Download Insulin Lecture

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
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•
Adrenocortical Axis (Glucocorticoids)
Thyroid Axis (Thyroid Hormones)
Ovarian Axis (Estrogen/Progesterone)
Testicular Axis (Testosterone)
Hypothalamic-Pituitary
Neuroendocrine Reflex Systems
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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
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•
•
•
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