DIABETES MELLITUS 2010

ETIOPATHOGENESIS

Presented by- AVIK BASU

ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS

1. Type I Diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

A. Immune mediated B. Idiopathic2. Type II Diabetes ( may range from predominantly insulin resistance with

relative insulin deficiency to a predominantly insulin secretory defect with insulin resistance)

3. Other specific types of Diabetes A. Genetic defects of β-cell function characterized by mutations in: i) Hepatocyte Nuclear Transcription Factor (HNF) 4α (MODY 1) ii) Glucokinase (MODY 2) iii) HNF 1α (MODY 3)

iv) Insulin Promoter Factor(IPF) 1 (MODY 4) v) HNF 1β (MODY 5) vi) Neuro D1 (MODY 6) vii) Mt DNA viii) Subunits of ATP sensitive Potassium Channel

ix) Proinsulin or insulin conversion B. Genetic defects in insulin action: i) Type A insulin resistance ii) Leprechaunism iii) Rabson-Mendenhall syndrome iv) Lipodystrophy syndrome C. Diseases of 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. Infections-congenital rubella, cytomegalovirus, cox sackie

G. Uncommon forms of immune mediated diseases-stiff person syndrome, anti- insulin receptor antibodies H. Other genetic diseases sometimes associated with diabetes-Down’s syndrome, Kleinfelter’s syndrome, Turner’s syndrome, Wolfram’s syndrome, Freiderich’s ataxia, Huntington’s chorea, Lawrence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome4. Gestational diabetes mellitus

F. Drug or chemical induced-Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, β-adrenergic agonists, thiazides, phenytoin, α-interferon, protease inhibitors, clozapine

TYPE -I DIABETES

(1)Genetic Factor: Genetic factor accounts for about

one-third of the susceptibility to Type-I diabetes mellitus. Over 20 diferent regions of human genome show linkage with the disease, but the main focus remains on the HLA region within the major histocompatibility complex on the short arm of chromosome 6; the locus being designated as the IDDM 1.

The region of the insulin gene on chromosome 11p is also linked with the disease, the locus being designated as IDDM 2. Other loci lying on chromosomes 15q, 11q and 6q are IDDM 3, IDDM 4 and IDDM 5 respectively.

RISK OF DEVELOPING TYPE-I DIABETES IN AN INDIVIDUAL WHO HAS A FIRST DEGREE RELATIVE WITH THE DISEASE

Relative with Type-I Diabetes % Overall Risk

Identical twin 35

Non-identical twin 20

HLA-identical sibling 16

Non-HLA-identical sibling 3

Father 9

Mother 3

Both parents Up to 30

TEMPORAL MODEL FOR DEVELOPMENT OF TYPE-I DIABETES

(2) ENVIRONMENTAL FACTOR: Although genetic susceptibility appears to be a prerequisite for the development of Type-I diabetes, the concordance rate between monozygotic twins is less than 40%, and environmental factors have an important role in promoting clinical expression of the disease.

(3) VIRUS: Several viruses like mumps virus, Coxsackie B4, retrovirus, rubella (in utero), cytomegalovirus and Epstein-Barr virus have been found to be associated with the etiogenesis of the disease. (4) DIET : Dietary factors like Bovine Serum

Albumin (BSA) of cow’s milk, nitrosamines (in smoked and cured meats) and coffee have been proposed as potentially diabetogenic.

(5) STRESS: Stress may progress development of Type-I diabetes by stimulating secretion of counter-regulatory hormones and possibly by modulating immune activity.

(6) IMMUNOLOGICAL FACTORS: Type-I diabetes is a slow T-cell mediated autoimmune disorder. Family studies have produced evidence that destruction of the insulin secreting cells in the pancreatic islets takes place over many years. Hyperglycemia accompanied by the classical symptoms of diabetes occurs only when 70-90% of beta cells have been destroyed. In humans and animals with spontaneous type-I diabetes the immune system retains the capacity to recognize and destroy transplanted pancreatic beta cells indefinitely.

(7) PANCREATIC PATHOLOGY:

Proposed pathogenesis of Type-I Diabetes

Normal islet

Viral infection in pancreatic beta cells

Secretion of interferon-α by islet cells

Hyper expression of MHC class-I antigen within islets

Insulinitis

SelectiveDestruction ofBeta cells Insulin deficient

islet

TYPE-II DIABETES

(1) GENETIC FACTORS: Type-II diabetes has a strong

genetic component. The concordance of the disease in identical twins is between 70 and 90%. Individuals with a parent having the disease have an increased risk of diabetes. If both the parents have type-II diabetes, then the risk is about 40%. Of the genes that predispose to type-II diabetes, the most prominent is a variant of the transcription factor-7 like gene and the genes encoding PPARγ, IRS, calpain 10,etc.

RISK OF DEVELOPING TYPE-II DIABETES UPTO AGE OF 80 YEARS FOR SIBLINGS OF PROBANDS

WITH THE DISEASE

Age at Onset of Type-II Diabetes in Probands

Age-corrected Risk of Type-II Diabetes for Siblings (%)

25-44 53

45-54 37

55-64 38

65-80 31

SINGLE GENE DEFECTS OF PANCREATIC BETA CELL FUNCTION CAUSING MATURITY ONSET DIABETES OF THE YOUNG (MODY)

Gene Inheritance Clinical Features

Glucokinase (GCK) Autosomal dominant 10% of MODY in UK; mild hyperglycemia from birth, stable and managed by diet alone

Hepatic Nuclear Factor (HNF) 1α

Autosomal dominant 65% of MODY in UK; diabetes presents during adolescence, progressive with requirement of insulin or oral agents for control

HNF 4α Autosomal dominant 5% of MODY in UK; similar to HNF 1α, begins later

Insulin Promoter Factor (IPF) 1

Autosomal dominant Rarely begins before 25 years

HNF 1β Autosomal dominant Rare; presents renal cysts and renal failure

(2) LIFESTYLE: Epidemiological studies of Type-II diabetes provide evidence that overeating, especially when combined with obesity and underactivity, is associated with the development of this type of diabetes.(3) MALNUTRITION IN UTERO: Retrospective analysis of

the birth weight of males born in England in 1930s has demonstrated an inverse relationship between weight at birth and at 1 year, and the development of type-II diabetes in late adulthood.

(4) AGE: Type-II diabetes is principally a disease of the

middle age and elderly, affecting 10% population over the age of 65.

(5) PREGNANCY: During normal pregnancy, insulin

sensitivity is reduced through the action of placental hormone and this affects glucose tolerance. The insulin secreting cells of pancreatic islets are unable to meet this increased demand in women genetically predisposed to the disease.

(6) IMPAIRED INSULIN SECRETION: In type-II diabetes, 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.

Though the reason for the decline in the insulin secretory capacity is unclear, it is assumed that a second genetic defect-superimposed upon insulin resistance leads to beta cell failure. Islet amyloid polypeptides secreted from beta cells is deposited on the islets in long standing cases of the disease.

INSULIN SECRETORY CAPACITY IN TYPE-II DIABETES

(7) INSULIN RESISTANCE SYNDROMES: Insulin resistance syndrome or Metabolic syndrome or Syndrome X are terms used to describe a constellation of metabolic derangements that includes hyperinsulinemia, impaired glucose tolerance, hypertension, low HDL cholesterol, elevated triglycerides, central obesity, microalbuminuria, increased fibrinogen, increased plasminogen activator inhibitor-1 and elevated plasma uric acid. A number of relatively rare forms of severe insulin resistance include features of type-II diabetes. Two distinct syndromes of severe insulin resistance have been described in adults-Type A affecting young women and Type B affecting middle aged women. Insulin resistance is seen in a significant subset of women with Polycystic Ovarian Syndrome.

(8) INCREASED HEPATIC GLUCOSE AND LIPID PRODUCTION: 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. As a result of insulin resistance in adipose tissue and obesity, free fatty acid flux from adipocytes is increased, leading to increased lipid synthesis in hepatocytes.

This lipid storage or steatosis in the liver may lead to Non Alcoholic Fatty Liver Disease and abnormal liver function tests.

(9) ABNORMAL MUSCLE AND FAT METABOLISM: Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output, both contributing to hyperglycemia. In skeletal muscle, there is greater impairment in the non-oxidative glucose usage (Glycogen formation) than in oxidative glucose metabolism through glycolysis. Though the precise molecular mechanism of insulin resistance is not known, it is believed that insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to the hyperinsulinemia and not primary defect. Therefore, ‘post-receptor’ defects in insulin mediated phosphorylation/dephosphorylation may play the predominant role in insulin resistance. For example, a PI3 kinase signalling defect may reduce translocation of GLUT4 to the plasma membrane. The obesity accompanying type-II diabetes, particularly in a central or visceral location is thought to be a part of the pathogenic process. The increased adipocyte mass leads to increased levels of circulating free fatty acids and other fat cell products like non-esterified free fatty acids, retinol binding protein 4, leptin, TNFα, resistin and adiponectin that modulate insulin sensitivity. This increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver.

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