Diabetes mellitus

Normal endocrine pancreas 1 million microscopic clusters of cells 1 million microscopic clusters of cells Β,α,δ,PP cells Β,α,δ,PP cells β cells → insulin β cells → insulin α → glucagon α → glucagon Δ → somatostatin Δ → somatostatin PP → VIP PP → VIP

Diabetes mellitus Definition: group of metabolic disorders sharing the common underlying feature of hyperglycemia Definition: group of metabolic disorders sharing the common underlying feature of hyperglycemia Multisystem disease with biochemical and structural consequences. Multisystem disease with biochemical and structural consequences. Defect of insulin secretion, insulin action or both Defect of insulin secretion, insulin action or both Effect on carbohydrate, protein and fat metabolism Effect on carbohydrate, protein and fat metabolism

Epidemiology 21 million people in US 21 million people in US Asians Asians Some tribals eg Pima indians Some tribals eg Pima indians Complications- eye,renal,PNS,blood vessels etc. Complications- eye,renal,PNS,blood vessels etc.

Classification PRIMARY PRIMARY Type I- 10%,absolute deficiency of insulin Type I- 10%,absolute deficiency of insulin Autoimmune disease,β cell destruction Autoimmune disease,β cell destruction Type % Type % Peripheral resistance to insulin & inadequate insulin secretion Peripheral resistance to insulin & inadequate insulin secretion Genetic defects of β cell function (MODY) Genetic defects of β cell function (MODY) Genetic defects in insulin processing or insulin action Genetic defects in insulin processing or insulin action

Classification (cont.) SECONDARY SECONDARY Exocrine pancreatic defects Exocrine pancreatic defects Endocrinopathies Endocrinopathies Infections Infections Drugs –CS etc Drugs –CS etc Genetic syndrome associated with diabetes. Genetic syndrome associated with diabetes. Gestational diabetes mellitus Gestational diabetes mellitus

Role of insulin Glucose uptake & utilization in the peripheral tissues esp skeletal muscle, adipocytes Glucose uptake & utilization in the peripheral tissues esp skeletal muscle, adipocytes (brain independent of insulin) (brain independent of insulin) Anabolic action- ↑ synthesis, ↓ degradation of glycogen, lipid & protein. Anabolic action- ↑ synthesis, ↓ degradation of glycogen, lipid & protein. Mitogenic → ↑ DNA, growth & differentiation Mitogenic → ↑ DNA, growth & differentiation Opposing actions of insulin and glucagon Opposing actions of insulin and glucagon

Metabolic actions of insulin

Mechanism of insulin release Insulin release – Glucose, Intestinal hormones Insulin release – Glucose, Intestinal hormones Aminoacids: leucine, arginine Aminoacids: leucine, arginine Insulin synthesis Insulin synthesis Glucose Glucose

Mechanism of insulin action

Pathogenesis of Type 1 DM Organ specific autoimmune disease Organ specific autoimmune disease Genetic susceptibility gene-HLA DR 3,HLA DR4, both Genetic susceptibility gene-HLA DR 3,HLA DR4, both Environment- viral infections Environment- viral infections T lymphocytes against ill defined β cell antigens ? epitopes on insulin hormone T lymphocytes against ill defined β cell antigens ? epitopes on insulin hormone Autoimmune antibodies against insulin Autoimmune antibodies against insulin Glutamic acid decarboxylase (GAD)etc. Glutamic acid decarboxylase (GAD)etc.

Pathogenesis of Type 1 DM (cont) T lymphocytes TH-1, CD4+,Activate macrophages T lymphocytes TH-1, CD4+,Activate macrophages CD 8+ directly cytotoxic, release cytokines that stimulate monocytes CD 8+ directly cytotoxic, release cytokines that stimulate monocytes Cytokines produced by T lymphocytes & macrophages inc IFN γ,TNF,IL-1 Cytokines produced by T lymphocytes & macrophages inc IFN γ,TNF,IL-1 Insulitis Insulitis overt diabetes >90% cells damaged overt diabetes >90% cells damaged

Stages in the development of type 1 DM

Microscopy Type 1 Type 1 Insulitis –lymphocytic inflitrate in islets +/- macrophages, neutrophils Insulitis –lymphocytic inflitrate in islets +/- macrophages, neutrophils Depletion of beta cells of islets Depletion of beta cells of islets Fibrosis of islets Fibrosis of islets NO AMYLOID DEPOSITION NO AMYLOID DEPOSITION

Type 2 diabetes mellitus Heterogenous disorder characterized by a combination of reduced tissue sensitivity to insulin and inadequate secretion of insulin from the pancreas. Heterogenous disorder characterized by a combination of reduced tissue sensitivity to insulin and inadequate secretion of insulin from the pancreas. Adult Adult Central obesity Central obesity

Pathogenesis of type 2 DM Predisposing factors Environmental - sedentary, diet, obesity Genetic predisposition-polygenic Insulin resistance in peripheral tissues Β cell dysfunction (impaired insulin secretion in response to glucose)

Insulin resistance Resistance to the effects of insulin on glucose uptake, metabolism or storage. (inability of tissues to respond to insulin) Resistance to the effects of insulin on glucose uptake, metabolism or storage. (inability of tissues to respond to insulin) yrs before DM yrs before DM Predictor of subsequent progress to DM Predictor of subsequent progress to DM ↓ uptake of glucose in muscle and adipose ↓ uptake of glucose in muscle and adipose Inability to supress hepatic gluconeogeneisis Inability to supress hepatic gluconeogeneisis

Quantitative & qualitative abnormality of insulin signaling pathway

Obesity and insulin resistance Obesity-central Obesity-central FFA levels inversely proportional to insulin sensitivity → acquired insulin resistance. FFA levels inversely proportional to insulin sensitivity → acquired insulin resistance. Adipocytokines dysregulation Adipocytokines dysregulation Resistin- acquired insulin resistance Resistin- acquired insulin resistance

Β cell dysfunction Inability of β cells to adapt to the long term demands of peripheral insulin resistance and increased insulin secretion. Inability of β cells to adapt to the long term demands of peripheral insulin resistance and increased insulin secretion. Inadequate β cell compensation -? lipotoxic ? glucotoxic Inadequate β cell compensation -? lipotoxic ? glucotoxic Qualitative & quantitative dysfunction of Qualitative & quantitative dysfunction of β cells β cells Overt diabetes Overt diabetes

Morphology of type 2 DM NO morphological lesion in beta cells or consistent reduction in their numbers. NO morphological lesion in beta cells or consistent reduction in their numbers. Fibrous tissue accumulation in some islets Fibrous tissue accumulation in some islets Amyloid deposit in islets (amylin) Amyloid deposit in islets (amylin)

An islet of Langerhans demonstrates amorphous pink deposition of amyloid in a patient with type II diabetes mellitus

Monogenic forms of diabetes Uncommon Secondary to loss of function mutations within a single gene. Primary defect in β cell function (MODY) Primary defect in β cell function (MODY) Defect in insulin /insulin receptor signaling Defect in insulin /insulin receptor signaling

Clinical features Sir William Osler Sir William Osler 3 P’s polydypsia,polyphagia,polyuria 3 P’s polydypsia,polyphagia,polyuria Frequent infections Frequent infections Unexplained weight loss Unexplained weight loss

H igh fasting glucose or impaired glucose tolerance H igh fasting glucose or impaired glucose tolerance (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period) (without diabetes, oral glucose loads cause only slight rise in blood glucose due to brisk insulin response; with diabetes, blood glucose rises markedly for a sustained period) Diagnosis

Random glucose (mg/dL ) >200 FastingGlucose < >126 AbnormalOGTT< >200 DIAGNOSISEuglycemic Impaired glucose toleranceDiabetesmellitus DIAGNOSIS OF DIABETES DIAGNOSIS OF DIABETES

Glucose tolerance test Fasting overnight Fasting overnight Oral glucose 75 mg Oral glucose 75 mg 2 hrs later 2 hrs later Draw the graph Draw the graph

Glycosylated hemoglobin (Hemoglobin A 1C) (Hemoglobin A 1C) Proportional to the average glucose concentration and life span of RBC Proportional to the average glucose concentration and life span of RBC Normal range (< 6%) Normal range (< 6%) Used as a monitor of good glucose level control by patients. Used as a monitor of good glucose level control by patients.

Summary Normal glucose control Normal glucose control Release &Action of insulin Release &Action of insulin Definition of Diabetes Definition of Diabetes Classification of Diabetes Classification of Diabetes Aetiology, pathogenesis morphology of Type 1 & type 2 DM Aetiology, pathogenesis morphology of Type 1 & type 2 DM Lab diagnosis of DM Lab diagnosis of DM