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CHAPTER-1

INTRODUCTION

Diabetes is a metabolic disorder that is characterized by high blood glucose

and either insufficient or ineffective insulin. 5.9% of the population in the United
States has diabetes, and diabetes is the seventh leading cause of death in our
country. Diabetes is a chronic disease without a cure; however, with proper
management and treatment, diabetics can live normal, healthy lives .

Type I Diabetes

Insulin-dependant is caused by damage to the pancreas. The pancreas contains beta

cells, which make insulin. With Type I diabetes, the deficiency of insulin is due to a
decline in the number of beta cells the pancreas contains. It appears that certain genes
make Type I diabetics more susceptible, but a triggering factor (usually a viral
infection) sets it off. In most people with Type I diabetes, the immune system makes a
mistake, attacking the beta cells and causing them to die. Without the beta cells, you
cannot produce insulin. Glucose then builds up in the blood and causes diabetes.

Type II Diabetes
Type II diabetes is the most common form of diabetes, with about 90% of diabetes
falling into the Type II category. With Type II diabetes, glucose builds up in the blood
– not because not enough insulin is present, but probably because cells lose their insulin
receptors and become less sensitive to insulin. Type II diabetes usually (though not
always) occurs in individuals who are over 40 years of age who are overweight.

Type II diabetes produces mild symptoms, and can be controlled with a healthy diet,
exercise and weight loss. Type II diabetics should also monitor their glucose levels to
be sure they are maintaining healthy levels. In some cases, weight loss, diet and
exercise are not enough to control the glucose levels. In those cases, your physician
may control your diabetes by prescribing diabetes pills or insulin shots.

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CHAPTER-2

Literature review

1. Introduction
Diabetes mellitus (DM) is probably one of the oldest diseases known to man. It was
first reported in Egyptian manuscript about 3000 years ago.

1 In 1936, the distinction between type 1 and type 2 DM was clearly made.

2 Type 2 DM was first described as a component of metabolic syndrome in 1988.3Type

2 DM (formerly known as non-insulin dependent DM) is the most common form of
DM characterized by hyperglycemia, insulin resistance, and relative insulin deficiency.

3 Type 2 DM results from interaction between genetic, environmental and behavioral

risk factors.5,6

People living with type 2 DM are more vulnerable to various forms of both short- and
long-term complications, which often lead to their premature death. This tendency of
increased morbidity and mortality is seen in patients with type 2 DM because of the
commonness of this type of DM, its insidious onset and late recognition, especially in
resource-poor developing countries like Africa.

Mechanism

The prevalence of diabetes is rapidly rising all over the globe at an alarming rate. Over
the last three decades, the status of diabetes has been changed, earlier it was considered
as a mild disorder of the elderly people. Now it becomes a major cause of morbidity
and mortality affecting the youth and middle aged people. According to the Diabetes
Atlas 2006 published by the International Diabetes Federation, the number of people
with diabetes in India currently around 40.9 million is expected to rise to 69.9 million
by 2025 unless urgent preventive steps are taken. The main force of the epidemic of
diabetes is the rapid epidemiological transition associated with changes in dietary
patterns and decreased physical activity as evident from the higher prevalence of
diabetes in the urban population. The most disturbing trend is the shift in age of onset
of diabetes to a younger age in the recent years. This could have long lasting adverse

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effects on nation’s health and economy. Therefore, it is necessary to identify the
diabetic patients at the earliest and provide appropriate lifestyle intervention in
preventing or postponing the onset of diabetes. In the present review, detailed
mechanism and management of the diabetes have been emphasized.

2. History of diabetes

Diabetes was considered a disease of the wealthy in ancient India, and was known
as Madhumeha (sweet urine disease); it was observed that ants were attracted to the
urine. The ancient Greeks coined the term "diabetes", meaning excessive urination with
dehydration, but neither they nor the Romans appreciated that the urine contained
sugar; "diabetes" was considered a kidney disease until the 18th century.
The sweet taste of the urine was known to Avicenna (~1000 AD) and to Thomas
Willis in the 17th century. The sweet taste was known to be due to glucose by the start
of the 19th century, and raised glucose in the blood was recognised soon afterwards.
The modern era was heralded by the discovery of Oskar Minkowski that removal of the
pancreas resulted in diabetes, followed by the discovery of insulin in 1921-22.
The herbalists of the Middle Ages already knew the beneficial effects of the
herb Galega officinalis, which ultimately led to the discovery of metformin.
Likewise, Claude Bernard with his 'piqûrediabetique' already suspected that the brain
was somehow involved in the causation of diabetes, a topic that continues to attract
research attention today. These examples show that many people have made the same
observations and considered the same hypotheses at widely differing times, and that
valuable findings are sometimes obscured by the fogs of time.

Epidemiology

IDF is the global reference for accurate, up-to-date estimates of the prevalence of
diabetes and its burden on individuals and health economies. Our prevention
initiatives aim to help stem the ever increasing incidence of type 2 diabetes and
promote specific models of care and resources to support optimal management of
people with diabetes.

The IDF Diabetes Atlas is the authoritative resource on the global burden of
diabetes. First published in 2000, it is produced by IDF in collaboration with experts
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from around the world and contains data on diabetes cases, prevalence, mortality
and expenditure on the global, regional and national level. A full IDF Diabetes
Atlas report is produced every two years. The next edition of the IDF Diabetes Atlas
will be published in November 2017.

IDF BRIDGES (Bringing Research in Diabetes to Global Environments and

Systems) is an International Diabetes Federation programme, supported by an
educational grant from Lilly Diabetes. IDF BRIDGES funds translational research
projects in primary and secondary prevention of diabetes to provide the opportunity
to ‘translate’ lessons learned from clinical research to those who can benefit most:
people affected by diabetes.

Type 1 Diabetes Risk Factors

There are several risk factors that may make it more likely that you’ll develop type 1
diabetes—if you have the genetic marker that makes you susceptible to diabetes. That
genetic marker is located on chromosome 6, and it’s an HLA (human leukocyte
antigen) complex. Several HLA complexes have been connected to type 1 diabetes, and
if you have one or more of those, you may develop type 1. (However, having the
necessary HLA complex is not a guarantee that you will develop diabetes; in fact, less
than 10% of people with the “right” complex(es) actually develop type 1.)
Other risk factors for type 1 diabetes include:

 Viral infections: Researchers have found that certain viruses may trigger the
development of type 1 diabetes by causing the immune system to turn against the
body—instead of helping it fight infection and sickness. Viruses that are believed to
trigger type 1 include: German measles, coxsackie, and mumps.
 Race/ethnicity: Certain ethnicities have a higher rate of type 1 diabetes. In the United
States, Caucasians seem to be more susceptible to type 1 than African-Americans and
Hispanic-Americans. Chinese people have a lower risk of developing type 1, as do
people in South America.
 Geography: It seems that people who live in northern climates are at a higher risk for
developing type 1 diabetes. It’s been suggested that people who live in northern
countries are indoors more (especially in the winter), and that means that they’re in
closer proximity to each other—potentially leading to more viral infections.

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Conversely, people who live in southern climates—such as South America—are less

likely to develop type 1. And along the same lines, researchers have noticed that more
cases are diagnosed in the winter in northern countries; the diagnosis rate goes down in
the summer.
 Family history: Since type 1 diabetes involves an inherited susceptibility to developing
the disease, if a family member has (or had) type 1, you are at a higher risk.

If both parents have (or had) type 1, the likelihood of their child developing type 1 is
higher than if just one parent has (or had) diabetes. Researchers have noticed that if the
father has type 1, the risk of a child developing it as well is slightly higher than if the
mother or sibling has type 1 diabetes.
 Early diet: Researchers have suggested a slightly higher rate of type 1 diabetes in
children who were given cow’s milk at a very young age.
 Other autoimmune conditions: As explained above, type 1 diabetes is an autoimmune
condition because it causes the body’s immune system to turn against itself. There are
other autoimmune conditions that may share a similar HLA complex, and therefore,
having one of those disorders may make you more likely to develop
 type
 Other autoimmune conditions that may increase your risk for type 1 include: Graves'
disease, multiple sclerosis, and pernicious anemia.

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Signs and symptoms

Overview of the most significant symptoms of diabetes

The classic symptoms of untreated diabetes are weight loss, polyuria (increased
urination), polydipsia (increased thirst), and polyphagia (increased
hunger).[19]Symptoms may develop rapidly (weeks or months) in type 1 DM, while
they usually develop much more slowly and may be subtle or absent in type 2 DM.

Several other signs and symptoms can mark the onset of diabetes although they are not
specific to the disease. In addition to the known ones above, they include blurry vision,
headache, fatigue, slow healing of cuts, and itchy skin. Prolonged high blood glucose
can cause glucose absorption in the lens of the eye, which leads to changes in its shape,
resulting in vision changes. A number of skin rashes that can occur in diabetes are
collectively known as diabetic dermadromes.[20]

Definition and classification

When thinking about a disease, it helps to have a clear picture of what it is, and what it
isn't. And for a disease that affects hundreds of millions of people worldwide, one
would expect the definition and classification of diabetes to be fairly straightforward.
This, however, is not the case. The definition of diabetes is updated every decade or so,

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and for the classification we should still heed the words of Elliot Joslin in 1946: 'No
method for the classification of diabetics to my mind is satisfactory. ... No sooner are
the boundary lines drawn than one case after another like sheep breaks through the
fence.' This of course reflects the variation in pathogenetic mechanisms underlying the
clinical picture of diabetes.
There are in fact many possible causes of diabetes, and many factors (both genetic and
environmental) which influence development of its two main forms, known as type 1
and type 2 diabetes. This section will provide a brief overview of the ways in which
diabetes has been defined and classified

3. Epidemiology

It is estimated that 366 million people had DM in 2011; by 2030 this would have risen
to 552 million.8 The number of people with type 2 DM is increasing in every country
with 80% of people with DM living in low- and middle-income countries. DM caused
4.6 million deaths in 2011.8 It is estimated that 439 million people would have type 2
DM by the year 2030.9 The incidence of type 2 DM varies substantially from one
geographical region to the other as a result of environmental and lifestyle risk
factors.10

Literature search has shown that there are few data available on the prevalence of type
2 DM in Africa as a whole. Studies examining data trends within Africa point to
evidence of a dramatic increase in prevalence in both rural and urban setting, and
affecting both gender equally.11

The majority of the DM burden in Africa appears to be type 2 DM, with less than 10%
of DM cases being type 1 DM.11 A 2011 Centre for Disease Control and Prevention
(CDC) report estimates that DM affects about 25.8 million people in the US (7.8% of
the population) in 2010 with 90% to 95% of them being type 2 DM.12

It is predicted that the prevalence of DM in adults of which type 2 DM is becoming

prominent will increase in the next two decades and much of the increase will occur in
developing countries where the majority of patients are aged between 45 and 64
years.13 It is projected that the latter will equal or even exceed the former in
developing nations, thus culminating in a double burden as a result of the current trend
of transition from communicable to non-communicable diseases.14

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Pathophysiology
Type 2 DM is characterized by insulin insensitivity as a result of insulin resistance,
declining insulin production, and eventual pancreatic beta-cell failure.28,29 This leads
to a decrease in glucose transport into the liver, muscle cells, and fat cells. There is an
increase in the breakdown of fat with hyperglycemia. The involvement of impaired
alpha-cell function has recently been recognized in the pathophysiology of type 2
DM.30

As a result of this dysfunction, glucagon and hepatic glucose levels that rise during
fasting are not suppressed with a meal. Given inadequate levels of insulin and increased
insulin resistance, hyperglycemia results.

A majority of individuals suffering from type 2 DM are obese, with central visceral
adiposity. Therefore, the adipose tissue plays a crucial role in the pathogenesis of type 2
DM. Although the predominant theory used to explain this link is the portal/visceral
hypothesis giving a key role in elevated non-esterified fatty acid concentrations, two
new emerging theories are the ectopic fat storage syndrome (deposition of triglycerides
in muscle, liver and pancreatic cells). These two hypotheses constitute the framework
for the study of the interplay between insulin resistance and beta-cell dysfunction in
type 2 DM as well as between our obesogenic environment and DM risk in the next
decade.30

Pathophysiology

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The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in
humans during the course of a day with three meals. One of the effects of a sugar-rich
vs a starch-rich meal is highlighted.

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Treatments for Diabetes

Type 2 diabetes has a number of drug treatment options to be taken by mouth known as
oral antihyperglycemic drugs or oral hypoglycemic drugs.

Oral diabetes drugs are usually reserved for use only after lifestyle measures have been
unsuccessful in lowering glucose levels to the target of an HbA1c below 7.0%,
achieved through an average glucose reading of around 8.3-8.9 mmol/L (around 150-
160 mg/dL).1-3

The lifestyle measures that are critical to type 2 diabetes management

are diet and exercise, and these remain an important part of treatment when pills are
added.2,3

People with type 1 diabetes cannot use oral pills for treatment, and must instead
take insulin.

How do oral drugs lower glucose levels?

Metformin is the most widely used oral antihyperglycemic drug and reduces the
amount of glucose released by the liver into the bloodstream.

Oral antihyperglycemic drugs have three modes of action to reduce blood glucose
levels:3

 Secretagogues enhance insulin secretion by the pancreas

 Sensitizers increase the sensitivity of the peripheral tissues to insulin

 Inhibitors impair gastrointestinal absorption of glucose.

Each class of antihyperglycemic drug has a different adverse event or safety profile,
and side effects are the main consideration when it comes to choosing a medication.

Possible side effects range from weight gain, through gastrointestinal ones such as
diarrhea, to pancreatitis and more serious problems. Hypoglycemia is also a possible
adverse event.2

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What oral drugs are available for type 2 diabetes?

No one particular choice of oral hypoglycemic is considered the most effective form of
treatment - the decision over which drug to use is instead based on:1-3

 Consideration of the adverse side effects

 Convenience and overall tolerability

 Personal preference.
In reality, weighing up each drug is something to do in partnership with a prescriber -
guidelines partly drawn up by the American Diabetes Association list a great number
of advantages and disadvantages for each of the available drug treatments, including
the consideration of cost.2

The use of a single drug can be escalated to combination therapy with a second drug in
an effort to improve glycemic control.1,2

Metformin is usually the first treatment offered, however, and it is the most widely
used oral antihyperglycemic. Metformin is a sensitizer in the class known as
biguanides; it works by reducing the amount of glucose released by the liver into the
bloodstream and increasing cellular response to insulin. A metformin pill is usually
taken twice a day.1-4

This drug is a low-cost antihyperglycemic with mild side effects that can include
diarrhea and abdominal cramping. Metformin is not associated with weight gain or
hypoglycemia.2-4

Sulphonylureas are secretagogues that increase pancreatic insulin secretion. There are
several drug names in this class, including:1,3

 Chlorpropamide

 Glimepiride

 Glipizide

 Glyburide.

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Again, the choice of drug is an individual one. In the case of sulphonylureas, the choice
depends on daily dosing and the level of side effects. These drugs are associated with
weight gain and hypoglycemia.2

Glitazones (also known as thiazolidinediones) are sensitizers - they increase the effect
of insulin in the muscle and fat and reduce glucose production by the liver.1-3

Two glitazones are available: pioglitazone and rosiglitazone. These drugs can have the
side effects of weight gain or swelling and are associated with increased risks of heart
disease and stroke, bladder cancer and fractures.

In the UK, rosiglitazone was withdrawn from the market over concerns about adverse
events.4 In 2015, it remains available in the US, with information on its safety provided
by the US Food and Drug Administration (FDA).

Alpha-glucosidase inhibitors are intestinal enzyme inhibitors that block the breakdown
of carbohydrates into glucose, reducing the amount absorbed in the gut.1,3,4

Available as acarbose and miglitol, they are not usually tried as first-line drugs because
of common side effects of flatulence, diarrhea and bloating, although these may reduce
over time.1,3,4

Dipeptidyl peptidase-4 (DPP4) inhibitors include alogliptin, linagliptin, saxagliptin and

sitagliptin.1

Also known as gliptins, DPP4 inhibitors have a number of effects, including

stimulating pancreatic insulin (by preventing the breakdown of the hormone GLP-1).
They may also help with weight loss through an effect on appetite.1-4

These drugs do not increase the risk of hypoglycemia. Mild possible side effects are
nausea and vomiting.1-4

Sodium-glucose co-transporter 2 (SGLT2) inhibitors include canagliflozin and

dapagliflozin. They work by inhibiting the reabsorption of glucose in the kidneys,
causing glucose to be excreted in the urine (glycosuria).1,3

SGLT2s may also cause modest weight loss. Side effects include urinary infection.1,3

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Meglitinides include repaglinide and nateglinide. They stimulate the release of insulin
by the pancreas. Meglitinides are associated with a higher chance of hypoglycemia and
must be taken with meals three times a day. As a result, these drugs are less commonly
used.1,4

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CHAPTER-3

Discussions
Oral insulin replacement therapy remains a very appealing alternative to subcutaneous
injections for patients with diabetes. However, it seems that the search for an
acceptable insulin formulation is much more difficult than initially thought. After
decades of failed attempts to produce an insulin pill, technological innovation and
renewed ambition in the past 10 years are driving the pharmaceutical industry to once
again try to come up with an oral solution.The documented progress of oral insulin
developments made in the past 5 years is disappointing: although a large amount of
data from in vitro and animal experiments was published during this period, clinical
trial reports with human data only made up 4% of all the oral insulin publications. In
our view, this small number of clinical reports in comparison to published
pharmacological studies indicates that oral insulin development is still struggling to
move on from the workbench into clinical testing. Moreover, some of the recently
published clinical data represent results from trials that were conducted more than 10
years ago and/or from developments that have been discontinued.In addition to the low
number of clinical trial publications, the quality of the clinical trial designs in many
cases is also not satisfactory. Furthermore, with the exception of Emisphere’s 3-month
phase II trial and Biocon’s 6-month phase III trial, all presented trials are early-phase,
feasibility, and proof-of-concept trials with a small number (typically 8-12) of subjects
tested. Although the conclusion of these proof-of-concept trials is without exception
that oral insulin delivery is feasible and that the results are promising for further
development, a closer look at the design and data reveal there is room for
improvement:Many of the trials did not use an active comparator when testing the
pharmacodynamic effect of the oral insulin and none of the trials used an insulin analog
(either rapid- or long-acting) as state of the art active comparator.For oral insulin
formulations designed to provide prandial glycemic control, the effect of food on
insulin absorption should be thoroughly investigated as timing of premeal
administration can be key to the observed glucose lowering effect.9 Intake of oral
insulin just prior to starting a meal seems to significantly hamper insulin absorption for
most formulations. As is true for injectable short-acting insulins, (longer) application-
meal intervals are bothersome from a patient perspective. Taking a prandial insulin 60

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minutes before food ingestion may work in a trial setting with fixed times for meals,11
but will be less attractive for the majority of patients in real-life, especially in light of
available fast-acting injectable insulin analogs.The variable response to oral insulin
intake is quite frequently ignored and was not systematically studied to our knowledge.
A reported mean reduction in glucose concentration of up to 35% after oral insulin
intake could indeed be regarded as promising, but perhaps more important for treating
physicians and patients would be to know that the insulin elicits a reproducible effect in
a group of patients (low between-subjects variability) and in the same patient with
multiple dosings (low within-subject variability). Published results indicate that
between-subjects variability may be high, with approximately 1 out of 4 oral insulin
dosings not resulting in a measurable glucose lowering response at all. No recently
published study has yet looked into within-subject variability, although data also
suggest that the response to oral insulin in the same patient may be highly
variable.With the relatively high doses of insulin that need to be ingested to achieve a
significant metabolic effect, there is a theoretical possibility of an insulin overdose if
insulin absorption is acutely increased by biological or environmental factors (eg,
unique foods, stress or activity). Furthermore, the obvious impact of food intake on
bioavailability and pharmacodynamic properties of oral insulin formulations (as well as
the variability thereof) would most certainly become less important in the context of a
basal oral insulin formulation. In light of the current treatment practices, this may be a
true alternative for use of long-acting insulin analogs in addition to other oral
antidiabetic drugs in the treatment of patients with type 2 diabetes mellitus.With at least
a dozen companies that to our understanding are actively working on oral insulin
formulations in the clinical stage, what may be expected during the next 5 years? Based
on the current picture it is hard to imagine that an oral insulin product will be approved
for marketing by 2019. Given the limited number of published clinical trial reports so
far, the hope clearly is to see more clinical data. Companies like Tamarisk
Technologies have released rather bold press statements claiming to have “solved the
oral insulin puzzle” and to have “succeeded where others will continue to fail,” but the
scientific community has been waiting for years now for conclusive proof in support of
these statements. Moreover, in a number of cases, indication of the conduct or
completion of a clinical trial in the form of an entry in a national/international database
is also missing. Negligence with regard to registering a trial in a clinical database not

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only is in violation of standard ethical principles of clinical trials as set out in the
Declaration of Helsinki, but also makes it difficult to objectively assess the status of a
development. A transparent process for clinical trial conduct and publication is key to
ensure integrity of data and achieve scientific progress. It is our hope that our structured
approach offers some fuel for thought in this regard.

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CHAPTER-4
Conclusion

This course has introduced the subject of diabetes and how it is diagnosed. It has
discussed the structures and processes in the body that are important for controlling
blood glucose levels and described what goes wrong when diabetes develops. The
differences between Type 1 and Type 2 diabetes and other forms of diabetes have been
highlighted. The concepts of genetics, risk and risk management have been introduced.

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REFERENCES

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