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:

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 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