ETIOPATHOGENESIS OF DIABETES MELLITUS

I. BASED ON CLASSIFICATION
II.TO DIFFERENTIATE THE TYPES OF DM
 ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS
I. Type 1 diabetes
II. Type 2 diabetes
III. Other specific types of diabetes
A. Genetic defects of beta cell function characterized by
mutations
B. Genetic defects in insulin action
C. Diseases of the exocrine pancreas
D. Endocrinopathies
E. Drug- or chemical-induced
F. Infections
G. Uncommon forms
H. Other genetic syndromes
IV. Gestational diabetes mellitus (GDM)
 ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS
I. Type 1 diabetes (beta cell destruction, usually leading
to absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly
insulin resistance with relative insulin deficiency to a
predominantly insulin secretory defect with insulin
resistance)
III. Other specific types of diabetes
A. Genetic defects of beta cell function characterized by
mutations
Maturity onset diabetes of the young (MODY)
characterized by autosomal dominant inheritance, early
onset of hyperglycemia, and impairment in insulin
secretion.
(HNF) alpha4 Glucokinase HNF1alpha (IPF) 1 HNF-1beta
(MODY 1) (MODY 2) (MODY 3) (MODY 4) (MODY 5)

caused by result of begin w/ rare variant these

mutations in mutations in mild caused by transcription
hepatocyte glucokinase hyperglycemia mutations factors
nuclear gene that , but in insulin expressed in
transcription lead to progressive promoter liver, tissues,
factors (HNF) mild-to- impairment of factor (IPF) 1, pancreatic islets
4, HNF-1, (as moderate insulin a and kidney (as a
Mody 3 and hyperglyce secretion transcription result, patients
5) mia requires factor may have renal
treatment w/ that absorption
oral agents or regulates abnormalities
insulin. pancreatic and renal cysts).
development (same w/ Mody
and insulin 1,3)
gene
transcription.
ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS
III. OTHER SPECIFIC TYPES OF DIABETES
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA

8. Proinsulin or insulin conversion

B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipodystrophy syndromes
III. OTHER SPECIFIC TYPES OF DIABETES

C. Diseases of the exocrine pancreas: pancreatitis,

pancreatectomy, neoplasia, cystic fibrosis,
hemochromatosis, fibrocalculous pancreatopathy.
DM can result from pancreatic exocrine disease when
pancreatic islets (80%) are destroyed. Hormones that
antagonize the action of insulin can lead to DM.
 III. OTHER SPECIFIC TYPES OF DIABETES
D. Endocrinopathiesacromegaly, Cushings syndrome,
glucagonoma, pheochromocytoma,
hyperthyroidism,somatostatinoma,aldosteronoma
E. Drug- or chemical-induced:

Vacor, pentamidine, nicotinicacid, glucocorticoids,

thyroid hormone, diazoxide, beta adrenergic agonists,
thiazides, phenytoin, alpha-interferon, protease
inhibitors, clozapine, beta blockers
 III. OTHER SPECIFIC TYPES OF DIABETES
F. Infections:
Congenital rubella, cytomegalovirus, coxsackie viral
infections been implicated in pancreatic islet
destruction, but are an extremely rare cause of DM.
Congenital rubella greatly increases the risk for DM.
 III. OTHER SPECIFIC TYPES OF DIABETES
G. Uncommon forms of immune mediated diabetes:
stiff-man syndrome, anti insulin receptor antibodies
H. Other genetic syndromes sometimes associated
with diabetes:
Downs syndrome, Klinefelters syndrome, Turners
syndrome, Wolframs syndrome, Friedreichs ataxia,
Huntingtons chorea, Laurence-Moon-Biedl
syndrome, myotonic dystrophy, porphyria, Prader-
Willi syndrome
 III. OTHER SPECIFIC TYPES OF DIABETES
GESTATIONAL DIABETES MELLITUS (GDM)
Glucose intolerance may develop during pregnancy.

Insulin resistance related to the metabolic changes of

late pregnancy increases insulin requirements and
may lead to IGT.
Most women revert to normal glucose tolerance post-
partum but have a substantial risk (30 to 60%) of
developing DM later in life.
EPIDEMIOLOGY DM WORLDWIDE (2000)
AGE PERCENTAGE
<20 years old 0.19%
>20 years old. 8.6%
>65 years 20.1%.

GEOGRAPHICAL LOCATION PERCENTAGE

United 13%
States African Americans
Hispanic Americans 10.2%
Native Americans (American Indians and Alaska 15.5%
natives)
non-Hispanic whites. 7.8%
EPIDEMIOLOGY
Incidence type1 DM prevalence of type 2
DM
Scandinavia highest incidence
35/100,000 per year

Japan and China 1 to 3/100,000 per

year

Northern Europe and intermediate rate (8 to

United States 17/100,000 per year).

Pacific islands, highest

India and United intermediate
States
Russia and China low
PATHOGENESIS TYPE 1
DM
 Individuals with genetic susceptibility have normal beta cell mass at birth
but begin to lose beta cells secondary to autoimmune destruction that
occurs over months .
Beta cell mass begins to decline, beta cells are destroyed (80%)
The events that trigger the transition from glucose intolerance to frank
diabetes are associated with increased insulin requirements, as might
occur during infections or puberty.
honeymoon phase ensue during which time glycemic control is achieved
with modest doses of insulin or, rarely, insulin is not needed.
This fleeting phase of endogenous insulin production from residual beta
cells disappears in years.
As the autoimmune process destroys the remaining beta cells, and the
individual becomes completely insulin deficient
GENETIC CONSIDERATIONS (TYPE 1 DM)
HLA region on chromosome 6

class II MHC molecules

antigen helper T cells

(immune response)

antigen-binding sites

(altering the binding affinity of different antigens for
class II molecules)

MHC class II associations, 17 different genetic loci

contribute susceptibility to type 1A DM. The risk of
developing type 1A DM is increased tenfold in
relatives of individuals with the disease
 AUTOIMMUNE FACTORS TYPE 1 DM
Abnormalities in both the humoral and cellular arms
of the immune system:
(1) islet cell autoantibodies
(2) activated lymphocytes in the islets, peripancreatic
lymph nodes, and systemic circulation
(3) T lymphocytes that proliferate when stimulated with
islet proteins
(4) release of cytokines within the insulitis.

Insulitis pancreatic islet molecules are infiltrated with

lymphocytes.
AUTOIMMUNE FACTORS TYPE 1 DM
Beta cells are susceptible to toxic effect of cytokines
[ (TNF-), interferon , and (IL-1)]

nitric oxide metabolites, apoptosis, and direct CD8 T

cell cytotoxicity

beta cells are destroyed, inflammatory process abates

( the islets become atrophic, and immunologic markers
disappear)
AUTOIMMUNE FACTORS TYPE 1 DM
Theory:
autoimmune process

one beta cell molecule

spreads to other islet molecules

immune process destroys beta cells

creates a series of secondary autoantigens

IMMUNOLOGIC MARKERS ISLET CELL AUTOANTIBODIES
(ICAS)

ICAs are different antibodies directed at pancreatic

islet molecules such as GAD, insulin, IA-2/ICA-512,
and an islet ganglioside and serve as marker of
autoimmune process type 1A DM.
ICAs are present in individuals

1. (75%) diagnosed with new-onset type 1A DM

2. Minority of individuals with newly diagnosed type
2 DM (5 to 10%)
3. occasionally in individuals with GDM (5%).
4. 3 to 4% of first-degree relatives of individuals
with type 1A DM
IMMUNOLOGIC MARKERS ISLET CELL
AUTOANTIBODIES (ICAS)

Presence of ICAs with impaired insulin secretion after

intravenous glucose tolerance testing, predict a 50%
risk of developing type 1A DM within 5 years.
Presence of ICAs without impairment in insulin
secretion, predicts a 5year risk of 25%.
Measurement of ICAs in nondiabetic individuals is a
research tool because no treatments have been
approved to prevent the occurrence or progression of
type 1A DM.
ENVIRONMENTAL FACTORS
Identification of environmental trigger has been
difficult because the event may precede the onset of
DM by several years.
Environmental triggers include viruses (coxsackie
and rubella ), bovine milk proteins, and nitrosourea
compounds.
TYPE 2 DM
Insulin resistance and abnormal insulin secretion
are central to the development of type 2 DM.
Most studies support the view that insulin
resistance precedes insulin secretory defects and
that diabetes develops only if insulin secretion
becomes inadequate.
RISK FACTORS FOR TYPE 2 DIABETES MELLITUS
Family history of diabetes (i.e., parent or sibling with
type 2 diabetes)
Obesity (BMI >or equal to 25 kg/m2)
Habitual physical inactivity
Race/ethnicity (e.g., African American, Hispanic
American, 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> or equal to 140/90
mmHg)
HDL cholesterol level < or equal to 35 mg/dL (0.90
mmol/L) and/or a triglyceride
level 250>or equal to mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigracans
History of vascular disease
GENETIC CONSIDERATIONS TYPE 2 DM
Various genetic loci contribute to susceptibility, and
environmental factors (such as nutrition and physical
activity) further modulate phenotypic expression of the
disease.
Type 2 DM in identical twins is between 70 and 90%.
Individuals with parent with type 2 DM have increased
risk of diabetes
If both parents have type 2 DM, the risk approaches 40%
Mutations in various molecules involved in insulin action
a. the insulin receptor and enzymes involved in glucose
homeostasis) account for a very small fraction of type 2
DM.
The gene for the protease, calpain 10, is associated with
type 2 DM in Hispanic and some other populations.
PATHOPHYSIOLOGY TYPE 2 DM
Characterized by three pathophysiologic abnormalities:
1. impaired insulin secretion
2. peripheral insulin resistance
3. excessive hepatic glucose production
Obesity is very common in type 2 DM.

Adipocytes secrete number of biologic products

(leptin, TNF-, free fatty acids, resistin, and
adiponectin) that modulate insulin secretion, insulin
action, and body weight and contribute to the insulin
resistance.
PATHOPHYSIOLOGY TYPE 2 DM
Early stages of the disorder

( glucose tolerance remains normal, despite insulin resistance,
because the pancreatic beta cells compensate by increasing
insulin output)

Insulin resistance and compensatory hyperinsulinemia
progress

The pancreatic islets are unable to sustain the

hyperinsulinemic state.

IGT develops (characterized by elevations in postprandial

glucose)

A further decline in insulin secretion and an increase in

hepatic glucose production lead to overt diabetes with fasting
hyperglycemia.

Beta cell failure may ensue.

 METABOLIC ABNORMALITIES
INSULIN RESISTANCE
Decreased ability of insulin to act effectively
on peripheral target tissues (especially
muscle and liver) is prominent feature of type
2 DM and results from a combination of
genetic susceptibility and obesity.
Insulin resistance impairs glucose utilization
by insulin-sensitive tissues and increases
hepatic glucose output; both effects
contribute to the hyperglycemia.
 INSULIN RESISTANCE

Increased hepatic glucose output accounts

increased FPG levels, decreased peripheral glucose
usage results in postprandial hyperglycemia.
In skeletal muscle a greater impairment in
nonoxidative glucose usage (glycogen formation)
than in oxidative glucose metabolism through
glycolysis.
Glucose metabolism in insulin-independent tissues
is not altered in type 2 DM.
 INSULIN RESISTANCE
Pathogenesis of insulin resistance is focused on
a PI-3-kinase signaling defect, which reduces
translocation of GLUT4 to the plasma
membrane.
Not all insulin signal transduction pathways are
resistant to the effects of insulin [e.g., those
controlling cell growth and differentiation and
using the mitogen-activated protein (MAP)
kinase pathway.
Hyperinsulinemia may increase insulin action
through these pathways, potentially
accelerating diabetes-related conditions such
as atherosclerosis.
 INSULIN RESISTANCE
Theory:
Elevated levels of free fatty acids
(obesity)

impair glucose utilization in skeletal

muscle
AND
promote glucose production by the liver

impair beta cell function

IMPAIRED INSULIN SECRETION
Type 2 DM, insulin secretion initially increases in
response to insulin resistance to maintain normal
glucose tolerance.
Initially, the insulin secretory defect is mild and
selectively involves glucose-stimulated insulin
secretion.
The response to other non glucose secretagogues,
such as arginine, is preserved.
Eventually, insulin secretory defect progresses to a
state of grossly inadequate insulin secretion.
Despite the assumption that a second genetic
defect superimposed upon insulin resistance
leads to beta cell failure, intense genetic
investigation has so far excluded mutations in islet.
 INCREASED HEPATIC GLUCOSE
PRODUCTION
In type 2 DM, insulin resistance in liver
reflects the failure of hyperinsulinemia to
suppress gluconeogenesis, which results
fasting hyperglycemia and decreased
glycogen
Storage by liver in the postprandial state.
Increased hepatic glucose production occurs
early in the course of diabetes, though likely
after the onset of insulin secretory
abnormalities and insulin resistance in
skeletal muscle.
INSULIN RESISTANCE SYNDROMES
Insulin resistance comprises a spectrum of disorders, with
hyperglycemia.
Metabolic syndrome, insulin resistance syndrome, or
syndrome X are terms used to describe a constellation of
metabolic derangements that includes insulin resistance,
hypertension, dyslipidemia [low high-density lipoprotein
(HDL) and elevated triglycerides], central or visceral
obesity, type 2 diabetes or IGT/IFG, and accelerated
cardiovascular disease.
Epidemiologic evidence supports hyperinsulinemia as
marker for coronary artery disease risk.
Acanthosis nigricans and signs of hyperandrogenism
(hirsutism, acne, and oligomenorrhea in women) are also
common physical features.
 INSULIN RESISTANCE SYNDROMES
Two distinct syndromes of severe insulin resistance:
(1) type A - affects young women, characterized by
severe hyperinsulinemia, obesity, and features of
hyperandrogenism
(2)type B - affects middle-aged women,
characterized by severe hyperinsulinemia, features of
hyperandrogenism, and autoimmune disorders.
Individuals with type A insulin resistance have
undefined defect in insulin-signaling pathway.
Individuals with type B insulin resistance have
autoantibodies directed at insulin receptor.
Receptor autoantibodies may block insulin binding or
stimulate the insulin receptor, leading to intermittent
hypoglycemia.
 POLYCYSTIC OVARY SYNDROME (PCOS)
Affects premenopausal women
Characterized by:
a. chronic anovulation
b. hyperandrogenism
Insulin resistance is seen in a significant subset of
women with PCOS.
The disorder increases the risk for type 2 DM,
independent of the effects of obesity.