OST 529 Systems Biology: Endocrinology

1. OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology

5. Organization of the Endocrine System • Peripheral Substrate-Regulated Systems • Hormone Negative Feedback-Regulated Systems • Hypothalamic-Pituitary Neuroendocrine Reflex Systems

6. Peripheral Substrate Systems • Glucose - Insulin/Glucagon • Calcium - PTH/Calcitonin/Vitamin D • Sodium/Potassium - Aldosterone

7. Hormone Negative Feedback Hypothalamic-Pituitary Systems • Adrenocortical Axis (Glucocorticoids) • Thyroid Axis (Thyroid Hormones) • Ovarian Axis (Estrogen/Progesterone) • Testicular Axis (Testosterone)

8. Hypothalamic-Pituitary Neuroendocrine Reflex Systems • Growth Hormone • Prolactin • Oxytocin • Vasopressin (Antidiuretic Hormone)

9. Insulin & Oral Glycemic Control Agents Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 61: 1679-1714

10. Insulin & Oral Glycemic Control Agents • Insulin • Synthesis and metabolism • Secretion • Actions • Diabetes mellitus • Type 1 insulin-dependent (juvenile) • Type 2 non-insulin-dependent (maturity onset) • Insulin resistance • Molecular basis • Pharmacological strategies

11. Physiology Underlies Pharmacological Principles!

12. Insulin

14. Control of Insulin Secretion • Glucose • Hormonal • Gastrointestinal • Pancreatic (paracrine) • Neural • Parasympathetic • Sympathetic

15. Glucose

16. Endocrine Mechanisms • Gastrointestinal Hormones • gastric inhibitory peptide (GIP), cholecystokinin (CCK), secretin, gastrin enhance glucose-induced insulin secretion • Intrapancreatic Hormones • glucagon (alpha cells) stimulates insulin • somatostatin (delta cells) inhibits insulin

17. Neural Mechanisms • Sympathetic • alpha-adrenergic receptors inhibits insulin • stress, exercise • Parasympathetic • beta-adrenergic or cholinergic receptors stimulate insulin • postprandial vagal stimulation

21. Diabetes mellitus • metabolic disorder characterized by elevated blood glucose concentrations (hyperglycemia) • due impaired insulin secretion by pancreatic Beta cells or reduced biological efficacy at target tissues

22. Insulin Deficiency • Acute • Catabolism of carbohydrates, lipids, proteins • Hyperglycemia, hyperlipidemia, ketonemia • ketoacidosis, glycosuria, polyuria, dehydration, polydipsia, polyphagia, fatigue • Chronic • Pathological changes in microcirculation • gangrene, retinal impairment, myocardial infarction, polyneuropathy, nephrosis

24. Type 1 Insulin-dependent Diabetes mellitus • “juvenile” onset prior to 30 years of age • infectious or toxic induced autoimmune destruction of Beta cells • no circulating insulin • insulin replacement required to reverse catabolic state

27. Commercial Insulin Preparations • Species • Purity and Concentration • Onset and Duration of Action

29. Insulin Replacement Therapy

32. Pharmacokinetics of Insulin • rapidly inactivated in gastrointestinal tract when taken orally • absorbed well following subcutaneous injection • circulates as free hormone • metabolized in liver, kidney and target cell internalization

33. Common Side Effects of Insulin • mild hypoglycemia • functional abnormalities of CNS • drowsiness, fatigue, headache, mild tremor, nausea • local allergic reactions at injection sites

34. Adverse Reactions of Insulin • marked hypoglycemia • pronounced abnormalities of CNS • mental confusion, bizarre behavior, coma • hyperactivity of ANS • sympathetic - tachycardia, palpitations, sweating • parasympathetic - nausea, hunger • systemic allergic reactions (anaphylaxis) • insulin resistance

35. Insulin Analogs • Modified Insulins • Insulin Lispro • Lys (B28), Pro (B29) • Insulin Aspart (B28) • decreases hexameric association • accelerated absorption • injected immediately before a meal

37. Insulin Analogs • Modified Insulin • Insulin Glargine (A21;B30) • precipitation • delayed absorption

38. Type 2 Insulin-independent Diabetes mellitus • Late onset after 40 years of age • obesity • impaired Beta cell response to glucose • hyperglycemia • no ketoacidosis

39. Therapeutic Options • dietary restrictions • exercise • oral hypoglycemics • sulfonylureas, meglitinides • oral antihyperglycemics • biguanides • thiozolidinediones “glitazones” • glucosidase inhibitors • insulin

40. Oral Hypoglycemics

43. Pharmacokinetics of Sulfonylureas • well absorbed when taken orally • circulates bound to plasma proteins • metabolized in liver • half-lives and duration of action vary dependent upon chemical structure

44. Common Side Effects • mild hypoglycemia and associated functional abnormalities of CNS • drowsiness, fatigue, headache, mild tremor, nausea • Adverse reactions • marked hypoglycemia and associated CNS and PNS abnormalities

45. Sulfonylureas are Contraindicated in Type 1 Diabetes mellitus

46. Meglitinides • Repaglinide • induces closure Beta cell K+/ATP channels • multiple binding sites • ineffective in the absence of glucose • Orally-active • short half-life • Fewer hypoglycemic episodes than sulfonylureas

47. Insulin Resistance • Hyperglycemia + Hyperinsulinemia • Altered insulin, insulin receptor and/or post-receptor intracellular mechanisms

48. Insulin Resistance and Type 2 Diabetes

49. Oral Antihyperglycemic Agents • Metformin (Glucophage) • blocks hepatic gluconeogenesis • circulates unbound, half-life 1.5-4.5 hr • side effects • acute - diarrhea,abdominal discomfort, nausea, metallic taste, anorexia • chronic - lactic acidosis

50. Oral Antihyperglycemic Agents • Thiazolindinediones - “glitazones” • troglitazone, rosiglitazone, pioglitazone • potentiates translocation of GLUT 4 transporter • Acarbose • alpha glucosidase inhibitor • reduces intestinal absorption of carbohydrates • reduces postprandial plasma glucose • side effects • malabsorption, flatulence, abdominal bloating