XIV. PANCREATIC HORMONES 1.Insulin - secreted by ß-cells 2.Glucagon - secreted by  -cells 3.Both hormones regulate blood glucose levels A. 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

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 A. Regulation of release

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

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

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

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

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 D. Types of diabetes mellitus

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

1. Hypoglycemia — insulin requirement reduced, failure to eat, unaccustomed exercise, or insulin overdose 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 chronic administration XIV. PANCREATIC HORMONES F. Insulin side effects

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 (Orinase) 2)Mechanism of action -- stimulate ß-cells to secrete insulin 3)Adverse effects -- associated with cardiovascular disease, hypoglycemia Effectiveness questioned b) Sulfonylureas (second generation) a) Agents - glyburide (Diabeta, Micronase) and glipizide (Glucotrol) and Glimepride (1996) b) Mechanism of action: Stimulate insulin release from ß cells (K channel blockers) 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

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

1.Physiological actions a)Insulin and glucagon are mutual antagonists Glucagon mobilizes fuel -- increases [glucose] plasma 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 XIV. PANCREATIC HORMONES H. Glucagon