XIV PANCREATIC HORMONES Diabetes mellitus 16 million in

XIV. PANCREATIC HORMONES Diabetes mellitus - 16 million in U. S. , half unaware, 650, 000 new diagnoses/year Occurs most often in adults But is most prevalent chronic disorder in teenagers — 127, 000 A. Hormones 1. Insulin - secreted by ß-cells 2. Glucagon - secreted by -cells 3. Both hormones regulate blood glucose levels

XIV. PANCREATIC HORMONES A. Regulation of release 1. Gastrointestinal nutrients and hormones — glucose, amino acids, fatty acids, ketone bodies and gastrointestinal hormones stimulate secretion. 2. Autonomic mechanisms -Norepinephrine and epinephrine inhibit secretion Selective ß-receptor stimulation stimulates release Cholinergic stimulation (e. g. , vagus) stimulates release 3. Hormones a) glucagon b) somatostatin 4. Glucose — increase in blood glucose increases release decrease in blood glucose decreases release

XIV. PANCREATIC HORMONES B. Mechanism of release Leads to depolarization Glucose Closes Potassium channel Glucose transporter R Glucose Decreases potassium conductance Calcium channels ATP Ca+ Metabolism Insulin granules Insulin

XIV. PANCREATIC HORMONES C. Role in metabolic processes 1. Review Glucagon Glucose Glycogen synthetase R Gluco-1 phosphatase Glycogen Energy utilization Gluconeogenesis Lipase Urea excretion Protein Lipid Amino Acids Free Fatty Acids Ketone Bodies Liver

XIV. PANCREATIC HORMONES C. Role in metabolic processes 2. Insulin effects Increases Glucose Decreases Glycogen synthetase Insulin R Glycogen Gluco-1 phosphatase Energy utilization Gluconeogenesis Lipase Urea excretion Protein Free Fatty Acids Ketone Bodies Liver Lipid Amino Acids

XIV. PANCREATIC HORMONES C. Role in metabolic processes 3. Insulin deficiency Hyperglycemia Increases Decreases Insulin Glycogen synthetase R Glycogen Gluco-1 phosphatase Gluconeogenesis Lipase Urea excretion (Azoturia) (Ketonemia and Acidosis) Energy utilization Protein Free Fatty Acids Ketone Bodies Liver Amino Acids Lipid Hyperlipemia

XIV. PANCREATIC HORMONES D. Types of diabetes mellitus 1. Insulin-dependent diabetes mellitus (IDDM, Type I) a) Characteristics: Severe form Usually in juveniles Occasionally in adults Insulin virtually absent Plasma glucagon elevated b) Etiology Pancreatic B cell unresponsive to insulin stimuli Damaged pancreatic B cells Autoimmune response Environmental insult Genetic defect

XIV. PANCREATIC HORMONES D. Types of diabetes mellitus 2. Non-insulin-dependent diabetes mellitus (NIDDM, Type II) a) Characteristics: Milder than IDDM Usually adults, occasionally juveniles Heterogenous group b) Etiology Subnormal levels of insulin Tissue insensitivity to insulin Pancreatic B cell unresponsive to insulin Hyperglycemia impairs B cell response

XIV. PANCREATIC HORMONES E. Replacement therapy in IDDM 1. 2. 3. 4. 5. 6. 5. Preparations of insulin are divided into three catagories according to promptness, duration and intensity of action. Fast-acting — zinc insulin Intermediate acting — Isophane insulin suspension is a modified protamine zinc insulin Long-acting -- Hagedorn insulin-zinc-protamine complex Humalog Mix 25 (Canada) Velosulin BR New modes of treatment - infusion pumps and inhalers

XIV. PANCREATIC HORMONES F. Insulin side effects 1. Hypoglycemia — insulin requirement reduced, failure to eat, unaccustomed exercise, or ins can all cause hypoglycemia a) A rapid fall in blood glucose b) A slow fall in blood glucose Treatment of hypoglycemia is to administer fruit juice or glucose; if not available, then glucagon 2. Other adverse reactions — mostly allergic reactions, but usually subside after c

XIV. PANCREATIC HORMONES G. Treatment of NIDDM 1. Diet 2. Insulin -- most patients treated with insulin and diet 3. Oral hypoglycemic agents: Used when diet control insufficient Used with insulin to lower dosage of insulin. Not when insulin requirements exceed 200 units/day.

XIV. PANCREATIC HORMONES G. Treatment of NIDDM 3. Oral hypoglycemic agents (cont. ) a) Sulfonylureas (first generation) 1) Agents - acetohexamide (Dymelor), chlorpropamide (Diabinese), tolazamide (Tolinase), tolbutamide (Orinas 2) Mechanism of action -- stimulate ß-cells to secrete insulin 3) Adverse effects -- associated with cardiovascular disease, hyp Effectiveness questioned b) Sulfonylureas (second generation) a) Agents - glyburide (Diabeta, Micronase) and glipizide (Glucotrol) a Glimepride (1996) b) Mechanism of action: Stimulate insulin release from ß cells (K channel bl Release glucogon and somatostatin Inhibit hepatic gluconeogenesis Enhance insulin receptor sensitivity c) Adverse effects - less than with first generation

XIV. PANCREATIC HORMONES G. Treatment of NIDDM c) Biguanides Phenformin introduced in 1957 Metformin (Glucophage) available in 1994 Mechanism of action -increases the utilization of glucose by decreasing cellular respiration decreases glucose levels by inhibiting gluconeogenesis inhibits intestinal absorption of glucose Adverse effects -- phenformin produced fatal lactic acidosis, metformin much less so Contraindications — hepatic disease or past history of lactic acidosis

XIV. PANCREATIC HORMONES G. Treatment of NIDDM d) Thiazolidinediones (antihyperglycemic) Troglitazone (Rezulin) - marketed in 1997 Ciglitazone, Pioglitazone (Actos) - FDA approval pending, Rosiglitazone (Avandia) Action - reduce plasma glucose, insulin and lipid levels in insulin-rresistant animal models Mechanism of action - increases synthesis of insulin transporters Toxicity - troglitazone implicated in acute liver failure, FDA recommends other in this class carry warning label rosiglitazone elevates LDL rosiglitazone may be fetotoxic

XIV. PANCREATIC HORMONES G. Treatment of NIDDM e) Alpha-glucosidase inhibitors Acarbose (Precose) Mechanism of action - reduces intestinal absorption of starch dextrin, and disaccharides — postprandial reduction in plasma glucose Side effects - malabsorption, flatulence and abdominal bloating

XIV. PANCREATIC HORMONES H. Glucagon 1. Physiological actions a) Insulin and glucagon are mutual antagonists Glucagon mobilizes fuel -- increases [glucose] plasm Increased glucose leads to increase in insulin and decrease in glucagon b) Following a meal, decreased glucagon secretion. c) Starvation (decrease in blood glucose) causes increase in glucagon secretion 2. Regulation of secretion -- glucose is primary stimulus. Increased plasma glucose decreases glucagon secretion and vice versa 3. Therapeutic use -- used to treat insulin-induced hypoglycemia