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OST 529 Systems Biology: Endocrinology Keith Lookingland Associate Professor Dept. Pharmacology & Toxicology Organization of the Endocrine System • Peripheral Substrate-Regulated Systems • Hormone Negative Feedback-Regulated Systems • Hypothalamic-Pituitary Neuroendocrine Reflex Systems Peripheral Substrate Systems • Glucose - Insulin/Glucagon • Calcium - PTH/Calcitonin/Vitamin D • Sodium/Potassium - Aldosterone Hormone Negative Feedback Hypothalamic-Pituitary Systems • • • • Adrenocortical Axis (Glucocorticoids) Thyroid Axis (Thyroid Hormones) Ovarian Axis (Estrogen/Progesterone) Testicular Axis (Testosterone) Hypothalamic-Pituitary Neuroendocrine Reflex Systems • • • • Growth Hormone Prolactin Oxytocin Vasopressin (Antidiuretic Hormone) Insulin & Oral Glycemic Control Agents Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” 10th Edition Chapter 61: 1679-1714 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 Physiology Underlies Pharmacological Principles! Insulin Control of Insulin Secretion • Glucose • Hormonal – Gastrointestinal – Pancreatic (paracrine) • Neural – Parasympathetic – Sympathetic Glucose 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 Neural Mechanisms • Sympathetic – alpha-adrenergic receptors inhibits insulin – stress, exercise • Parasympathetic – beta-adrenergic or cholinergic receptors stimulate insulin – postprandial vagal stimulation 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 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 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 Commercial Insulin Preparations • Species • Purity and Concentration • Onset and Duration of Action Insulin Replacement Therapy 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 Common Side Effects of Insulin • mild hypoglycemia – functional abnormalities of CNS • drowsiness, fatigue, headache, mild tremor, nausea • local allergic reactions at injection sites 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 Insulin Analogs • Modified Insulins • Insulin Lispro – Lys (B28), Pro (B29) • Insulin Aspart (B28) – decreases hexameric association – accelerated absorption – injected immediately before a meal Insulin Analogs • Modified Insulin • Insulin Glargine (A21;B30) – precipitation – delayed absorption Type 2 Insulin-independent Diabetes mellitus • Late onset after 40 years of age • obesity • impaired Beta cell response to glucose – hyperglycemia – no ketoacidosis Therapeutic Options • dietary restrictions • exercise • oral hypoglycemics – sulfonylureas, meglitinides • oral antihyperglycemics – biguanides – thiozolidinediones “glitazones” – glucosidase inhibitors • insulin Oral Hypoglycemics 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 • 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 Sulfonylureas are Contraindicated in Type 1 Diabetes mellitus 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 Insulin Resistance • Hyperglycemia + Hyperinsulinemia • Altered insulin, insulin receptor and/or post-receptor intracellular mechanisms Insulin Resistance and Type 2 Diabetes 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 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