes. According to the Advisory
Committee on Immunization Practices (ACIP), the American College of Physicians, the
American Academy of Pediatrics, and the American Academy of Family Physicians,
vaccinating individuals at high risk before influenza season each year is the most effective measure for reducing the impact of influenza2. The effective implementation
of immunization can reduce the cost of human suffering and health care expenditures
in people with diabetes. The recommendations that follow are based in large part
on observational studies with high potential for bias. The narrative review1 supports
expert opinion that immunization intervention is low risk, is low cost, and may have
a moderate to substantial impact on the care of people with diabetes.
280
Influenza Vaccination
Consistent with the recommendations of the ACIP, the influenza vaccine should be recommended for patients with diabetes, beginning of each September 2. It is strongly suggested
that specific systematic intervention strategies be considered for patients with diabetes
who are 64 years of age, residents of nursing homes or other chronic care facilities, require
regular medical follow-up or hospitalization, or have additional secondary chronic disorders
of the cardiopulmonary system. Intramuscular dosage and type of influenza vaccine (split or
whole virus) vary based on the patients age2. Each year, a trivalent vaccine is constituted
with strains of influenza A and B, which are most likely to circulate in the US during the
winter. Because the vaccine consists of egg-grown viruses, it should not be administered
to individuals known to have anaphylactic hypersensitivity to chicken eggs or additional
components of the influenza vaccine. Because immunity from influenza vaccination declines after an year of vaccination, early vaccination is recommended. Although antibody
responses to repeat immunization have been reported to be greater in some people with
diabetes, repeated immunization within the same season is not recommended3. The ACIP
does recommend two doses of influenza vaccine administered at least 1 month apart (the
last administered before December) for children <9 years of age who have never been
vaccinated2. Because infection with influenza virus can be transmitted from person to
person, vaccination of health care workers and family of patients with diabetes may be
justified. Influenza is a universal illness occurring throughout the year in the tropics and
primarily from April to September in the Southern Hemisphere2. Patients traveling to these
areas should consider influenza vaccination before travel. The influenza vaccine contains
only noninfectious viruses and cannot cause influenza or other respiratory disease. Most
frequently experienced side effect from vaccination is mild soreness at the vaccination site.
In individuals with chicken egg allergy, immediate allergic reactions have been reported. In
these patients, chemoprophylaxis with Amantadine / Rimantadine or immunization using a
protocol as reported by Murphy and Strunk 4 should be considered. A recent study reported
a slight increased risk of Guillain-Barre syndrome in the 6 weeks after influenza vaccination
during the 19921993 and 19931994 flu seasons5. For this reason, it is recommended not
to administer the influenza vaccine to individuals known to have developed Guillain-Barre
syndrome within 6 weeks of a previous influenza vaccination.
Two versions of the influenza vaccine: Injectable (inactivated) and inhaled (live).
Either type is safe in diabetes. Both forms can cause mild symptoms, but not an influenza
infection. Side effects of the inactivated injection: erythema, swelling, and pain at injection site. Both types of vaccine can cause upper respiratory infection-type symptoms (e.g.,
fever, myalgias). More serious (but rare) risks include life-threatening allergic reactions and
Guillain-Barre Syndrome (seen with inactivated swine flu vaccine in 1970s).
Pneumococcal Immunization
The current Pneumococcal vaccine includes 23 purified capsular polysaccharide antigens
representing 8590% of the serotypes of Streptococcus pneumoniae that cause invasive
Pneumococcal infections among children and adults in the US6. People with diabetes are
susceptible to Pneumococcal infection and are at increased risk for the morbidity and
mortality of bacteremia from this organism1. Additional risk is associated with being age
65 years and having chronic cardiovascular, pulmonary, and renal disease. According to the
ACIP, Pneumococcal vaccination is indicated to reduce invasive disease from pneumococcus
in people with diabetes6. Special efforts in implementation strategies for immunization
should include the same target groups as for influenza. Additional emphasis has been
suggested for Native American groups who have a high incidence of diabetes and invasive
Pneumococcal disease7, 8. There is insufficient evidence to support revaccination of people
with diabetes unless other special circumstances exist. A one-time revaccination is recommended for individuals 64 years of age previously immunized when they were 65 years of
age if the vaccine was administered more than 5 years ago. Other indications for repeat
vaccination potentially relevant to patients with diabetes include nephrotic syndrome,
281
chronic renal disease and other immunocompromised states, such as post-organ transplantation 6. Approximately one-third to one-half of individuals receiving Pneumococcal
vaccine develops mild local side effects similar to influenza (lasting for 48 h). Severe local
or systemic reactions are rare, and neurologic syndromes such as Guillian- Barre syndrome
have not been causally associated with Pneumococcal vaccine administration6. Pneumococcal vaccine may be administered with other vaccines (by a separate injection in another
anatomic site) without an increase in side effects or decrease in efficacy.)
Conclusions
Influenza and Pneumococcal immunization in patients with diabetes has the potential for
significant reduction in morbidity and mortality related to influenza and Pneumococcal
disease. Effective immunization strategies will require implementation strategies that are
multidimensional and target the patient, provider, support staff/family/ friends, and health
system. The goal should be to immunize all patients with diabetes, particularly those
with complicating factors such as cardiac or renal disease or those who are or have been
recently hospitalized. Targeted educational interventions using immunization opportunities and staff empowerment are all effective clinical strategies. Identification of patients,
creation of registries, and effective recall and reminder systems has all proven efficient
in improving immunization rates. Benchmarking organizations and national policy should
emphasize guideline implementation strategies for improving immunization rates as one
of the initial efforts in chronic disease management. Lastly, organizational strategies for
immunization of patients with diabetes could serve as a model for national efforts in
chronic disease management.
282
References
1.
Smith SA, Poland GA: The use of influenza and Pneumococcal vaccines in people with diabetes (Technical
Review). Diabetes Care 23:95108, 2000
2.
Advisory Committee on Immunization Practices (ACIP): Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 46 (No. RR-9): 125, 1997
3.
Gross PA, Weksler ME, Quinnan GV Jr,Douglas RG Jr, Gaerlan PF, Denning R: Immunization of elderly people
with two doses of influenza vaccine. J Clin Microbiol 25:17631765, 1987
4.
Murphy KR, Strunk RC: Safe administration of influenza vaccine in asthmatic children hypersensitive to
egg proteins Pediatr 106:931933, 1985
5.
Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M, Nash D, Clark S, Haber P, Stolley PD, Schonberger
LB, Chen RT: The Guillain-Barre syndrome and the 19921993 and 19931994 influenza vaccines. N Engl
J Med 339:17971802, 1998
6.
Advisory Committee on Immunization Practices (ACIP): Prevention of Pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 46 (no. RR-8): 125, 1997
7.
Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA, Peters HV, Parks DJ: The epidemiology of invasive
Pneumococcal disease in Alaska, 19861990: ethnic differences and opportunities for prevention. J Infect
Dis 170:368376, 1994
8.
Cortese MM, Wolff M, Almedio-Hill J,Reid R, Ketcham J, Santoshain M: High incidence rates of invasive
Pneumococcal disease in the White Mountain Apache population. Arch Intern Med 152:22772282, 1992
9.
Gyorkos TW, Tannenbaum TN, Abrahamowicz M, Bedard L, Carsley J, Franco E, Delage G, Miller MA, Camping DL, Grover SA: Evaluation of the effectiveness of immunization delivery methods. Can J Public Health
85:S14S30, 1994
10. Crouse BJ, Nichol K, Peterson DC, Grimm MB: Hospital-based strategies for improving influenza vaccination
rates. J Fam Pract 38:258261, 1994 11. Klein RS, Adachi N: An effective hospital based Pneumococcal
immunization program. Arch Intern Med 146:327329, 1986
11. CDC: Increasing Pneumococcal vaccination rates: United States. MMWR 44:741 744, 1993
12. Hershey CO, Karuza J: Assessment of preventive health care: design considerations. Prev Med 26:5967, 1997
13. Buffington J, Bell KM, LaForce FM: A target- based model for increasing influenza immunizations in private
practice. J Gen Intern Med 6:204209, 1991
14. Cheney C, Ramsdell JW: Effect of medical records checklists on implementation of periodic health measures.
Am J Med 83: 129136, 1987
15. Cohen DI, Littenberg B, Wetzel C, Neuhauser D: Improving physician compliance with preventive medicine
guidelines. Med Care 20:10401045, 1982
16. Clancy CM, Gelfman D, Poses RM: A strategy to improve the utilization of Pneumococcal vaccine. J Gen
Intern Med7:1418, 1992
17. Barton MB, Schoenbaum SC: Improving influenza vaccination performance in an HMO setting: the use of
computer-generated reminders and peer comparison feed-back. Am J Public Health 80:534 536, 1990
18. Klachko DM, Wright DL, Gardner DW: Effect of a microcomputer-based registry on adult immunizations. J
Fam Pract 29: 169172, 1989
19. US Department of Health and Human Services: Healthy People 2010: Understanding and Improving Health.
2nd ed. Washington, DC, U.S. Govt. Printing Office, 2000
20. CDC: Influenza and Pneumococcal vaccination levels among adults aged 65 years: United States, 1997.
MMWR 47: 797802, 1998
21. Fedson DS: Improving the use of Pneumococcal vaccine through a strategy of hospital-based immunization:
a review of its rationale and implications. J Am Geriatr Soc 33:142150, 1985
22. Fedson DS, Harward MP, Reid RA, Kaiser DL: Hospital-based Pneumococcal immunization: epidemiologic
rationale from the Shenandoah Study. JAMA 264:1117 1122, 1990
23. Barker WH, Mullooly JP: Pneumonia and influenza death during epidemics: implications for prevention.
Arch Intern Med 142: 8589, 1992
283
Current and Future Strategies for

Preservation of Beta Cells
284
Dr Sarita Bajaj
Director-Professor and Head Medicine

Post Graduate Dept. of Medicine
MLN Medical College
Allahabad-211 002.
Ph: 0532-2256461
e-mail: drsarita.bajaj@gmail.com
Introduction
Insulin resistance in muscle and liver and b-cell failure represent the major pathophysiologic defects in type 2 diabetes. b-cell failure occurs much earlier and is more severe
than previously thought. Even subjects with Impaired Glucose Tolerance (IGT) are insulin
resistant and have lost over 80% of their b-cell function The natural history of type 2
diabetes (T2DM) is characterized by progression of disease severity, eventually leading to
reliance on exogenous insulin. At the time of initial diagnosis, most patients with T2DM
have high levels of fasting and postprandial plasma insulin, indicating that their pancreatic b-cells are still producing the hormone in an attempt to overcome peripheral insulin
resistance. As the disease progresses, most patients eventually exhibit evidence of b-cell
dysfunction, often leading to nearly complete loss of insulin secretion. Indeed, individuals
with T2DM have fewer b-cells on average at death compared with non diabetic individuals.
Although dysfunction of the b-cells may contribute to the underlying causes of disease, the
continuing demand for high insulin output, resulting from insulin resistance of peripheral
tissues and from hyperglycemia, may also contribute to the decline in function of b-cells.
All these factors in combination dictate that treatment should be based upon reversal of
known pathogenic abnormalities and therapy must be started early to prevent/slow the
progressive b-cell failure that already is well established even in subjects with IGT.
Preservation of cell function in Type 2 Diabetes

Mechanisms of b-cell dysfunction that can be targeted by pharmacological intervention:
The concept that pancreatic islets are a target for adverse effectors associated with adiposity and insulin resistance, which result in islet (target organ) damage, indicates thatpharmacological intervention strategies could be aimed at counteracting these factors or
protecting the target b-cells. Monitoring such a strategy is not easy because neither can
the b-cell mass be visualized nor are there any circulating biomarkers for it. Preservation
of b-cell function in clinical practice is delineated over time by stability of glycemic control, with no change to the dose of anti-hyperglycemic drugs or lifestyle factors (weight,
exercise and dietary habits).
Protection of -cells
GLP-1 and GLP-1 Receptor Agonists
Activation of the GLP-1 receptor on pancreatic b cells stimulates insulin secretion and
biosynthesis in a glucose dependent fashion, thus lowering blood glucose levels. A synergistic action between glucose and GLP- 1 has been reported and in patients with T2DM,
the incretin effect is considerably reduced. Although glucose-dependent insulin secretion
is their key mechanism, other mechanisms including inhibition of glucagon release, a
delay in gastric emptying and a reduction in appetite contribute to improving glucose
homeostasis. In addition to its glucose-dependent stimulation of insulin secretion, GLP-1
receptor signaling improves cell survival by inhibiting apoptosis of human and rodent b
cells exposed to high levels of glucose, inflammatory cytokines and free fatty acids. This
anti-apoptotic effect can also be observed in islets from mice after the administration of
streptozotocin, and in mouse and rat models that are prone to developing diabetes. There
is no conclusive evidence that GLP-1 receptor activation protects islet b cells through
reductions in inducible nitric oxide synthase activation and nitric oxide production.
Current and Future Strategies for Preservation of Beta Cells
285
DPP-IV Inhibitors
Sitagliptin, Vildagliptin and Saxagliptin are DPP-IV inhibitors that increase the concentration of endogenously secreted GLP- 1 by preventing its inactivation. Mice with targeted
disruption of the gene encoding DPP-IV are resistant to the combined effects of a high
fat diet and streptozotocin, which induce b-cell apoptosis. These modulating effects on
b-cell apoptosis can also be achieved by treatment with DPP-IV inhibitors in rats during exposure to the b-cell toxin streptozotocin or in mice treated with streptozotocin in
combination with a high-fat diet. These data possibly indicate a potential role for DPP-IV
inhibitors in preventing b-cell death.
Metformin
Insight into incretin physiology has also surprisingly identified pharmacological agents that
increase GLP-1 secretion. Metformin increases GLP-1 secretion after nutrient stimulus in
healthy subjects and patients with T2DM offering a rationale for the combined use of
Metformin and DPP-IV inhibitor. Metformin also has direct effects on islet function and
survival. In islets isolated from patients with T2DM, Metformin improves glucose-stimulated
insulin secretion and attenuates apoptosis, associated with a reduction in reactive oxygen
species. Metformin might therefore improve b-cell function and mass indirectly, through
its anti-hyperglycemic method of action in combination with increased GLP-1 secretion,
or directly, through protective effects on b cells.
Thiazolidinediones
286
Thiazolidinediones improve b-cell function, possibly through improvements in glycemia,

insulin resistance and inflammation and have direct effects on pancreatic islets. They improve islet function and protect cultured human islets from apoptosis during incubation
with cytokines or high glucose concentration. Treatment with thiazolidinediones prevents
b-cell destruction and diabetes in obese diabetes-prone rats and reduces b-cell apoptosis
in other animal models of diabetes. The Troglitazone in Prevention of Diabetes (TRIPOD)
study is a landmark investigation into the potential of pharmacological intervention for
the preservation of b-cell function. There was a 55% reduction in the incidence of diabetes in Hispanic women with a history of gestational diabetes treated with Troglitazone.
The women who did not progress to diabetes during the study were also protected from
diabetes after the drug was discontinued.
Inhibitors of Nuclear Factor-Kappa B

NF- Kappa B is an intracellular master regulator of inflammation and programmed cell
death. In most cell types, NF- Kappa B protects against apoptosis, but many in vitro studies
indicate a pro-apoptotic role for NF- Kappa B activation upon exposure to inflammatory
cytokines in b cells.
Future Pharmacological Targets for Expansion of -cell Mass

Interestingly GLP-1 receptor signaling has the potential to expand b-cell mass. In rodents,
GLP-1 receptor signaling increases the expression of key transcription factors such as
Pancreatic Homeodomain Protein (PDX)-1, increases b-cell mass by both islet neogenesis
and b-cell proliferation and stimulates differentiation of putative precursor duct cells
into a b-cell phenotype. Epidermal Growth Factor (EGF) receptor signaling has also been
identified as a significant mechanism in the modulation of b-cell mass. EGF and other
EGF receptor ligands such as betacellulin and TGF- a increase b-cell differentiation and
proliferation, particularly the proliferation of ductal progenitor cells.
Gastrin also stimulates islet neogenesis, and a combination of gastrin- and EGF- receptor
signaling increases b-cell mass. This has led to the development of an EGF analog and a
gastrin analog that are currently being investigated in patients with T2DM.
Thyrotropin Releasing Hormone (TRH) has also been found in the b-cell of the pancreas
co-localised with insulin. TRH may have a physiologic role in the regulation of carbohydrate metabolism. TRH is capable of reversing diabetes in an experimental animal model,
by promoting neogenesis of b cells through induction of adult stem cells in the pancreas
pointing to a potential therapeutic role for TRH in the treatment of diabetes.
Priorities in the treatment of T2DM remain lifestyle changes and pharmacological intervention to minimize the hostile metabolic and inflammatory environment for human b cells
and the consequent progressive impairment in insulin secretion. If substantial weight-loss
and reduced insulin resistance following lifestyle changes or bariatric surgery are a therapeutic option, normoglycemia could be achieved if an adequate b-cell mass is still present. However, if b-cell mass is below the threshold for normoglycemia, the expansion of
b-cell mass is the only option for achieving normoglycemia without the use of additional
glucose-lowering strategies.
Type1 Diabetes : Prediction and Prevention

Type 1 Diabetes Mellitus (T1DM) results, from the autoimmune destruction of beta cells. T
cell mediated b cell injury results in the release of antigens with the production of numerous antibodies, including Islet Cell Antibodies (ICA), insulin autoantibodies, Glutamic Acid
Dehydrogenase (GAD) antibodies, and antibodies against tyrosine phosphatase. Complex
interactions between genetic susceptibility and environment influence the immunological
compartment during the prodromal period, leading in some individuals to overt immunological abnormalities, including occurrence of autoantibodies and islet-reactive T cells.
These antibodies are not causative but are useful in the prediction of diabetes because
they can be detected years before symptoms develop. Recent research has helped to define
the prediabetes phase.
Antigen-Specific Immunotherapy
As T1DM results from the failure to maintain tolerance to auto-antigens, targeting them
through antigen-specific therapies should provide effective means of controlling the autoimmune process by inducing tolerance and also avoid the unwanted side effects associated
with non-specific immunosuppression. The rationale behind administration of auto antigen
in a tolerogenic regimen is induction of protective immunity by generation
of antigen-specific regulatory T cells (Tregs), which act by releasing inhibitory cytokines eg
interleukin (IL)-10, IL-4], by induction of anergy/deletion of autoreactive effector T cells
and possibly by deviation of their phenotype towards a nonpathogenic one.
Current and Future Strategies for Preservation of Beta Cells
287
Restoration of pancreatic -cell mass

The clinical significance of any interventional therapy for T1DM relies on its ability to
maintain, or even increase pancreatic b cell mass and function up to the point of insulin
independence. Because at the time of clinical diagnosis a significant proportion
of the b-cell mass has been destroyed (although there may be less than has been appreciated because of the dysfunctional islets), restoration of -cell mass should be attempted
along with methods of immune tolerance; this can be accomplished by b-cell regeneration
or substitution.
Beta-cell regeneration
It has been suggested that, in the absence of the autoimmune process that causes cell
death, b-cell regeneration is achievable mostly by releasing b-cells from glucose toxicity
and oxidative stress and by using regeneration-compatible drugs, that is by substitution
of steroids and cyclosporine (and probably also sirolimus and tacrolimus) with agents that
seem unlikely to interfere with b-cell proliferation (such as anti-CD3, anti-CD20).
The Edmonton Protocol (currently accepted as important guidelines for islet cell transplantation) uses a cyclosporin- and steroid-free immunosuppressive regimen; the reported
5-year insulin independent rate is less than 10%. C-peptide secretion, however was maintained in 80% of the patients up to 5 years post-islet transplantation and that the hypoglycaemic score, lability index and HbA1c improved significantly in those who retained
detectable C-peptide.
288
Advantages and Disadvantages of new therapeutic interventions for

Type 1 diabetes
Aim of intervention :
I) Prevention of -cell loss

Type of intervention

Immune based therapy
a) Antigen specific insulin HSP60, GAD65 (and their peptides)
Advantages: Safe; Induction immunoregulatory mechanisms; Moderate clinical benefit

(preservation of C-peptide over a limited time period) in intervention trials.
Disadvantages: No/partial success in prevention trials so far.

b) Non-antigen specific Immunosuppresants
Advantages: Induce depletion/inactivation of pathogenic cells.

Disadvantages: Limited/no effect;and long term side effects.

c) Nicotinamide
Advantages: Safe; Protection against b-cell death.

Disadvantages: No efficacy for diabetes prevention.

d) Anti-CD3 mAb
Advantages: Induction of tolerance by apoptosis/anergy of activated T cells and expansion of Tregs; No chronic immunosuppression. Prevention of loss of insulin production
>1 year in intervention trials.
Disadvantages: Side effects (moderate cytokine release syndrome; transient reactivation
of EBV; potential anti-idiotypic antibodies); Reoccurrence of B-cell failure.
II) Regeneration /Restoration of -cell mass

Type of intervention :

a) Transplantation
Pancreas/islet cells
Advantages: Feasible; Improved glycaemic control; Preferable in simultaneous renal graft

(when immunosuppression is already necessary).
Disadvantages: Modest success of the procedure, continuous immunosuppression is
needed. Islet isolation proceduretechnically challenging; costly; lack of
sufficient
pancreata (multiple donors per recipient). Whole pancreas-more invasive surgery.

b) Pharmacologic agents (e.g. GLP-1 receptor agonists, DPP-4 inhibitors)
Advantages: Approved for Type 2 diabetes therapy; Eliminate need for

procedures; Presumably stimulates b-cell regeneration.
surgical
Disadvantages: Definite effect of -cell regeneration not yet fully evaluated;

term safety needs further evaluation.

Long-
c) Stem cells/genetic therapy
Advantages: Good potential source of surrogate insulin producing cells.

Disadvantages: Still in preclinical research phase 4.
Selective depletion of B lymphocytes with Rituximab to b preserve cell function
Rituximab - a chimeric anti-CD20 monoclonal antibody has shown promise for the treatment of autoimmune disorders. It targets an antigen present on the cell surface of mature
B cell lymphocytes. In a study of 87 patients aged 840 years with newly diagnosed T1DM
in which participants were randomly allocated to receive either Rituximab or placebo. The
primary outcome measure was the mean Area Under the Curve (AUC) for the stimulated
C-peptide response during the first 2 h of a 4 h mixed-meal tolerance test. Secondary
outcome measures included the HbA1c level, insulin dose and rate of infusion-related adverse effects. The mean AUC for the level of C-peptide at year 1 was around 20% higher
in the group that received rituximab than in the control group.
Treatment with Rituximab was also associated with higher absolute levels of C-peptide at
3, 6 and 12 months after the first infusion. The decline in the C-peptide levels detected
during follow-up was reduced in the rituximab group (37.7% versus 55.8% in the placebo group). Treatment with Rituximab was also associated with lower HbA1c levels and
exogenous insulin requirements than were observed after infusion with placebo. Adverse
events after the first infusion were more common among patients in the rituximab group
than in the placebo group (93% versus 23%, respectively). The results of this study sugCurrent and Future Strategies for Preservation of Beta Cells
289
gest that selective depletion of B lymphocytes can preserve -cell function in patients
with new-onset T1DM.
T1DM is a heterogeneous disease with an age at onset spanning from childhood to adult
age. Therefore, interventions to protect or regenerate b-cell function may vary depending
on the age of onset of the disease and the extent of pancreatic b-cell damage. It is likely
that in most cases a rationally designed combination approach with immunotherapeutic
methods which target suppression of pathogenic autoreactivity and induction of immunoregulatory pathways coupled with islet regeneration will prove to be most effective.
References
1.
De Koning Eelco JP, Bonner-Weir S, Rabelink TJ. Preservation of b-cell function by targeting -cell mass.
Trends in Pharmacological Sciences 2008; 29: 218-27.
2.
Luo L-G, Jackson I. Thyrotropin Releasing Hormone may preserve pancreatic islet cell function: potential
role in the treatment of diabetes mellitus. Acta Biomed 2007; 78: Suppl 1: 216-21.
3.
deFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2
diabetes mellitus. Diabetes 2009; 58: 773-95.
4.
Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, Defronzo RA. Thiazolidinediones improve b-cell
function in type 2 diabetic patients. Am J Physiol Endocrinol Metab 2007 292: E871-83.
5.
Cernia S, Pozzilli P. New potential treatments for protection of pancreatic -cell function in type 1 diabetes.
Diabetic Medicine 2008; 25: 1259-67.
6.
Razack NN, Wherrett DK. Type 1 diabetes: New horizons in prediction and prevention. Paedtr Child Health
2005; 10(1): 35-7.
7.
Pescovitz, M. D. et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl.
J Med 2009; 361: 2143-52.
290
Therapeutic Approaches in T2DM:

Whats in the Offing?
Dr M Shunmugavelu
Specialist in Internal Medicine & Diabetologist

Chairman, Trichy Diabetes Speciality Centre (P) Ltd.,
Trichy.
Ph: 98431 78131
e-mail: msv_diabesity@sify.com
Therapeutic Approaches in T2DM: Whats in the Offing?
291
Introduction
Type 2 Diabetes Mellitus has become world wide epidemic with anticipated increases in
prevalence in Asian Sub continent. Indians are more prone to develop diabetes and its
complication at a younger age group. Uncontrolled hyperglycaemia is a global problem.
Consequently, the burden of uncontrolled diabetes in India is high.
Type 2 Diabetes is a chronic progressive disease and is often diagnosed late; as a result,
patients are exposed to detrimental effects of hyperglycaemia for a longer period. Getting the patients to goal becomes challenging as the disease progresses with the available
agents. As new concept emerges, there is a potential for new treatment modalities. Thus
the quest to develop therapeutic agents with novel mechanisms of action continues.
Pathogenesis of Type 2 Diabetes

Type 2 diabetes is a chronic progressive disease characterized by continued worsening
-cell failure and target glycaemic levels are not maintained long term.
Mechanism giving rise to hyperglycaemia of type 2 diabetes has been shown in the following illustration
292
Picture 1: Pathogenesis of Hyperglycemia
Type 2 Diabetes is a heterogeneous disorder, the various causes contributing to insulin

resistance are primary predisposing factors namely genetic influence, adverse intrauterine
environment, secondary precipitating factors like obesity, low physical activity, age, smoking, sleep disturbance and tertiary accelerating factors namely glucolipotoxicity. Insulin
resistance precedes, several years before the onset of type 2 diabetes. At diagnosis, nearly
40% of insulin sensitivity has already been lost. Thereafter insulin resistance remains stable
and constant for long time.
Both insulin resistance and -cell dysfunction are present at the time of diagnosis of type
2 diabetes. -cell failure occurs much earlier in the natural history of type 2 diabetes
and is more severe than previously appreciated. At diagnosis, there has been 50% loss
of functional -cell resulting from age, gene polymorphism (TCF 7L2), insulin resistance,
lipotoxicity, glucose toxicity, amyloid deposition and diminished incretin effect.
-cell mass is maintained by continual birth and death of cells by neogenesis and apoptosis. Loss of -cell function and glucagon over secretion both play key roles in type 2
diabetes development. Progressive -cell decline is coupled with inadequate insulin secretion. Glucagon is not suppressed during the postprandial period. Meal-related insulin
and glucagon dynamics are abnormal in type 2 diabetes. Hepatic glucose production is
increased during the fasting period and is not suppressed during the postprandial period.
GLP-1 and GIP are the major incretin gut hormones released in response to food ingestion. The incretin effect is diminished in type 2 diabetes. GLP-1 and GIP enhance insulin
secretion from -cells in a glucose dependent manner. GLP-1 suppresses glucagon released
from -cells, in a glucose dependent manner.
Sodium-glucose cotransporter 2 (SGLT2), plays a role in renal glucose reabsorption in
proximal tubule. Renal glucose reabsorption is increased in type 2 diabetes. Selective inhibition of SGLT2 increases urinary glucose excretion; thereby it helps to reduce blood glucose.
Studies in subjects with obesity and type 2 diabetes have shown that there is an alteration
in dopaminergic tone in hypothalamus resulting in alterations in neural activities, overstimulation of hepatic glucose production, adipose lipolysis, and peripheral insulin resistance
in the post meal state. This hypothalamic alteration potentiates circulating glucose, free
fatty acids and triglycerides and contributes to IR in liver, muscle and cell dysfunction
via lipotoxicity and glucose toxicity.
Unmet Needs in the Management of Type 2 Diabetes Mellitus

Currently numerous antihyperglycaemic agents are available but, still there is a need.
Picture 2: Unmet Needs in the Management of Type 2 Diabetes

The two most important unmet needs in the present management of type 2 diabetes mellitus are the ability of an agent to exhibit prolonged efficacy in reducing hyperglycaemia and
to be disease modifying i.e. to target the underlying cause rather than its symptoms.
293
Initial therapy with OAD can be effective at achieving glycaemic control. However this
reduction may not be enough for patients with longer duration of diabetes whose A1C
is greater than the recommended targets. In addition, even if good glycaemic control is
achieved many agents failed to maintain their anti hyperglycaemic effect over a prolonged
period as the disease progresses. Wide glycaemic fluctuations may persist despite treatment and this is one of the major contributing factors driving, combination therapy and
the need for switches between different drug classes.
No single available antidiabetic agent addresses all of the underlying pathophysiologic
mechanisms. No agent has yet been shown to yield sustainable HbA1c reductions.
Criteria for an Ideal Antidiabetic Agent
Picture 3: An Ideal OAD?
294
1. It should target underlying causes of type 2 diabetes namely insulin resistance, -cell
dysfunction.
2. It should control fasting and PP hyperglycaemia without producing hyperinsulinaemia,
weight gain and hypoglycaemia.
3. It should be effective in once a day dosing.
4. It should not interact with other drugs.
5. It should preserve -cell function.
Oral Antidiabetic Agents Currently Available
Oral therapy for type 2 diabetes mellitus when used appropriately can safely assist patients
to achieve glycaemic targets in the short to medium term. However, the progressive nature
of type 2 diabetes mellitus usually requires two or more oral agents in the long term, often
as a prelude to insulin therapy. Moreover, the impact of different drugs, even within a
single class, on the risk of vascular complications has come under scrutiny.
Several new drugs with glucose lowering efficacy that may offer certain advantages have
recently become available.
Metformin
Is the only Biguanide currently in use. The principal action is to reduce hepatic glucose
production and also to improve insulin stimulated glucose utilization. Recently, the enzyme
adenosine- 5 monophosphate activated proteinkinase (AMPK) has been identified as a

target of the drug. AMP regulates and coordinates cellular glucose and lipid metabolism.
Metformin may also suppress inflammation independently of actions on glucose or fatty
acids. Metformin is now widely regarded as the foundation of oral therapy for most
patients with type 2 diabetes mellitus. In UKPDS, the drug was unique in significantly
reducing myocardial infarction and diabetes related deaths in patients who were randomized initially to the drug as monotherapy. Several studies have shown Metformin to be
associated with a lower risk of cancer than insulin or SU, the antitumor effect of Metformin
seems to be mediated via AMPK signaling pathway, activity also leads to an inhibition of
the downstream mammalian target of Rapamycin complex (mTOR ). Metformin restores
both the metabolic defect and generation of memory T cells.
Metformin is widely used in women with PCOS and its proposed effect on ovulation and
androgen levels is assumed to be due to the effect on insulin sensitivity. It has also been
suggested that Metformin increases plasma concentrations of GLP-1 and GIP both by increasing GLP-1 biosynthesis and secretion and also by inhibiting DPP-4, thereby inhibiting
the GLP-1 degradation.
Metformin improves C-peptide Resistance in Patients with T2DM.
Rapid Acting Insulin Secretagogues

Rapid acting, prandial insulin releasers Nateglinide, Repaglinide stimulate rapid but short
lived insulin secretion and are conveniently taken immediately prior to a meal. These
agents lower postprandial glucose levels although fasting hyperglycaemia is also improved
to some extent with Repaglinide. They are appreciably more expensive and clinical experience remains limited. These drugs can be useful with mild to moderate renal impairment
and for individuals with varying daily meal pattern.
Sulphonylureas
SUs have been extensively used for the treatment for half a century. These agents lower
blood glucose levels primarily by stimulating insulin secretion from the cells of the pancreatic islets. They are regarded as particularly suitable first line drugs when used early
following diagnosis. However because they have the potential to stimulate insulin release
at low glucose levels and inhibit hepatic glucose production, they can cause hypoglycaemia. Weight gain is regarded as a class effect. Concern about the cardiovascular safety
of some sulfonylureas persists.
Glibenclamide
It is a 2nd generation sulfonylurea which binds to the 140kda receptor on the cell. Therapy
has been associated with more weight gain, prolonged action at receptor sites and greater
risk of hypoglycaemia (because of higher C-peptide levels causing more insulin release from
cells). It inhibits ischemic preconditioning of the myocardium.
Glipizide
Glipizide is a potent, easily absorbed, rapid acting, second generation SU with a shortest
effect duration in its class. It is effective in reducing postprandial glucose levels.
295
Gliclazide
It has the SU nucleus and side chain ring. Azabicyclooctyl ring is unique to this molecule.
It possesses high affinity for the pancreatic sulfonylurea receptor. However, Gliclazide demonstrates rapidly reversible binding to the -cell sulfonylurea receptor, the free reversibility
of Gliclazide cell receptor binding is likely to contribute both to very low hypoglycaemia
and secondary failure rates and to weight neutrality.
Glimepiride
It is the first representative of third generation. This agent demonstrates numerous cardio
protective features. It is a long acting drug that augments insulin secretion by mechanism
involving inhibition of K+ATP channels in pancreatic cells and appears to increase insulin
sensitivity due to the extra pancreatic activity. It has a lower binding affinity and causes
less insulin release but produces a more rapid and pronounced blood glucose lowering
activity. It stimulates insulin mediated glucose utilization in hepatocytes, skeletal muscles
and adipocytes. Several studies have endorsed the cardiovascular safety of Glimepiride.
Alpha Glucosidase Inhibitor
296
This, class of agents bind reversibly, competitively and in a dose dependent manner to the
oligosaccharide binding site of glucosidase enzymes in the brush border of the small
intestinal mucosa. As a consequence, hydrolysis is prevented. The drug delays the intestinal
hydrolysis of oligo and disaccharides by -glucosidases, mainly in the upper half of the
small intestine. Consequently, the absorption of monosaccharides after a meal is delayed
and transport through the mucosal surfaces into the circulation is interrupted. The suppression of glucosidase is reversible, although pharmacological activity is reliable and
persistent with long-term use.
Acarbose
Acarbose is a pseudotetrasaccharide, a natural microbial product derived from culture
broths of Actinoplanes strain SE 50. Acarbose has no direct effect on the absorption of
glucose. Acarbose significantly lowers postprandial blood glucose. The beneficial effect of
Acarbose on fasting plasma glucose is probably potentiated by an increased late rise in
GLP-1.
Acarbose treatment caused a decrease in proinsulin / insulin ratio and a significant (p <
0.05) increase in insulin sensitivity, probably based on lowering fasting and postprandial
hyperglycaemia and decreasing glucose toxicity. Treatment with Acarbose is associated
with several changes in lipid profile.
Acarbose has a favourable therapeutic profile for the long-term treatment of patients
with type 2 diabetes and liver cirrhosis. The drug has been reported to lower levels of
hydroxybutyrate significantly (p < 0.01), and to reduce hyperammonaemia and gut pH.
Acarbose treatment may be associated with a reduction in the risk of colon carcinogenesis.
Flatulence, abdominal distension, diarrhea and borborygmus, meteorism, caused by fermentation of unabsorbed carbohydrates in the large bowel, are the most frequent adverse
effects of Acarbose. Slow titration from a low dosage to the maintenance dosage is recommended. Acarbose use is appropriate in elderly patients.
Miglitol
Miglitol decreases the postprandial glucose excursion, insulin, C-peptide levels and insulin
resistance indirectly by reducing both PPG and postprandial insulin levels. It also reduces
fasting triglyceride levels. It can be safely combined with Metformin, sulfonylureas and
insulin. It does not cause increase in serum transaminases. It does not cause drug interaction and tends to have lower GI tract disturbances.
Voglibose
It exerts competitive dose dependent inhibition of glucosidase enzymes, in the small
intestine. It has a wide range of therapeutic and pharmacological properties. Treatment,
results in a significant decline of triglyceride level and an elevation of HDL cholesterol
and apolipoprotein A-1. It also decreases significantly the plasma levels of intracellular
adhesion molecules and reduces oxidative stress.
Thiazolidinediones
Novel class of antidiabetic agents that directly reduce insulin resistance at sites of insulin
action, activate novel nuclear receptor, modify a key pathophysiologic defect in type 2
diabetes.
It improves cell function, elicits effective, safe glycaemic control and may exert favourable cardiovascular effects independent of glycaemic control.
Stimulation of PPAR- promotes differentiation of preadipocytes with effects on lipogenesis
that promote the local effects of insulin. The combination of TZD + Insulin can improve
glycaemic control although troublesome oedema has been reported. Some studies of TZD
have provided the data that have been interpreted as evidence of improved cell function so called triple therapy i.e SU + Metformin + TZD can be an effective alternative to
insulin therapy.
Picture 4: Actions of Thiazolidinediones
297
Actions of Thiazolidinediones
It reduces Inflammation by inhibiting the effects of TNF-, NF-KB, ICAM, VCAM expression,
small denseLDL, alters the fibrinolytic pathway and decreases the excretion of microalbumin in urine.
It also decreases carotid intima-media thickness and inflammation, blood pressure and
induces coronary artery relaxation by decreasing cytosolic calcium and its influx, vascular
smooth muscle cell migration.
It increases adiponectin, decreases CRP levels and improves endothelial function. Adverse
effects are related to fluid retention and fat redistribution and include weight gain, peripheral edema, and anemia and heart failure. The cardiovascular benefit risk ratio of
the individual TZD is not entirely clear. Controversy exists over the apparent increase in
cardiovascular risk.
DPP-4 Inhibitor
It is known that blood glucose is a key regulator of serum insulin levels. A greater amount
of insulin is secreted after an oral glucose load as compared to an equivalent amount of
glucose given IV. Incretins are gut-derived factors that increase glucose-stimulated insulin
secretion. It is released from the intestine in response to ingestion of food, particularly
glucose. The release of insulin in response to physiological levels of the hormone occurs
only when glucose levels are elevated.
298
GLP-1 and GIP are two important incretin hormones. Both are released in response to
the ingestion of food, increase the release of Insulin in response to a meal and responsible
for about 60% of the insulin that is normally released after meals. It inhibits glucagon
secretion, reduces gastric emptying, induces satiety, improves insulin sensitivity, the cell
mass and function. It has established pancreatic and extra pancreatic effects.
DPP-4 is a glycoprotein that contains 766 aminoacids; large part of the molecule that
lies outside the cell inactivates incretins. High concentrations are present in the kidneys,
lungs, adrenal glands, small intestine and liver.
Half-Lives of GLP-1 and GIP are short as incretins are quickly inactivated immediately
upon synthesis by DPP-4 enzyme. Inhibition of DPP-4 increases the levels of active GLP-1.
Sitagliptin
Sitagliptin 100mg once daily is indicated as an adjunct to diet and exercise to improve
glycaemic control in patients with T2DM. It can be used in combination with Metformin
and SU or TZD. It has a neutral effect on body weight.
Vildagliptin
It is approved for use in combination with Metformin or SU or TZD. Fonseca et al. explored
the effect of adding Vildagliptin to insulin therapy in a multicentered study.
Saxagliptin
Saxagliptin is indicated as an adjunct to diet and exercise to improve glycaemic control in
adults with type 2 diabetes mellitus. It improves glycaemic control by significantly reducing
A1C and its key contributors - FPG & PPG. A lower dose of the insulin secretagogue may be
required to reduce the risk of hypoglycaemia when used in combination with Saxagliptin.
It should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor.
GLP-1 Mimetic / Analogues

Exenatide
It is isolated from the venom of the Gila-Monster, a lizard native to Mexco. It is delivered
by twice daily subcutaneous injection for patients with T2 DM with inadequate glycaemic
control who are taking Metformin, SU, TZD, combination of Metformin and SU. Control
of blood glucose is evident for 6-8 hrs. The potential for GI adverse effects should be
explained.
Liraglutide
Another, novel GLP-1 receptor agonist a modified GLP-1 sequence that confers an affinity
to albumin resulting in an extended plasma half life of 10-14 hrs. It is suitable for administration by once daily injection; the avoidance of peaks of plasma drug concentration
appears to attenuate the GI adverse effect.
Alternate Routes of Insulin Delivery

Frequent injections of insulin may increase resistance to acceptance of insulin therapy.
Insulin therapy is likely to change within the next decade. Inhalation of insulin offers
an alternative regimen. Buccal insulin also shows promise. Oral insulin therapy is in a
nascent phase but holds promise. Nasal and dermal insulin formulations are also being
experimented with.
Pulmonary Insulin
To date, the most promising alternative route of insulin administration is the pulmonary
delivery of insulin by inhalation, which is likely to lead to a practically usable system
within the next few years. For maximal rate of absorption, insulin must be applied deep
into the lung, i.e. into the alveoli. The pharmacodynamic effects of insulin formulations
administered via the lung are comparable to, or even faster than, those of subcutaneous
injected regular insulin or rapid-acting insulin analogues. The dose of insulin administered
must be 10-fold higher than with subcutaneous injection. The published results of clinical trials thus far, indicate that metabolic control is comparable to that of conventional
insulin therapy and no serious side effects have been reported.
Inhalation of regular insulin for meal time glucose control has been found to be safe,
efficacious and reliable in both type 1 and type 2 diabetics. A potential advantage of
aerosol insulin is that it is more rapidly absorbed and cleared than SC injection, which
provides a more relevant and convenient therapy for meal time glucose control.
Early clinical trials showed that taking inhaled insulin before meals was as safe and effective as injection, with greater patient satisfaction. Inhalers presently use only rapid-acting
insulin to be taken before meals; longer acting insulin formulations are under development.
The common problems with inhaled insulin are higher frequency of development of antibodies against insulin, lung irritation, cough and low bioavailability.
299
Technosphere insulin particles appear to be the most rapidly absorbed with 30% - 40%
bioactivity and are composed of regular insulin loaded into a diketopiperazine, molecule
which dissolves rapidly providing for rapid insulin absorption from the lungs. Technosphere,
particles are absorbed within 15mts with an onset of action of 25 30 mts and has a
duration of action of 2 3 hrs. Cigarette smoking leads to more rapid and greater degree
of absorption. There is some decrease in absorption with asthma.
Long term safety of inhaled insulin needs to be established. All subjects need a bed time
dose of injectable long or intermediate acting insulin for proper control of diabetes.
Nasal Insulin
Insulin is absorbed rapidly across the nasal mucosa. However, the bioavailability is low and
requires the use of absorption enhancers and more importantly the metabolic effect lasts
too short to be of clinical usefulness. Use of nasally administered insulin has been tested
but so far results have been discouraging. Other problems associated with nasal insulin
include irritation of the nasal passages and upper respiratory tract infections.
Oral Insulin
Insulin is degraded very quickly by the stomach acidic environment and proteolytic enzymes. Researchers are currently examining whether insulin absorbed into a microsphere
can bypass these enzymes and pass through the wall of the intestine.
Buccal Insulin
300
Several trials are testing an insulin preparation that is placed under the tongue or in
between the cheek and gum and is slowly absorbed. An insulin (Oralin) spray which can
be delivered via the companys Rapid Mist device is under development. It was concluded
that Oralin can be used safely in combination with oral hypoglycaemic agents to control postprandial glucose levels. Oralin spray at meals produced insulin peaks significantly
greater than endogenous insulin production in patients receiving oral agents and less
postprandial glucose elevation.
Insulin Patches
Dermal insulin application does not result in reproducible and sufficient transfer of insulin
across the highly efficient skin barrier. Attempts have been made to develop dermal patches
to be placed on the skin to provide a continuous low level of insulin supplemented by
pre-meal doses that are released by pulling a tab. However, insulin is poorly absorbed
through the skin and to date this method has been proved inefficient.
Conclusion
The incidence of type 2 diabetes mellitus continues to increase as does our challenge to
manage this chronic condition. Understanding of the pathophysiology of type 2 diabetes
is an evolving process. Exciting new therapies become available and have provided us
ever increasing treatment options to assist in effectively managing this condition. But it
is unknown whether they will have an impact on the course of the disease or alter the
micro and macrovascular consequences of uncontrolled diabetes. Optimal management of
type 2 diabetes requires a multi faceted approach the targets multiple defects in glucose
homeostasis.
References
1.
Diabetes Spectrum Vol.22; No.2; 2009
2.
Clin Drug Invest 2002; 22 (3): 141-156, 1173-2563/02/0003-0141/$25.00/0
3.
INT. J. DIAB. DEV. COUNTRIES (2002), VOL. 22
4.
Pharmaceutical Research, Vol. 24, No. 7, July 2007 (# 2007), DOI: 10.1007/s11095-007-9256-x
5.
Diabetes Care 33:12241229, 2010
6.
J. Clin. Endocrinol. Metab. 2009 94:603-608 originally published online Dec 2, 2008; doi: 10.1210/jc.20081731
7.
SA Pharmaceutical Journal July 2010
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Prescriber 5 March 2010
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Diabetes Care 29:510514, 2006
10. J. Clin. Endocrinol. Metab. 2003 88: 5248-5254, doi: 10.1210/jc.2003-030649

11. Expert Opin. Pharmacother. (2010) 11(2): 269-279
12. J Am Soc Nephrol 14: 2873-2882, 2003
13. Diabetes Care 33: 1224-1229, 2010
14. Metabolism Clinical and Experimental Vol.58; No.5; May 2009
15. J Diabetes Complications. 2000;14:192-196.
16. Diabetes. Res Clin Prac. 1992;18:197-206
17. International Diabetes Center, Minneapolis, MN.
18. Diabetes Care; 2000; 23; 1703
19. American Journal of Medicine 2005; 118, 205-211
301

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Diabetes Care in India

Today and by 2025?

MD (AIIMS)., FICA., FICP., FIMSA., FICC

MICRO LABS LIMITED

Diabetes Care in India Today... and by 2025?

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Diabetes Care in India Today... and by 2025?

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Diabetes Care in India Today... and by 2025?

Mrs Kamlesh Sethi,

Diabetes Care in India Today... and by 2025?

Dr Samith A Shetty, MBBS., MDRC

Dr Sunil Gupta, MD., FIAMS., FIACM., FICP.,

Diabetes Care in India Today... and by 2025?

Translational Research in India: Today

Type 2 Diabetes: The Present International Classification

Dr Viswanathan Mohan, Chennai

Problems Of Obesity In Type 2 Diabetes

Dr Anil Bhansali, Chandigarh

DIAGNOSIS AND MONITORING

Self Monitoring of Blood Glucose:

Dr Jay Deshmukh, Nagpur

Diabetes Care in India Today... and by 2025?

Burden of CV Disease in T2DM

Management of Hypertension in Diabetes:

Antiplatelet Agents in T2DM

Diabetes and Angiogenesis

Recent Trends & Future Perspectives

Diabetic Retinopathy: With Special Reference

Diabetic Kidney Disease: Clinical Manifestation,

Neuropsychiatric Screening In T2DM

Gestational Diabetes: Screening and Treatment

Management of Women with Pre-existing

Dr Banshi Saboo, Ahmedabad

Dr Subhankar Chowdhury, Kolkata

Dr Vijay Viswanathan, Chennai

Dr Sunil Gupta, Nagpur

Diabetes Care in India Today... and by 2025?

LIFE STYLE MODIFICATION & PHARMACOTHERAPY

Yoga & Meditation in The Prevention of Type 2 Diabetes

Diabetes Care in a Hospital Setup

Mrs Kamlesh Sethi, New Delhi

EDUCATION & COUNSELLING

Dr K M Prasanna Kumar, Bangalore

T2DM Education for the Urban and

Education In Diabetic Foot Care

Dr Apurba Kumar Mukherjee, Kolkata

Information Technology and Diabetes:

Dr Ashok Kumar Das, Puducherry

Dr Shashank R Joshi, Mumbai

Diabetes Care in India Today... and by 2025?

Current and Future Strategies for

Therapeutic Approaches In T2DM: Whats in the Offing?

Dr Sarita Bajaj, Allahabad

Diabetes Care in India Today... and by 2025?

Burden of Type 2 Diabetes in India:

President India Diabetes Research Foundation &

Burden of Type 2 Diabetes in India: