DIABETES_ LECTURE

PROF. DR. DOINA CATRINOIU

Diabetes Mellitus

One of the most common noncommunicable diseases

Fourth leading cause of death in most
developed countries
More than 194 million people with
diabetes worldwide
Incidence of diabetes is increasing
estimated to rise to 333 million by 2025
To more than double in Africa, the Eastern
Mediterranean and Middle East, and South-East Asia
To rise by 50% in North America, 20% in Europe,
85% in South and Central Americas and 75% in the
Western Pacific
: International Diabetes Federation website

Types of Diabetes Mellitus

Type 1 diabetes (insulin-dependent

diabetes)
mainly in childhood/early adult life
10-20% of cases

Type 2 diabetes (non-insulin-dependent

diabetes)
usually develops in the middle-age/elderly
incidence increasing at a younger age
80-90% of cases

At least 50% of all people with

diabetes are unaware of their
condition
: International Diabetes Federation website

CLASSIFICATION OF DIABETES
Impaired glucose tolerance without
diabetes (IGT)
Primary diabetes mellitus
Insulin dependent (IDDM or Type 1)
Noninsulin dependent (NIDDM or Type 2)

Malnutrition-related diabetes mellitus

(MRDM)
Secondary diabetes mellitus

Pancreatic disease
Endocrine disorders
Drug therapy
Inherited disorders

Secretia de insulina

ose
G lu c

Basal-bolus therapy attempts to recreate physiological insulin secretion

Predicted plasma insulin concentration
profile (mU/l)

Rapid-acting insulin
Basal insulin
Total

Time of day

Diabetes is defined biochemically by the

following criteria

A fasting venous plasma glucose

level greater than 7.8 mmol/litre
(126 mg/dl) on more than one
occasion;

or A 2-hour (plus one other) venous

plasma glucose level in excess of
11.1 mmol/litre (200 mg/dl) in a
formal 75 g oral glucose tolerance
test (GTT).

Clinical features of diabetes at

diagnosis
Type 1
Type 2
Polyuria and thirst ++
+
Weakness or fatigue ++
+
Polyphagia with weight loss++

Recurrent blurred vision +

++
Vulvovaginitis or pruritus +
++
Peripheral neuropathy +
++
Nocturnal enuresis ++

Often asymptomatic
++

A diagnostic algorithm for diabetes

mellitus

Blood glucose > 200 mg/dl

Classical
Symptoms* +

Blood glucose 100 -200 mg/dl

DIABETES
A
S
Y
M
P
T
O
M
A
T
I
C

Fasting plasma glucose

> 126 mg/dl
Fasting plasma glucose
109-125 mg/dl
postprandial plasma
glucose > 200mg/dl
Blood glucose > 200 mg/dl
"occasionally"

2-h Plasma glucose after

"OGTT" > 200 mg/dl
and/or
Fasting plasma glucose >
126 mg/dl

INVESTIGATIONS

Blood glucose is the key to diagnosis in

diabetes.
Glycosylated haemoglobin and other
proteins: measurement of these proteins
reflects the degree of diabetic control in
the previous 4-6 weeks and is of value in
long-term management and control .

INVESTIGATIONS

Urine testing for glucose-glucose will

be found in the urine only when it rises
above the renal threshold (usually about
10 mmol/l
Urine testing for ketone bodies the
presence of ketones suggests loss of
control.
Proteinuria is a reflection of the
development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.

INVESTIGATIONS

Proteinuria is a reflection of the

development of renal complications and
is an early indicator of diabetic renal
disease Multiple test strips allow rapid
testing for all these substancesin urine.
Microalbuminuria is a very sensitive
marker of early and potentially reversible
renal impairment; it is the term given to
the presence of protein below the level of
detection with the stick methods, that is
200 mg/litre.

INVESTIGATIONS

Serum electrolytes, blood gases,

osmolality and anion gap are all of
value in metabolic crises if there is
loss of water, sodium and potassium
and acidosis is developing, or if there
is a hyperosmolar state.
Lipid profile: elevations in serum
cholesterol are common, and
elevation of serum triglycerides is a
reflection of poor glycaemic control,
which usually reverts to normal when
euglycaemia is achieved.

PRESENTING FEATURES OF DIABETES

Acute: the typical presentation of the young

patient with IDDM; features include polyuria,
polydipsia and weight loss of short duration,
often associated with, or apparently
precipitated by, a viral infection;visual
disturbance or impairment of the conscious
level associated with severe ketoacidosis
Chronic: the typical presentation of a patient
with NIDDM; the symptoms have usually been
present for some months and often include
weight loss, thirst, excess urine volume, genital
and skin infections

PRESENTING FEATURES OF DIABETES

Coincidental discovery: routine

screening for urine or blood glucose as
part of a pre-employment medical, during
pregnancy or in local campaigns
Complications: visual disturbance or
overt retinopathy, neuropathy,
nephropathy or after major thrombotic
events such as premature stroke or
myocardial infarction

PRESENTING FEATURES OF DIABETES

Drug-related diabetes may develop in

patients on long-term steroids or thiazide
diuretics
Disease-related as in acromegaly,
Cushing's syndrome,
phaeochromocytoma, thyrotoxicosis,
pancreatitis, haemochromatosis, cystic
fibrosis, carcinoma or surgical removal of
the pancreas
Gestational: pregnancy may unmask
diabetes in a woman who is predisposed.
A full history and clinical examination are
essential to detect any of the causative
diseases and document the consequences.

PRESENTING FEATURES OF DIABETES

Patients with type 2 diabetes may
or may not have characteristic
features. The presence of obesity
or a strongly positive family
history for mild diabetes
suggests a high risk for the
development of type 2 diabetes.

DM Kendall et al. Eur J Intern Med 20, ( 2009) S329S339

Prin amabilitatea Prof. Dr. N. Hncu

Treatmentul DZ tip 2: inlocuirea deficitului

Obesitate

IGT

Diabet

[necontrolat]

Postprandial

Glicemia
(mg/dl)
126

Fasting
insulinorezistenta

Functia
-celulara
(%)

100

Insulin Level
-20

-10
0
10
20
Diabetes duration (years)

30
Adapted from IDC, Minneapolis

The Progression from CV Risk Factors to Endothelial Injury

and Clinical Events
LDL-C

BP

Risk factors

Diabetes

Smoking

Heart failure

Oxidative stress

Endothelial dysfunction

NO

PAI-1

Local mediators

VCAM

Tissue ACE-Ang II

Endothelium

ICAM cytokines
Thrombosis

Inflammation

Vasoconstriction

Growth factors
matrix

Vascular lesion
and remodelling

Proteolysis

Plaque rupture

Clinical endpoints
NO Nitric oxide

Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.

The Metabolic Syndrome and

Associated CVD Risk Factors
Hypertension
Abdominal obesity
Hyperinsulinaemia

Insulin
Resistance

Atherosclerosis

Diabetes
Hypercoagulability
Dyslipidaemia

high TGs
small dense LDL
low HDL-C

Endothelial
Dysfunction

Deedwania PC. Am J Med 1998;105(1A);1S-3S.

NCEP ATP III: The Metabolic

Recommends a diagnosis when 3 of these risk factors are present
Syndrome
Risk Factor

Abdominal obesity
(Waist circumference)
Men
Women
TG
HDL-C
Men
Women
Blood pressure
Fasting glucose

Defining Level
>102 cm (>40 in)
>88 cm (>35 in)
150 mg/dL (1.7
mmol/L)
<40 mg/dL (1.0
mmol/L)
<50 mg/dL
(1.3
130/85
mm
Hg
mmol/L)
110 mg/dL (6.0
mmol/L)
NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

WHO: The Metabolic Syndrome

A working definition is glucose intolerance, IGT or
diabetes mellitus and/or insulin resistance together
with two or more of the following:

Raised arterial pressure 160/90 mmHg

Raised plasma triglycerides (1.7 mmol/L, 150

mg/dL) and/or low HDL-C (men <0.9 mmol/L,
35 mg/dL; women <1.0 mmol/L, 39 mg/dL)

Central obesity

Microalbuminuria (UAER 20 g/min or

albumin: creatinine ratio 20 mg/g)

Alberti KGMM for the WHO. Diabet Med 1998:15;539-553.

TREATMENT

Type 1 diabetes ONLY INSULIN is a replacement

therapy
Type 2 diabetes ORAL DRUGS+/- INSULIN
THERAPY

Human insulins do not closely match the endogenous insulin

response

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

Insulin analogues address the limitations of human insulin

Adapted from: Polonsky et al. J Clin Invest 1988;81:4428

Strategy for engineering analogue safety: the importance of

molecular design
The following important factors are always
considered when developing new insulin
analogues:
IGF-1 receptor affinity relative to human IR
affinity should not be higher than for human
insulin
Insulin dissociation/off-rate from the IR should
be similar to that of human insulin
The mitogenic/metabolic potency ratio should
not exceed 1
IGF-1, insulin-like growth factor 1; IR, insulin receptor

Potential sites for modification of insulin

Kaarsholm and Ludvigsen. Receptor 1995;5:18

Molecular modifications of insulin analogues

Kaarsholm and Ludvigsen. Receptor 1995;5:18

Pires and Chacra. Arq Bras Endocrinol Metabol 2008;52:26878

The structure of insulin detemir monomer

Whittingham. Biochemistry 1997;36:2826

Defining glucose variability

Hypoglycaemic events
Postprandial glucose excursions
Minor fluctuations in blood glucose levels

Monnier and Colette. Diabetes Care 2008;31(Suppl.2):S1504

Nonglycemic effects of oral therapy

Cardiovascular
risk factor

Sulfonil
urea

Rapidacting
insulin
secretago
gues

Metform Thiazolidindi
in
ones

glucosida
se
inhibitors

Insulin resistance
Hyperinsulinemia
LDL chol levels
LDL particle pattern
HDL chol levels
Triglycerides
LP (a)
PAI-1
Endothelial function
Body weight
Visceral adiposity

0
0
0
0
0
0
0
0
0

0
0
0
0
0
0
0
0
0

or 0
Large buoyant

0
0
0
0
0
0
0
0
0

?
0

0 or

Modified fromHE Lebovitz, Endocrinol clin North Am, 2001, 30: 909-933

Potential down-sides of pharmacological

treatment modalities in patients with T2DM
Potential problem

Avoid or reconsider

Unwanted weight gain

Sulphonylureas, glinides,

Gastrointestinal symptoms

Biguanides, alpha-glucosidase
inhibitors

Hypoglycemia

Sulphonylureas, glinides,
insulin

Impaired kidney function

Impaired liver function

Impaired cardio-pulmonary
function

glitazones, insulin

Biguanides, sulphonylureas
Glinides, glitazones, biguanides,
alpha-glucosidase
Biguanides, glitazones
ESC, EASD Guidelines, 2007

Suggested policy for the selection of glucoselowering therapy according to the glucometabolic
situation
Post-prandial
hyperglycemia

alpha-glucosidase inhibitors, shortacting SU, glinides, short-acting regular

insulin or insulin analogs

Fasting hyperglycemia

Biguanides, long-acting SU, glitazones,

long-acting insulin or insulin analogs

Insulin resistance

Biguanides, glitazones, alphaglucosidase inhibitors

Insulin deficiency

SU, glinides, insulin

ESC, EASD Guidelines, 2007

Revisit T2DM treatment strategies:

the evolving HbA1c position
Persistent HbA1c >7%

ACTION
Realistic target:
lowest HbA1c possible without
unacceptable hypoglycaemia
Healthy individual HbA1c 46%
Achieving and maintaining HbA1c at target may require
incremental and combination therapies

Treat-to-target concept
Adapted from Rosenstock J, Riddle MC. Chapter 9: Insulin therapy in type 2 diabetes. In: Cefalu
WT, Gerich JE, LeRoith D (eds). The CADRE Handbook of Diabetes Management. New York:
Medical Information Press; 2004:14568.

Summary of antidiabetic interventions as

monotherapy
Interventions

Step 1: initial
Lifestyle to decrease weight
and increase activity
Metformin
Step 2: additional therapy
Insulin

Expected
decrease
in A1c
(%)
1-2
1.5
1.5-2.5

Advantages

Low cost, many

benefits
Weight neutral,
inexpensive
No dose limit,
inexpensive,
improved lipid profile
Inexpensive
Improved lipid
profile

Sulphonylureas
TZDs

1.5
0.5-1.4

Other drugs
-glucosidase inhibitors

0.5-0.8

Weight neutral

Exenatide

0.5-1.0

Weight loss

Glinides
Pramlintide

1-1.5
0.5-1.0

Short duration
Weight loss

Disadvantages

Fails for most in first year

GI side effects, rare lactic
acidosis
Injections, monitoring,
hypoglycemia, weight gain
Weight gain, hypoglycemia
Fluid retention, weight
gain, expensive
Frequent GI side effects,
expensive
Injections, frequent GI side
effects, expensive, little
experience
3x/ day dosing, expensive
Injections, frequent GI side
effects, expensive, little
experience

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Strategii si algoritmuri

Algorithm for the metabolic management of T2DM

Diagnosis
Lifestyle intervention + metformin
HbA1C7
%
Add basal insulin
-most efective

Add sulfonylurea
-least expensive

HbA1C7%

Add glitazone
-no hypoglycamia

HbA1C7%

Intensify insulin

Add glitazone

HbA1C7%

HbA1C7%

Add basal insulin

Add sulfonylurea

HbA1C7%
Add basal or intensify insulin

Intensive insulin + metformin +/- glitazone

A consensus statement from ADA and EASD. Diabetologia, 2006, 49: 1711-21

Management of hyperglycemia in type 2 diabetes

How do I establish and sustain glycemic control?
Lifestyle change: an
option?

Is metformin still the

first line drug?

&

Which drugs after

metformin?
Sulphonylureas, TZDs
or insulin?
And then? Three oral agents,
insulin as add-on or insulin alone?
What is the evidence for the
proposed algorithm?
Will new drugs be able to halt
the decline of beta-cell function?
RJ Heine et al. BMJ, 9 december 2006, 333: 1200-1204

Contraindications can damage your healthis

metformin a case in point?
Standard contraindications to the use of metformin should be relaxed,
and that the benefits of reducing the number of patients excluded from
using it would by far outweigh the potential risks
propose removal of the following contraindications from the list:
1. old age
2. chronic renal insufficiency (as long as GFR>40 ml/min)
3. chronic heart failure (NYHA stages I and II)
4. discontinuation of metformin therapy 2 days before surgery
and i.v. contrast medium administration
A clear re-definition of metformin contraindications will enable more
physicians to prescribe within the guidelines
The main effect of revising these contraindications and precautions will
be to bring the official guidelines into harmony with day-to-day clinical
practice
A Holstein, M. Stumwoll. Doiabetologia, 2005, 48:2454-59

Insulin

Oral agents
SIOFOR 1000

Chacra RA et al. Diabetes, Obesity, Metab, 2005, 7: 148-160

GLP-1
SNC

Stomac

Cord

Neuroprotecie
Apetitul

Cardioprotecie

Funcia cardiac

Intestinul

GLP-1
Ficat

Cli
ck
to
edi
t
Ma
ste
r
tex
t

Evacuarea
coninutului gastric

Pancreas
Producia de
glucoz

Muchi

Sensibilitate
la insulin

Secreia de insulin
Secreia de glucagon

esut

Sinteza de insulin

adipos

Proliferarea beta-celular
Preluarea i stocarea
glucozei

Apoptoza celulelor beta

Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier 2007.

Efects ofGLP-1 in healthy

subjects
Eliberare de
insulin

Insulin

54

Exenatid is not inactivated by

DPP-4
Eliberare de
insulin

Insulin

55

The basal/bolus insulin concept

Basal insulin
Suppresses glucose production between
meals and overnight
40% to 50% of daily needs

Bolus insulin (mealtime)

Limits hyperglycaemia after meals
Immediate rise and sharp peak at 1 hour
10% to 20% of total daily insulin
requirement at each meal

Acute complications of diabetes

Ketoacidosis

Diabetic ketoacidosis (DKA)

is a potentially life-threatening complication in patients

with dm
It happens predominantly in those with type1, but it can
occur in those with type2 under certain circumstances.
results from a shortage of insulin; in response the body
switches to burning FFA and producing acidic ketonic
bodies that cause most of the symptoms and
complications

Causes

intercurrent illness
poor compliance with insulin therapy.
Vomiting, dehydration, deep gasping breathing, confusion
and occasionally coma are typical symptoms.
DKA is diagnosed with blood and urine tests; it is
distinguished from other, rarer forms of ketoacidosis by
the presence of high blood sugar levels.

DKA is a medical emergency, and without

treatment it can lead to death.
was first described in 1886; until the introduction
of insulin therapy in the 1920s it was almost
universally fatal.
It now carries a mortality of less than 5% with
adequate and timely treatment

Signs and simptoms

nausea and vomiting,

pronounced thirst,
excessive urine production
abdominal pain that may be severe.

Signs and simptoms

hyperglycemia (high blood sugar levels).

In severe DKA, breathing becomes labored
and of a deep, gasping character (a state
referred to as "Kussmaul respiration").
The abdomen may be tender to the point
that an acute abdomen may be suspected,
such as acute pancreatitis, appendicitis or
gastrointestinal perforation
Coffee ground vomiting (vomiting of
altered blood) occurs in a minority of
patients; this tends to originate from
erosion of the esophagus or gastric

In severe DKA, there may be confusion, lethargy, stupor

or even coma (a marked decrease in the
level of consciousness).
On physical examination there is usually clinical evidence
of dehydration, such as a dry mouth and decreased
skin turgor.
The dehydration is profound enough to cause a decrease
in the circulating blood volume, tachycardia (a fast heart
rate) and low blood pressure

Often, a "ketotic" odor is present,

described as "fruity", often compared to
the smell of pear drops whose scent is a
ketone.
If Kussmaul respiration is present, this is
reflected in an increased respiratory rate.
Small children with DKA are relatively
prone to cerebral edema, which may cause
headache, coma, loss of the
pupillary light reflex, and progress to
death.
It occurs in 0.71.0% of children with
DKA, and has been described in young
adults, but is overall very rare in adults.
It carries a 20% mortality.

Cause

intercurrent illness (pneumonia, influenza,

gastroenteritis, a urinary tract infection),
pregnancy,
inadequate insulin administration (e.g.
defective insulin pen device),
myocardial infarction (heart attack),
stroke
use of cocaine.
eating disorder, or may be using
insufficient insulin for fear that it will cause
weight gain
In 5% of cases, no cause for the DKA

Mechanism

arises because of a lack of insulin in the

body.
The lack of insulin and corresponding
elevation of glucagon leads to increased
release of glucose by the liver (a process
that is normally suppressed by insulin)
from glycogen and through
gluconeogenesis.
High glucose levels spill over into the
urine, taking water and solutes (such as
sodium and potassium) along with it in a
process known as osmotic diuresis.
Ketones, too, participate in osmotic
diuresis and lead to further electrolyte

Mechanism

The absence of insulin also leads to the

release of free fatty acids from
adipose tissue, which are converted, again
in the liver, into ketone bodies (
acetoacetate and -hydroxybutyrate).
-Hydroxybutyrate can serve as an energy
source in absence of insulin-mediated
glucose delivery, and is a protective
mechanism in case of starvation.
The ketone bodies, however, have a low
ph and therefore turn the blood acidic (
metabolic acidosis).

Mechanism

The body initially buffers the change with

the bicarbonate buffering system, but this
system is quickly overwhelmed and other
mechanisms must work to compensate for
the acidosis.
One such mechanism is hyperventilation to
lower the blood carbon dioxide levels (
respiratory alkalosis). This
hyperventilation, in its extreme form, may
be observed as Kussmaul respiration.
In various situations such as infection,
insulin demands rise but are not matched
by the failing pancreas.
Blood sugars rise, dehydration ensues,
and

Mechanism

the average adult DKA patient has a total

body water shortage of about 6 liters (or
100 mL/kg),
substantial shortages in sodium,
potassium, chloride, phosphate,
magnesium and calcium.
Glucose levels exceed 13.8 mmol/L or
250 mg/dL1
-hydroxybutyrate, despite chemically not
actually being a ketone, is the principal
"ketone body" in diabetic ketoacidosis.
In type 2 diabetes, insulin production is
present but is insufficient to meet the

Mechanism

The clinical state of DKA is associated, in addition

to the above, with the release of various
counterregulatory hormones such as glucagon and
adrenaline as well as cytokines, the latter of which
leads to increased markers of inflammation, even
in the absence of infection.

Complications -cerebral edema, which is the most

dangerous DKA complication

is the result from overvigorous fluid

replacement
dehydration,
acidosis
low carbon dioxide levels
the increased level of inflammation and
coagulation may, together with these
factors, lead to decreased blood flow to
parts of the brain, which then swells up
once fluid replacement has been
commenced
The swelling of brain tissue leads to raised

Invvestigations

hyperglycemia (high blood sugars),

ketones in the blood or on urinalysis
acidosis
Arterial blood gas measurement is usually performed to
demonstrate the acidosis; this requires taking a blood
sample from an artery. Subsequent measurements (to
ensure treatment is effective), may be taken from a
normal blood test taken from a vein, as there is little
difference between the arterial and the venous pH

urea and creatinine (measures of

kidney function, which may be impaired in
DKA as a result of dehydration) and
electrolytes.
markers of infection (complete blood count
, C-reactive protein)
acute pancreatitis (amylase and lipase)
chest radiography
urinalysis
computed tomography if cerebral edema is
suspected, may be performed to assess
its severity and to exclude other causes
such as stroke.

Criteria

Diabetic ketoacidosis is distinguished from other diabetic emergencies by the

presence of large amounts of ketones in blood and urine, and marked metabolic
acidosis.
Hyperosmolar hyperglycemic state (HHS, sometimes labeled "hyperosmolar
non-ketotic state" or HONK) is much more common in type 2 diabetes and
features increased plasma osmolarity (above 320 mosm/kg) due to profound
dehydration and concentration of the blood; mild acidosis and ketonemia may
occur in this state, but not to the extent observed in DKA.
There is a degree of overlap between DKA and HHS, as in DKA the osmolarity
may also be increased, but in most situations it is possible to classify a case into
either DKA or HHS.

2006 ADA statement (for adults) categorizes DKA into one of three
stages of severity:

Mild- blood pH mildly decreased to between 7.25 and

7.30 (normal 7.357.45); serum bicarbonate decreased
to 1518 mmol/l (normal above 20); the patient is alert
Moderate-pH 7.007.25, bicarbonate 1015, mild
drowsiness may be present
Severe-pH below7.00, bicarbonate below10,stupor or
coma

Prevention

Attacks of DKA can be prevented in known diabetics to an

extent by adherence to "sick day rules"; these are clearcut instructions to patients on how to treat themselves
when unwell.
include advice on how much extra insulin to take when
sugar levels appear uncontrolled,
an easily digestible diet rich in salt and carbohydrates,
means to suppress fever and treat infection,
recommendations when to call for medical help

Management
The main aims in the treatment of diabetic ketoacidosis
are:
replacing the lost fluids and electrolytes
suppressing the high blood sugars and ketone production
with insulin.
admission to an intensive care unit or similar highdependency area or ward for close observation may be
necessary.

Fluid replecement

1.

2.

The amount of fluid depends on the

estimated degree of dehydration.
If dehydration is so severe as to cause
shock (severely decreased
blood pressure with insufficient blood
supply to the body's organs), or a
depressed level of consciousness, rapid
infusion of saline (1 liter for adults,
10 ml/kg in repeated doses for children)
Slower rehydration based on calculated
water and sodium shortage may be
possible if the dehydration is moderate,
and again saline is the recommended

Insulin

1.

2.

Some guidelines recommend

a bolus (initial large dose) of insulin of
0.1 unit of insulin per kilogram of body
weight. This can be administered
immediately after the potassium level is
known to be higher than 3.3 mmol/l; if
the level is any lower, administering
insulin could lead to a dangerously low
potassium level
Other guidelines recommend delaying
the initiation of insulin until fluids have
been administered

Insulin

insulin is given at 0.1 unit/kg per hour to reduce the

blood sugars and suppress ketone production.
guidelines differ as to which dose to use when blood
sugar levels start falling; some recommend reducing the
dose of insulin once glucose falls below 16.6 mmol/l
(300 mg/dl)
other recommend infusing glucose in addition to saline to
allow for ongoing infusion of higher doses of insulin

Potassium

potassium levels can fluctuate severely during the

treatment of DKA, because insulin decreases
potassium levels in the blood by redistributing it
into cells.
a large part of the shifted extracellular potassium
would have been lost in urine because of osmotic
diuresis.
increases the risk of
dangerous irregularities in the heart rate.
continuous observation of the heart rate is
recomended, as well as repeated measurement of
the potassium levels and addition of potassium to
the intravenous fluids once levels fall below
5.3 mmol/l.
If potassium levels fall below 3.3 mmol/l, insulin

Bicarbonat

The administration of sodium bicarbonate

solution to rapidly improve the acid levels
in the blood is controversial.
There is little evidence that it improves
outcomes beyond standard therapy, and
indeed some evidence that while it may
improve the acidity of the blood, it may
actually worsen acidity inside the body's
cells and increase the risk of certain
complications.
Its use is therefore disscouraged, although
some guidelines recommend it for extreme
acidosis (pH<6.9), and smaller amounts

Complications-Cerebral edema

Cerebral edema, if associated with coma, often

necessitates admission to intensive care,
artificial ventilation, and close observation.
The administration of fluids is slowed.
The ideal treatment of cerebral edema in DKA is not
established, but intravenous mannitol and hypertonic
saline (3%) are used, as in some other forms of cerebral
edema,in an attempt to reduce the swelling.

Resolution of DKA is defined as general

improvement in the symptoms, such as

1.
2.
3.

the ability to tolerate oral nutrition and fluids,

normalization of blood acidity (pH>7.3)
and absence of ketones in blood (<1 mmol/l) or
urine.
Once this has been achieved, insulin may be
switched to the usual subcutaneously
administred regimen, one hour after which the
intravenous administration can be discontinued
In patients with type 2 diabetes, determination
of antibodies against
glutamic acid decarboxylase and islet cells may
aid in the decision whether to continue insulin

Hypoglycemia

Also called low blood glucose or low blood sugar,

occurs when blood glucose drops below normal
levels.
Carbohydrates are the main dietary source of
glucose. Rice, potatoes, bread, tortillas, cereal,
milk, fruit, and sweets are all carbohydrate-rich
foods.
After a meal, glucose is absorbed into the
bloodstream and carried to the body's cells.
Insulin helps the cells use glucose for energy. If a
person takes in more glucose than the body
needs at the time, the body stores the extra
glucose in the liver and muscles in a form called
glycogen.
The body can use glycogen for energy between

Glucagon

When blood glucose begins to fall, glucagon signals the

liver to break down glycogen and release glucose into the
bloodstream. Blood glucose will then rise toward a normal
level.
In some people with diabetes, this glucagon response to
hypoglycemia is impaired and other hormones such as
epinephrine, also called adrenaline, may raise the blood
glucose level.

Hypoglycemia can happen suddenly. It is

usually mild and can be treated quickly
and easily by eating or drinking a small
amount of glucose-rich food. If left
untreated, hypoglycemia can get worse
and cause confusion, clumsiness, or
fainting.
Severe hypoglycemia can lead to seizures,
coma, and even death.
In adults and children older than 10 years,
hypoglycemia is uncommon except as a
side effect of diabetes treatment.
Hypoglycemia can also result, however,
from other medications or diseases,
hormone or enzyme deficiencies, or
tumors.

Hypoglycemia

intense hunger,
dizzy spells,
headaches,
irregular heartbeat and pulse,
pale skin,
profuse sweating
anxiety attacks

Nocturnal hypoglycaemia

1.
2.
3.

Hypoglycemia can also happen during sleep. Some signs

of hypoglycemia during sleep include
crying out or having nightmares
finding pajamas or sheets damp from perspiration
feeling tired, irritable, or confused after waking up

Reactive hypoglycemia -Fasting hypoglycemia

* Diabetes - hypos or hypoglycemic conditions

are caused by the treatments for diabetes rather
than diabetes itself.
* Pregnancy
* Fasting - Often extreme dieting or lengthy
periods without food bring about hyepoglycemic
symptoms.
* Strenuous exercise
* Alcoholism
* Insulinoma
* Hereditary enzyme deficiencies
* Hormone deficiencies
* Liver disease
* Hereditary fructose intolerance
* Galactosemia
* Growth hormone deficiency
* IGF-II producing tumors

occur as a side effect of various

medications given to diabetics, usually
intended to treat high blood sugar by
lowering the bodys blood glucose levels.
Hypoglycemia happens when the medicine
intended to regulate blood sugar lowers
the bodys glucose levels too much
(probably as a result of wrong dosage or
improper administration)
Results in the bodys natural glucoseregulating functions kicking in, forcing the
liver to release its glucose stores and for
other parts of the body such as the
hormones and the nervous system to
adjust to the changes, all of these are
happening too fast resulting in irregular
external effects.

Hypoglycemia in diabetes may also occur

after taking too much insulin compared to
the amount of your carbohydrates intake,
Problems relating to a diabetics eating
habits can also cause hypoglycemia
attacks.
Referred to as Reactive Hypoglycemia, a
person who tends to miss meals, or does
not eat enough, or eats much later than
usual, may develop hypoglycemia.
It can also result from drinking alcohol on
an empty stomach, or eating a meal with
too much simple sugar (candies,
chocolates, pastries that have icing, and
snacks that contain dried sugar).

How can hypoglycemia be prevented?

Their diabetes medications.
A health care provider can explain which diabetes
medications can cause hypoglycemia and explain how and
when to take medications.
For good diabetes management, people with diabetes
should take diabetes medications in the recommended
doses at the recommended times.
In some cases, health care providers may suggest that
patients learn how to adjust medications to match
changes in their schedule or routine.

1.

2.
3.

Their meal plan. A registered dietitian can help

design a meal plan that fits one's personal
preferences and lifestyle. They should eat regular
meals, have enough food at each meal, and try
not to skip meals or snacks. Snacks are
particularly important for some people before
going to sleep or exercising.
Their daily activity. To help prevent
hypoglycemia caused by physical activity, health
care providers may advise
checking blood glucose before sports, exercise, or
other physical activity and having a snack if the
level is below 100 milligrams per deciliter
(mg/dL)
adjusting medication before physical activity
checking blood glucose at regular intervals during
extended periods of physical activity and having
snacks as needed

Their use of alcoholic beverages.

Drinking alcoholic beverages, especially on
an empty stomach, can cause
hypoglycemia, even a day or two later.
Heavy drinking can be particularly
dangerous for people taking insulin or
medications that increase insulin
production. Alcoholic beverages should
always be consumed with a snack or meal
at the same time.
Their diabetes management plan.
Intensive diabetes management-keeping
blood glucose as close to the normal range
as possible to prevent long-term
complications-can increase the risk of

When people think their blood glucose is too low,

they should check the blood glucose level of a
blood sample using a meter. If the level is below
70 mg/dL, foods should be consumed right away
to raise blood glucose:
3 or 4 glucose tablets
1 serving of glucose gel-the amount equal to 15
grams of carbohydrate
1/2 cup, or 4 ounces, of any fruit juice
1/2 cup, or 4 ounces, of a regular-not diet-soft
drink
1 cup, or 8 ounces, of milk
5 or 6 pieces of hard candy
1 tablespoon of sugar or honey
The next step is to recheck blood glucose in 15
minutes to make sure it is 70 mg/dL or above. If
it's still too low, another serving of a quick-fix

Severe hypoglycemia

very low blood glucose-can cause a person

to pass out and can even be life
threatening.
is more likely to occur in people with type
1 diabetes.
Another person can help someone who has
passed out by giving an injection of
glucagon. Glucagon will rapidly bring the
blood glucose level back to normal and
help the person regain consciousness.
Hypertonic glucose in i.v.perfusion
Never give oral glucose when the person is
uncouncious

Hypoglycemia Unawareness

Some people with diabetes do not have early

warning signs of low blood glucose, a condition
called hypoglycemia unawareness. This condition
occurs most often in people with type 1 diabetes,
but it can also occur in people with type 2
diabetes.
People with hypoglycemia unawareness may need
to check their blood glucose level more often so
they know when hypoglycemia is about to occur.
They also may need a change in their
medications, meal plan, or physical activity
routine.
Hypoglycemia unawareness develops when
frequent episodes of hypoglycemia lead to
changes in how the body reacts to low blood
glucose levels. The body stops releasing the
hormone epinephrine and other stress hormones
when blood glucose drops too low.

Epinephrine causes early warning

symptoms of hypoglycemia such as
shakiness, sweating, anxiety, and hunger.
Without the release of epinephrine and the
symptoms it causes, a person may not
realize that hypoglycemia is occurring and
may not take action to treat it.
A vicious cycle can occur in which frequent
hypoglycemia leads to hypoglycemia
unawareness and HAAF, which in turn
leads to even more severe and dangerous
hypoglycemia.
Health care providers may therefore
advise people who have had severe
hypoglycemia to aim for higher-than-usual

Take home messages

When people with diabetes think their

blood glucose level is low, they should
check it and treat the problem right away.
To treat hypoglycemia, people should have
a serving of a quick-fix food, wait 15
minutes, and check their blood glucose
again. They should repeat the treatment
until their blood glucose is 70 mg/dL or
above.
People at risk for hypoglycemia should
keep quick-fix foods in the car, at workanywhere they spend time.
People at risk for hypoglycemia should be
careful when driving. They should check
their blood glucose frequently and snack

Nonketotic hyperosmolar coma

is a type of diabetic coma associated with a high

mortality seen in diabetes mellitus type 2.

Signs and simptoms

The increasing hemoconcentration and
volume depletion may result in:
Hypervyscosity and increased risk of
thrombosis
Disordered mental functioning
Neurologic signs including focal signs such
as sensory or motor impairments or focal
seizures or motor abnormalities, including
flaccidity, depressed reflexes, tremors or
fasciculations

Pathophysiology

is usually precipitated by an infection,

myocardial infarction, stroke or another
acute illness.
A relative insulin deficiency leads to a
serum glucose that is usually higher than
33 mmol/l (600 mg/dl), and a resulting
serum osmolarity that is greater than 320
mOsm.
This leads to polyuria (excessive urination,
an osmotic diuresis), which, in turn, leads
to volume depletion and
hemoconcentration that causes a further
increase in blood glucose level.

Management

Begins with reestablishing tissue perfusion using

intravenous fluids. People with HHS can be
dehydrated by 8 to 12 l Attempts to correct this
usually take place over 24 hrs with initial rates of
normal saline or glucose 5% often in the range of
1 l/hr for the first few hours.
Severe potassium deficits, usually range around
350 mEq in a 70 kg person. This is generally
replaced at a rate 10 mEq per hour as long as
there is urinary output.
Insulin is given to reduce blood glucose
concentration; however, as it also causes the
movement of potassium into cells, serum
potassium levels must be sufficiently high or
dangerous hypokalemia may result. Once
potassium levels have been verified to be greater

Lactic acidosis-is a physiological condition

characterized by

low pH in body tissues and blood (acidosis

) Lactic acidosis is characterized by lactate
levels >5 mmol/L and serum pH <7.35.
buildup of lactate especially D-lactate, and
is considered a distinct form of
metabolic acidosis.
The condition typically occurs when cells
receive too little oxygen (hypoxia), for
example, during vigorous exercise. In this
situation, impaired cellular respiration
leads to lower pH levels. Simultaneously,
cells are forced to metabolize glucose
anaerobically, which leads to lactate
formation. Therefore, elevated lactate is
indicative of tissue hypoxia, hypoperfusion

Pathophysiology

Most cells in the body normally

metabolize glucose to form water
and carbon dioxide in a two-step
process.
First, glucose is broken down to
pyruvate through glycolysis.
Then, mitochondria oxidize the
pyruvate into water and carbon
dioxide by means of the Krebs cycle
and oxidative phosphorylation. This
second step requires oxygen. The
net result is ATP, the energy carrier

Pathophysiology

If oxygen supply is inadequate (hypoxia), the

mitochondria are unable to continue ATP synthesis at a
rate sufficient to supply the cell with the required ATP.
In this situation, glycolysis is increased to provide
additional ATP, and the excess pyruvate produced is
converted into lactate and released from the cell into the
bloodstream, where it accumulates over time.

Signs and symptoms of lactic acidosis i

Nausea
Vomiting
Hyperventilation
Abdominal pain
Lethargy
Anemia
Hypotension
Tachycardia

Therapy

Same like in hyperosmolar coma

More alkalin substance for severe acidosis

Polineuropathy

Diabetic neuropathies are neuropathic

disorders that are associated with
diabetes mellitus. result from diabetic
microvascular injury involving small
blood vessels that supply nerves (
vasa nervorum) in addition to
macrovascular conditions that can
culminate in diabetic neuropathy.
common conditions which may be
associated with diabetic neuropathy
include third nerve palsy;
mononeuropathy; mononeuropathy
multiplex; diabetic amyotrophy; a painful

Signs and symtoms

affects all peripheral nerves including pain fibers,

motor neurons and the autonomic nervous
system.
It can affect all organs and systems, as all are
innervated.
There are several distinct syndromes based upon
the organ systems and members affected, but
these are by no means exclusive.
A patient can have sensorimotor and autonomic
neuropathy or any other combination.
Symptoms vary depending on the nerve(s)
affected and may include symptoms other than
those listed. Symptoms usually develop gradually
over years.

Symptoms

Numbness and tingling of extremities

Dysesthesia (abnormal sensation to a body part
Diarrhea
Erectile dysfunction
Urinary incontinence (loss of bladder control)

Pathophysiology-1.Microangiopathy

Vascular and neural diseases are closely related and

intertwined.
The first pathological change in the microvasculature is
vasoconstriction.
capillary basement membrane thickening and endothelial
hyperplasia, which contribute to diminished
oxygen tension and hypoxia.
Neuronal ischemia is a well-established characteristic of
diabetic neuropathy.

Pathophysiology2.Advanced glycation end product

Elevated intracellular levels of glucose cause a

non-enzymatic covalent bonding with proteins,
which alters their structure and inhibits their
function.
Some of these glycosylated proteins have been
implicated in the pathology of diabetic neuropathy
and other long term complications of diabetes.

Pathophysiology - 3.Protein kinase C

PKC is implicated in the pathology of diabetic

neuropathy.
Increased levels of glucose cause an increase in
intracellular diacylglycerol, which activates PKC.
PKC inhibitors will increase
nerve conduction velocity by increasing neuronal
blood flow.

Pathophysiology-4.Polyol pathway

Also called the sorbitol/aldose reductase pathway,

the polyol pathway may be implicated in diabetic
complications that result in microvascular
damage to nervous tissue, and also to the retina
and kidney.
Glucose is a highly reactive compound, and it
must be metabolized or it will find tissues in the
body to react with.
Increased glucose levels activates this alternative
biochemical pathway, which in turn causes a
decrease in glutathione and an increase in
reactive oxygen radicals.
The pathway is dependent on the enzyme
aldose reductase.

Sensoriomotor polyneuropathy

Longer nerve fibers are affected to a greater

degree than shorter ones, because nerve
conduction velocity is slowed in proportion to a
nerve's length.
Dysesthesia and night time pain. The pain can
feel like burning, pricking sensation, achy or dull.
Pins and needles sensation is common.
Loss of proprioception, the sense of where a limb
is in space, is affected early.
Multiple fractures of the knee, ankle or foot, and
develop a Charcot joint.
Loss of motor function results in dorsiflexion,
contractures of the toes, loss of the interosseous
muscle function and leads to contraction of the

Authonomic nervous system

is composed of nerves serving the heart, lungs,

blood vessels, bone, adipose tissue, sweat glands,
gastrointestinal system and genitourinary system.
orthostatic hypotension, or fainting when standing up.
loss of the usual change in heart rate seen with normal
breathing. These two findings suggest autonomic
neuropathy.

Treatment

tricyclic antidepressants (TCAs), serotonin reuptake inhibitors

(SSRIs) and antiepileptic drugs (AEDs). A systematic review
concluded that "tricyclic antidepressants and traditional
anticonvulsants are better for short term pain relief than newer
generation anticonvulsants.
A combination of these medication (gabapentin + nortriptyline)
may also be superior to a single agent.
The only two drugs approved by the FDA for diabetic peripheral
neuropathy are the antidepressant duloxetine and the
anticonvulsant pregabalin.

Other therapies

-lipoic acid, and anti-oxidant that is a non-prescription

dietary supplement once-daily oral doses of 600 mg to
1800 mg
Methylcobalamin, a specific form of Vitamin B-12 found in
spinal fluid, has been studied and shown to have
significant effect, taken orally or injected, in treating and
improving diabetic neuropathy.
Sativex, a cannabis based medicine has not been found to
be effective

Diabetic nephropathy

known as Kimmelstiel-Wilson
syndrome, or nodular diabetic
glomerulosclerosis and intercapillary
glomerulonephritis, is a progressive
kidney disease caused by angiopathy of
capillaries in the kidney glomeruli.
It is characterized by nephrotic syndrome
and diffuse glomerulosclerosis.
It is due to longstanding diabetes mellitus,
and is a prime indication for dialysis in
many Western countries.

Pathophysiology

The earliest detectable change in the

course of diabetic nephropathy is a
thickening in the glomerulus.
the kidney may leak more serum albumin
(plasma protein) than normal in the urine
(albuminuria),
As diabetic nephropathy progresses,
increasing numbers of glomeruli are
destroyed by progressive nodular
glomerulosclerosis. Urine albumin
increases to the point that it may be
detected by ordinary urinalysis techniques.
A kidney biopsy generally clearly shows
diabetic nephropathy.

Signs

Kidney failure provoked by glomerulosclerosis leads to fluid

filtration deficits and other disorders of kidney function.
Increase in blood pressure (hypertension) and fluid retention in the
body plus a reduced plasma oncotic pressure causes edema
Other complications may be arteriosclerosis of the renal artery and
proteinuria.
Throughout its early course, diabetic nephropathy has no
symptoms. They develop in late stages and may be a result of
excretion of high amounts of protein in the urine or due to renal
failure:

Treatment

slow the progression of kidney damage and

control related complications.
ACE inhibitor drugs, which usually reduces
proteinuria levels and slows the progression of
diabetic nephropathy.
angiotensin receptor blockers (ARBs), have a
similar benefit.

Diabetic Arteriopathy

In diabetic population the incidence of

arteriopathy is 14% after 2 years of diabetes,15%
after 10 years and 45% after 20 years.
In particular ischemic ulcers and gangrene are
present in about 10% of old diabetic people

Characteristics

In addition to atherosclerotic changes, the vessels of

diabetic patients are characterized by increased amounts
of connective tissue,such as fibronectin, collagen, and
glycoproteins, as well as increased amounts of calcium in
the medial layer of the arterial wall, a constellation named
diabetic macroangiopathy.
These changes lead to a loss of elasticity of the arterial
wall.

Diabetes rethinopathy

It is an ocular manifestation of systemic disease which

affects up to 80% of all patients who have had diabetes
for 10 years or more.1 Despite these intimidating
statistics, research indicates that at least 90% of these
new cases could be reduced if there was proper and
vigilant treatment and monitoring of the eyes.2 The
longer a person has diabetes, the higher his or her
chances of developing diabetic retinopathy.3

Often has no early warning signs.

Macular edema which may cause vision loss more
rapidly, may not have any warning signs for some
time.
As new blood vessels form at the back of the eye
as a part of proliferative diabetic retinopathy
(PDR), they can bleed (ocular hemorrhage) and
blur vision.
In most cases, it will leave just a few specks of
blood, or spots, floating in a person's visual field,
though the spots often go away after a few
hours.
These spots are often followed within a few days
or weeks by a much greater leakage of blood,
which blurs vision.
It may take the blood anywhere from a few days

Pathogenesis-is the result of microvascular

retinal changes.

Hyperglycemia-induced intramural pericyte

death and thickening of the
basement membrane lead to
incompetence of the vascular walls.
These damages change the formation of
the blood-retinal barrier and also make
the retinal blood vessels become more
permeable.4
The pericyte death is caused when
"hyperglycemia persistently activates
protein kinase
mitogen-activated protein kinase
This signaling cascade leads to
PDGF receptor- dephosphorylation and a
reduction in downstream signaling from

Pathogenesis

As the disease progresses, severe

nonproliferative diabetic retinopathy enters an
advanced, or proliferative, stage when blood
vessels proliferate
The lack of oxygen in the retina causes fragile,
new, blood vessels to grow along the retina and
in the clear, gel-like vitreous humour that fills the
inside of the eye.
Fibrovascular proliferation can also cause
tractional retinal detachment. The new blood
vessels can also grow into the angle of the
anterior chamber of the eye and cause
neovascular glaucoma.
Nonproliferative diabetic retinopathy shows up as
cotton wool spots, or microvascular abnormalities
or as superficial retinal hemorrhages. Even so,

Eye examination
Visual acuity test: This test uses an
eye chart to measure how well a person
sees at various distances
Pupil dilation: The eye care professional
places drops into the eye to widen the
pupil.
Ophthalmoscopy
(1) looks through a slit lamp biomicroscope
with a special magnifying lens that
provides a narrow view of the retina,
(2) wearing a headset (indirect
ophthalmoscope) with a bright light, looks
through a special magnifying glass and
gains a wide view of the retina. Hand-held
ophthalmoscopy is insufficient to rule

Management

laser surgery,
injection of corticosteroids or Anti-VEGF into the
eye,
vitrctomy.