DIABETES MELLITUS

b Diabetes mellitus is not a single disease entity but rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia.

Hyperglycemia in diabetes results from b defects in insulin secretion, b defects in insulin action, b most commonly, both.

chronic hyperglycemia and attendant metabolic dysregulation of diabetes mellitus b associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels. b Diabetes is a leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputations b greatly increases the risk of developing coronary artery disease and cerebrovascular disease.

Diagnosis b Blood glucose levels - 70 to 120 mg/dL. b Diagnosis - By Elevation Of Blood Glucose By Any One Of Three Criteria: b A random blood glucose concentration of 200 mg/dL or higher, with classical signs and symptoms b A fasting glucose concentration of 126 mg/dL or higher on more than one occasion, b An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 gm of glucose).

Normal glucose homeostasis is tightly regulated by three interrelated processes: b (1) glucose production in the liver, b (2) glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle, b (3) actions of insulin and counter- regulatory hormones (e.g., glucagon).

b The principal metabolic function of insulin is to increase the rate of glucose transport into certain cells in the body b These are the striated muscle cells (including myocardial cells) and, to a lesser extent, adipocytes, representing collectively about two-thirds of the entire body weight. b Glucose uptake in other peripheral tissues, most notably the brain, is insulin independent.

b Besides promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation (lipolysis) in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis while inhibiting protein degradation. b metabolic effects of insulin - anabolic, with increased synthesis and reduced degradation of glycogen, lipid, and protein. b In addition - several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation.

Etiologic Classification of Diabetes Mellitus b Type 1 Diabetes - β-cell destruction, leads to absolute insulin deficiency b Type 2 Diabetes -Insulin resistance with relative insulin deficiency b Genetic Defects of β-Cell Function b Genetic Defects in Insulin Processing or Insulin Action b Exocrine Pancreatic Defects b Endocrinopathies b Infections b Drugs b Genetic Syndromes Associated with Diabetes b Gestational Diabetes Mellitus

Pathogenesis of Type 1 Diabetes Mellitus b autoimmune disease in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly defined β-cell antigens, resulting in a reduction in β-cell mass b genetic susceptibility and environmental influences play important roles in the pathogenesis. b most commonly develops in childhood, becomes manifest at puberty, and is progressive with age. b Most individuals with type 1 diabetes depend on exogenous insulin supplementation for survival, and without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma.

b The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the β cells have been destroyed. b Several mechanisms contribute to β-cell destruction, and it is likely that many of these immune mechanisms work together to produce progressive loss of β cells, resulting in clinical diabetes:

Type 1 diabetes b complex pattern of genetic association b the principal susceptibility locus for type 1 diabetes resides in the region that encodes the class II MHC molecules on chromosome 6p21 (HLA-D). b Between 90% and 95% - HLA-DR3, or DR4, or both, b we do not know the actual genes in the many other susceptibility loci. b also evidence to suggest that environmental factors, especially infections, - viruses may be an initiating trigger, -molecular minicry

Pathogenesis of Type 2 Diabetes Mellitus b pathogenesis of type 2 diabetes remains enigmatic. Environmental influences, such as a sedentary life style and dietary habits, clearly have a role, b Nevertheless, genetic factors are even more important than in type 1 diabetes, with linkage demonstrable to multiple "diabetogenic" genes. Among identical twins, the concordance rate is 50% to 90%, while among first-degree relatives with type 2 diabetes (including fraternal twins) the risk of developing the disease is 20% to 40%, as compared with 5% to 7% in the population at large..

b The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of peripheral tissues to respond to insulin (insulin resistance) and (2) β-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. In most cases, insulin resistance is the primary event and is followed by increasing degrees of β- cell dysfunction.

Maturity onset Diabetes of Young {MODY } b Insulin secretory defect without beta cell loss b Autosomal dominant inheritance with high penetrance b Early onset before 25 b Impaired β - cell function, normal weight, lack of GAD antibodies, lack of INSULIN resistance syndrome lack of INSULIN resistance syndrome

Genetic defects in MODY b Mutations in HNF - 4 alpha on chromosome 20 - MODY 1 b Mutations in glucokinase gene on chromosome 7 - MODY 2 b Mutations in HNF - 1α on chromosome 12 q - MODY 3 12 q - MODY 3

Pathogenesis of Complications b NON - ENZYMATIC GLYCOSYLATION The degree of non-enzymatic glycosylation is related to the level of blood glucose The Early glycosylation products on collagen & other proteins in interstitial tissues & Blood vessels chemical rearrangement Irreversible advanced glycosylation end products (AGE )

A G E ( 1 ) On proteins such as collagen AGE CROSS LINKING between polypeptides of collagen molecule trap plasma / interstitial proteins CROSS LINKING between polypeptides of collagen molecule trap plasma / interstitial proteins

b Trapping of LDL Retards its efflux from vessel wall deposition of cholesterol in intima accelerates atherogenesis b In the Renal glomeruli, albumin binds to glycosylated BM thickening of BM - characterestic of DIABETIC MICROANGIOPATHY AGE [ contd. ….]

A G E b AGE BINDS TO RECEPTORS ON ENDOTHELIUM, MONOCYTES, LYMPHOCYTES, MESANGIAL CELLS Binding increases endothelial permeability, increased monocyte migration, release of cytokines, increased procoagulant activity, of endothelial cells, enhanced proliferation & synthesis of ECM by fibroblasts & SMC

POLYOL Pathways Nerves, lens, kidneys, blood vessels DO NOT require insulin for glucose transport Nerves, lens, kidneys, blood vessels DO NOT require insulin for glucose transport Hyperglycaemia intracellular glucose sorbitol fructose sorbitol & fructose increased intracellular osmolarity influx of water osmotic cell injury sorbitol & fructose increased intracellular osmolarity influx of water osmotic cell injury

MORPHOLOGY - PANCREAS b TYPE reduction in number & size of islets - reduction in number & size of islets - leukocytic infilteration of islets - leukocytic infilteration of islets b TYPE subtle reduction in islet cell mass - subtle reduction in islet cell mass - amyloid replacement of islets - amyloid replacement of islets

MORPHOLOGY – VASCULAR SYSTEM Vessels of all sizes are affected b Aorta, large, medium sized arteries - accelerated severe atherosclerosis b M I - most common cause of death b Gangrene times more common b Microangiopathy

MORPHOLOGY - KIDNEY [ Diabetic Nephropathy ] b Glomerular lesions - capillary BM thickening - capillary BM thickening - diffuse glomerulosclerosis - diffuse glomerulosclerosis - nodular glomerulosclerosis - nodular glomerulosclerosis [ K - W bodies ] [ K - W bodies ] b Renal vascular lesions b Pyelonephritis

OCULAR COMPLICATIONS b Retinopathy b Cataract b Glaucoma Total blindness is one of the most feared complications of DIABETES

Diabetic Neuropathy b Peripheral symmetric neuropathy of lower extremities b Both sensory & motor functions