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CHAIR: Prof.Dr.B.Jayakumar.
Introduction
The prevalence of Diabetes is increasing
rapidly,particularly in children and young
adults.
 One third of cases of Diabetes remain
undiagnosed.
 The burden of death and disability from
Diabetes remains great despite broad
advances in understanding and
therapeutic techniques.

Only few patients with Diabetes broadly
achieve targets for blood pressure,lipid, or
glucose management.
 Only few patients with Diabetes receive
all the recommended annual screening
evaluations for complications or
preventive services.
 Organised system of health care delivery
can achieve better control of diabetes and
its comorbidities.

Definition:
Second century understanding:
 Diabetes is a dreadful affliction, not very
frequent among men, being a melting
down of the flesh and limbs in to urine.
The patients never stop making water and
the flow is incessant…….Life is short and
unpleasant.
Greek Physician Aretaeus of Cappadocia
Present WHO definition:
The term diabetes mellitus describes a
metabolic disorder of multiple aetiology
characterized by chronic hyperglycaemia
with disturbances of carbohydrate, fat
and protein metabolism resulting from
defects in insulin secretion, insulin
action, or both.
 The effects of diabetes mellitus include
long-term damage, dysfunction and
failure of various organs.

Diabetes mellitus may present with
characteristic symptoms such as thirst,
polyuria, blurring of vision, and weight loss.
 In its most severe forms, ketoacidosis or a
non-ketotic hyperosmolar state may develop
and lead to stupor, coma and, in absence of
effective treatment, death.
 Often symptoms are not severe, or may be
absent, and consequently hyperglycaemia
sufficient to cause pathological and
functional changes may be present for a long
time before the diagnosis is made.

The long-term effects of diabetes mellitus
include progressive development of the
specific complications of retinopathy with
potential blindness, nephropathy that may
lead to renal failure, and/or neuropathy
with risk of foot ulcers, amputation,
Charcot joints, and features of autonomic
dysfunction, including sexual dysfunction.
 People with diabetes are at increased risk
of cardiovascular, peripheral vascular and
cerebrovascular disease

Several pathogenetic processes are
involved in the development of diabetes.
These include processes which destroy
the beta cells of the pancreas with
consequent insulin deficiency, and others
that result in resistance to insulin action.
 The abnormalities of carbohydrate, fat
and protein metabolism are due to
deficient action of insulin on target
tissues resulting from insensitivity or lack
of insulin.

Classification:


Now Diabetes Mellitus is classified on the
basis of the pathogenic process that leads
to hyperglycemia.
I. Type 1 diabetes
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes











III. Other specific types of diabetes
A. Genetic defects of Beta cell function
characterized by mutations in:
1. Hepatocyte nuclear transcription factor
(HNF) 4alfa (MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1alfa (MODY 3)
4. Insulin promoter factor-1 (IPF-1; MODY 4)
5. HNF-1beta (MODY 5)
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA
8. Subunits of ATP-sensitive potassium
channel
9. Proinsulin or insulin conversion
B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipodystrophy syndromes
 C. Diseases of the exocrine pancreas—
pancreatitis, pancreatectomy, neoplasia,
cystic fibrosis, hemochromatosis,
fibrocalculous pancreatopathy, mutations
in carboxyl ester lipase

D. Endocrinopathies—
acromegaly, Cushing's syndrome,
glucagonoma, pheochromocytoma,
hyperthyroidism, somatostatinoma,
aldosteronoma.
 E. Drug- or chemical-induced—
Vacor, pentamidine, nicotinic acid,
glucocorticoids, thyroid hormone,
diazoxide, -adrenergic agonists, thiazides,
phenytoin, -interferon, protease
inhibitors, clozapine

F. Infections—
congenital rubella, cytomegalovirus,
coxsackie.
 G. Uncommon forms of immunemediated diabetes —
"stiff-person syndrome , anti-insulin
receptor antibodies.


H. Other genetic syndromes sometimes
associated with diabetes—
Down's syndrome, Klinefelter's
syndrome, Turner's syndrome, Wolfram's
syndrome, Friedreich's ataxia,
Huntington's chorea, Laurence-MoonBiedl syndrome, myotonic dystrophy,
porphyria, Prader-Willi syndrome.

IV. Gestational diabetes mellitus
(GDM)
Aetiopathogenesis:
 I.Type 1 Diabetes

A. Immune-mediated:

Type 1 DM is the result of interactions of
Genetic
Environmental &
Immunological factors leading to
destruction of beta cells and insulin
deficiency.
 Genetic
factors:
Susceptibility to type 1 DM involves
multiple genes
 The major susceptibility gene for type 1
DM is located in the HLA region on
chromosome 6.
 Commonly associated haplotypes are
HLA DR3 and/or DR4, DQA1*0301,
DQB1*0302, and DQB1*0201.

Genetic loci contributing susceptibility to
Type 1 DM are polymorphisms in the
promoter region of the insulin gene, the
CTLA-4 gene, interleukin-2 receptor, and
PTPN22.
 Although the risk of developing type 1
DM is increased tenfold in relatives of
individuals with the disease, most
individuals with type 1 DM do not have a
first-degree relative with this disorder.

 Environmental factors:
Environmental triggers include
viruses (coxsackie and rubella most
prominently),
bovine milk proteins, and
nitrosourea compounds.
 Identification of an environmental trigger
has been difficult because the event may
precede the onset of DM by several years.

 Immunologic Factors:
Following abnormalities in humoral and
cellular arms of immune system have
been identified.
 1)Islet cell autoantibodies
2)Activated lymphocytes in
islets,peripancreatic lymph nodes and
systemic circulation
3) T lymphocytes that proliferate when
stimulated with islet proteins; and
4) release of cytokines within the insulitis


Pancreatic islet molecules targeted by the
autoimmune process include

Insulin,
glutamic acid decarboxylase (GAD),
ICA-512/IA-2 , and
phogrin (insulin secretory granule
protein).
These Genetic
Environmental &
Immunological factors interact leading
to destruction of beta cells and insulin
deficiency.
 Features of diabetes do not become
evident until a majority of beta cells are
destroyed.
 These patients may also have other
autoimmune disorders such as Graves’
disease,Hashimoto’s thyroiditis, and
Addison’s disease.


B. Idiopathic


Some individuals who have the clinical
phenotype of type 1 DM lack
immunologic markers indicative of an
autoimmune process involving the beta
cells.

These individuals are thought to develop
insulin deficiency by unknown,
nonimmune mechanisms.
 II. Type 2 diabetes

Environmental factors (such as obesity,
nutrition, and physical activity) in
Genetic susceptible patients leads to
.
a)Impaired insulin secretion
b)Insulin resistance
c)Excessive hepatic glucose & lipid
production
d)Abnormal fat metabolism.

a)Impaired insulin secretion
In type 2 DM, insulin secretion initially
increases in response to insulin resistance
to maintain normal glucose tolerance.
 Eventually, the insulin secretory defect
progresses to a state of grossly inadequate
insulin secretion.

The reason(s) for the decline in insulin
secretory capacity in type 2 DM is
 1)A second genetic defect—superimposed
upon insulin resistance—leads to beta
cell failure.
2)Glucose toxicity - Chronic
hyperglycemia paradoxically impairs islet
function.
3) Lipotoxicity - Elevation of free fatty
acid levels and dietary fat also worsen
islet function

b)Insulin resistance


Insulin resistance, the decreased ability of
insulin to act effectively on target tissues
is a prominent feature of Type2 DM.


Insulin binds to receptors on target site
Receptor autophosphorylation

Recruitment of intracellular signalling
molecules

Insulin Receptor Substrate(IRS) and other
protein complex initiate a cascade of
phosphorylation and autophosphorylation
reactions resulting in metabolic and
mitogenic effects of insulin.
Postreceptor defects in insulin-regulated
phosphorylation/dephosphorylation
plays the predominant role in insulin
resistance.
 The accumulation of lipid within skeletal
myocytes, which may impair
mitochondrial oxidative phosphorylation
and reduce insulin-stimulated
mitochondrial ATP production leading to
insulin resistance.


Insulin receptor levels and tyrosine kinase
activity in skeletal muscle are reduced,
but these alterations are most likely
secondary to hyperinsulinemia and are
not a primary defect.
Insulin resistance in Liver
Failure to supress gluconeogenesis
Fasting hyperglycemia.
.


Insulin Resistance in liver


Decreased glycogen storage in
postprandial state

Postprandial hyperglycemia

Peripheral insulin resistance.

Decreased peripheral gluose usage.


Postprandial hyperglycemia.

c)Excessive hepatic glucose & lipid
production:

Insulin resistance in liver
Excess
production of glucose.
 Insulin resistance in Adipose tissue
Free Fatty Acid flux from
adipocytes
Increased lipid
synthesis in hepatocytes.

d)Abnormal fat metabolism:

The obesity accompanying type 2 DM, is
thought to be part of the pathogenic process
 The adipocytes secrete a number of biologic
products.
 The increased production of
Resistin,TNFalfa, IL-6 by adipocytes are
associated with insulin resistance.
 Adiponectin and Leptin secreted by
adipocytes increase insulin sensitivity and
are decreased in obesity.

III. Other specific types of diabetes

A. Genetic defects of Beta cell function
characterized by mutations :
I. (MODY 1) : Mutation in Hepatocyte
nuclear transcription (HNF) 4 alfa.
 This transcription network plays a role in the
early development of the pancreas.
 In the pancreas these genes influence
expression of, among others, the genes for
insulin, the principal glucose transporter
(GLUT2), and several proteins involved in
glucose and mitochondrial metabolism.

MODY2:
 MODY 2 is due to any of several
mutations in the GCK gene on
chromosome 7 for glucokinase.
 Glukokinase serves as the glucose sensor
for the beta cell.
 These loss-of-function mutations result
in a glucokinase molecule that is less
sensitive or less responsive to rising levels
of glucose.

3. HNF-1alfa (MODY 3)
 MODY 3 is caused by mutations of the
HNF1α gene, a homeobox gene on
chromosome 12.
 HNF1α is a transcription factor important
for differentiation of beta cells.
 Mutations of this gene lead to reduced
beta cell mass or impaired function

4. Insulin promoter factor-1 (IPF-1; MODY
4)
MODY 4 arises from mutations of the
IPF1 homeobox gene on chromosome 13.
 IPF1 is a transcription factor vital to the
development of the embryonic pancreas.
 Even in adults it continues to play a role
in the regulation and expression of genes
for insulin, GLUT2, glucokinase, and
somatostatin


5. HNF-1 . (MODY5):
HNF1β is involved in early stages of
embryonic development of several
organs, including the pancreas.
 Most of those who develop diabetes show
atrophy of the entire pancreas, with mild
or subclincal deficiency of exocrine as
well as endocrine function (MODY 5).

6. NeuroD1 (MODY 6)
 MODY 6 arises from mutations of the
gene for the transcription factor referred
to as neurogenic differentiation .
 NeuroD1 promotes transcription of the
insulin gene as well as some genes
involved in formation of beta cells and
parts of the nervous system


7.MitochondrialDNA:
Point mutations in mitochondrial DNA
have been found to be associated with
diabetes mellitus and deafness.

8. Subunits of ATP-sensitive potassium
channel :
Mutations in subunits of the ATPsensitive potassium channel subunits are
the major causes of permanent neonatal
diabetes.

9. Proinsulin or insulin conversion:
Genetic abnormalities that result in the
inability to convert proinsulin to insulin
and the resultant carbohydrate
intolerance have been identified

B. Genetic defects in insulin action

1. Type A insulin resistance:


Individuals with the type A insulin
resistance syndrome have an undefined
defect in the insulin-signaling pathway

2. Leprechaunism
and
3. Rabson-Mendenhall syndrome
are two paediatric syndromes that
have mutations in the insulin receptor
gene with subsequent alterations in
insulin receptor function and extreme
insulin resistance.

C. Diseases of the pancreas :
Any process that diffusely injures the
pancreas can cause diabetes pancreas:
 pancreatitis,
pancreatectomy,
neoplasia,
cystic fibrosis,
hemochromatosis,
fibrocalculous pancreatopathy.


D. Endocrinopathies—

Several hormones (e.g. growth hormone,
cortisol, glucagon,
epinephrine) antagonize insulin action.

Diseases associated with excess secretion of
these hormones can cause diabetes.
(e.g. Acromegaly, Cushing’s Syndrome,
Glucagonoma and Phaeochromocytoma).

These forms of hyperglycaemia
typically resolve when the hormone excess is
removed.
E. Drug- or chemical-induced DM:
 Many drugs can impair insulin secretion.
 These drugs may not, by themselves,
cause diabetes but they may precipitate
diabetes in persons with insulin
resistance.
 Vacor, pentamidine, can permanently
destroy pancreatic beta cells.
 Nicotinic acid, glucocorticoids, can
impair insulin action.


F. Infections—
Certain viruses have been associated with
beta–cell destruction.
 Congenital rubella,
cytomegalovirus,
coxsackie,
adenovirus and mumps
have been implicated in inducing the
disease.


G. Uncommon forms of immune-mediated diabetes —

"stiff-person syndrome and anti-insulin receptor
antibodies.


The “stiff person syndrome” is an autoimmune
disorder of the central nervous system, characterized
by stiffness of the axial muscles with painful spasms
(87). Affected people usually have high titresof the
GAD autoantibodies and approximately one-half will
develop diabetes.

Anti–insulin receptor antibodies occasionally found
in patients with systemic lupus erythematosus and
other autoimmune diseases can cause diabetes by
binding to the insulin receptor.

Other genetic syndromes sometimes
associated with diabetes—
Many genetic syndromes are accompanied
by an increased incidence of diabetes
mellitus.
 These include the chromosomal
abnormalities of Down’s
syndrome,Klinefelter’s syndrome and
Turner’s syndrome, Wolfram's syndrome,
Friedreich's ataxia, Huntington's chorea,
Laurence-Moon-Biedl syndrome, myotonic
dystrophy, porphyria, Prader-Willi
syndrome.


IV. Gestational diabetes mellitus (GDM)
Gestational diabetes is carbohydrate
intolerance resulting in hyperglycaemia
of variable severity with onset or first
recognition during pregnancy.
 It does not exclude the possibility that the
glucose intolerance may antedate
pregnancy but has been previously
unrecognized.


Insulin resistance related to the
metabolic changes of late pregnancy,
and

The increased insulin requirements may
lead to IGT .
Screening & Diagnosis
 SCREENING FOR
DIABETES:
 Recommendations:

The ADA
recommends screening of all
individuals >45 years every 3 years.
 screening individuals at an earlier age if they
are overweight [body mass index (BMI) > 25
km/m2] and have one additional risk factor
for diabetes
Risk Factors for Type 2 Diabetes Mellitus


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


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

Family history of diabetes (i.e., parent or sibling with
type 2 diabetes)
Obesity (BMI 25 kg/m2)
Habitual physical inactivity
Race/ethnicity (e.g., African American, Latino, Native
American, Asian American, Pacific Islander)
Previously identified IFG or IGT
History of GDM or delivery of baby >4 kg (>9 lb)
Hypertension (blood pressure 140/90 mmHg)
HDL cholesterol level <35 mg/dL (0.90 mmol/L)
and/or a triglyceride level >250 mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigricans
History of vascular disease

● To screen for diabetes/pre-diabetes,
either
An FPG test or 2-h OGTT (75-g
glucose load) or both are appropriate.


(B) An OGTT may be considered in
patients with IFG to better define the risk
of diabetes.

Immunolical markers:
In contrast to type 2 DM, a long
asymptomatic period of hyperglycemia is
rare prior to the diagnosis of type 1 DM. A
number of immunologic markers for type
1 DM are becoming available (discussed
below), but their routine use is not
recommended now.
 Diagnosis of
Diabetes:
ADA Criteria for the diagnosis of
diabetes
 1. Symptoms of diabetes and a casual
plasma glucose 200 mg/dl (11.1 mmol/l).
OR
 2. FPG 126 mg/dl (7.0 mmol/l).
OR
 3. 2-h plasma glucose 200 mg/dl (11.1
mmol/l) during an OGTT. (75gm)


WHO Criteria for diagnosis of diabetes mellitus
Diabetes:
Fasting
Or 2-h post glucose load
or both



> 7.0 (> 126)
> 11.1 (> 200)
Impaired Glucose Tolerance (IGT):
Fasting (if measured)
< 7.0 (< 126)
& 2-h post glucose load
> 7.8 (> 140) & < 11.1(<200)
Impaired Fasting Glycaemia (IFG):
Fasting
> 6.1 (> 110) & < 7.0 (< 126) and
(if measured)
2-h post glucose load
< 7.8 (< 140
Some investigators have advocated the
hemoglobin A1C (A1C) as a diagnostic test
for DM.
 Though there is a strong correlation
between elevations in the plasma glucose
and the A1C , the relationship between
the FPG and the A1C in individuals with
normal glucose tolerance or mild glucose
intolerance is less clear, and thus the use
of the A1C is not currently recommended
to diagnose diabetes.

III. DETECTION AND DIAGNOSIS OF
GDM
Recommendations:
● Screen for diabetes in pregnancy using
risk factor analysis and, if appropriate,use of
an OGTT.
 The OGTT should be done in the
morning after an overnight fast of 8–14 h.


● Risk assessment for GDM should be undertaken at
the first prenatal visit.

Women with clinical characteristics consistent with a
high risk for GDM (those with marked obesity,
personal history of GDM, glycosuria, or a strong family
history of diabetes) should undergo glucose testing as
soon as possible.

An FPG _126 mg/dl or a casual plasma glucose _200
mg/dl meets the threshold for the diagnosis of
diabetes

High-risk women not found to haveGDM at the initial
screening and average-risk women should be tested
between 24 and 28 weeks of gestation.

Testing should follow one of two
approaches:
One-step approach: perform a diagnostic
100-g OGTT
 ● Two-step approach: perform an initial
screening by measuring the plasma or
serum glucose concentration 1 h after a 50-g
oral glucose load (glucose challenge test)
and perform a diagnostic 100-g OGTT on
that subset of women exceeding the glucose
threshold value on the glucose challenge
test.

●
When the two-step approach is used, a
glucose threshold value _140 mg/dl
identifies 80% of women with GDM, and
the yield is further increased to 90% by
using a cutoff of _130 mg/dl.
 criteria for the 100-g OGTT are as follows:
_95 mg/dl fasting, _180 mg/dl at 1 h, _155
mg/dl at 2 h, and _140 mg/dl at 3 h. Two
or more of the plasma glucose values
must be met or exceeded for a positive
diagnosis.
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