Glycemic Control I

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Glycemic Control I
2013-03-31 21:49:27
Pharmacology II Rutgers

For Rutgers P2 students; Studying for the second pharmacology II exam
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  1. Glucagon
    • Source: α-cells (pancreas)
    • Target: Liver (adipose, skeletal muscle)
    • Action: Promotes gluconeogenesis and glycogenolysis in liver
  2. Insulin
    • Source: β-cells (pancreas)
    • Target: Liver (adipose, skeletal muscle)
    • Action: Promotes uptake of glucose, amino acids, and fatty acids from blood into cells for storage as glycogen, protein and triglyceride
  3. Somatostatin: "body stay the same"
    • Source: δ-cells (pancreas)
    • Target: Other islet cells, GI tract, brain and pituitary gland
    • Action: Decrease release of insulin and glucagon, decrease GI tract motility, and decrease hormone secretion
    • Single gene, highly conserved in nature
  4. Epinephrine
    • Source: adrenal medulla
    • Target: many
    • Action: Promotes glycogenolysis in liver, and lipolytic via hormone-sensitive lipase
  5. Cortisol
    • Source: adrenal cortex
    • Target: many
    • Action: Antagonizes insulin action
  6. GLP-1: "incretins"
    • Source: Ileum
    • Target: Pancreas, stomach, brain, heart
    • Action: Increase β-cell mass and insulin secretion; delays gastric emptying, decreases food intake and glucagon secretion
    • Most effective when eating
  7. Leptin
    • Source: adipocytes
    • Target: CNS (basomedial hypothalamus)
    • Action: Signals adequacy of food stores, decreasing food intake
  8. Islet of Langerhans: cellular
    • β cells predominate (60-80%)
    • Cells linked by tight junctions; regulated entry of small molecules
    • Blood flows from β to α & δ cells, so Insulin is the primary hormone!
    • β cell is primary glucose sensor
  9. Structure of Insulin
    • Acts as a monomer, but travels in polymer form: dimeric, hexameric, N-lithocholyl
    • Signal peptidase cleaves the leader from preproinsulin
    • Protease cleaves the connecting sequence from proinsulin
  10. Regulation of Insulin Secretion: Autonomic Control
    • Adrenergic and cholinergic innervation of Islets
    • α2 and activation of the sympathetic branch = ⇩ insulin secretion
    • β2 and cholinergic receptors = ⇧ insulin secretion
    • Therefore, β2 antagonists decrease basal insulin levels
  11. Chemical regulation of Insulin Release
    • Glucose is the major stimulus for insulin release
    • Other stimulants- gastrin, secretin, cholecystokinin, VIP, and enteroglucagon
    • Insulin secretion is continuous, but increases after carbohydrate consumption (ingestion > IV nutrition)
    • Insulin response to glucose is biphasic: short lived peak in 1-2 minutes, then released over hours
  12. MoA Glucose regulation of Insulin Release
    • Glucose enters β-cell via GLUT2
    • Glucose undergoes glycolysis to G6P, then eventually pyruvate
    • This increases in ATP/ADP ratio, inhibiting the ATP-K+ channel (which normally pushes K+ out of the cell)
    • K+ accumulating in the cell leads to depolarization, which triggers entry of Ca2+ through the voltage dependent Ca2+ channel
    • Ca2+ increases cAMP signaling, which eventually activate the release of secretory granules containing insulin and peptide C
  13. cAMP Effects in β-cells
    • Stimulate Phospholipase C to increase free Ca2+
    • Gs linked receptors: glucagon, GIP, GLP-1
    • Gi linked receptors: somatostatin, α2 agonists
  14. ATP-Sensitive Potassium Channel
    • Open channel = hyperpolarization of β-cells
    • Close channel = insulin secretion
    • Allosteric inhibitors: Sulfonylurea/meglitinide, ATP
    • Allosteric activators: Diazoxide, Mg2+, ADP
  15. MoA Glucose regulation of Insulin Production
    • Translational > Transcriptional control
    • Without glucose, eIF-4F Complex (essential for translation of proinsulin mRNA) is inhibited by eIF-4EBPs
    • With glucose, eIF-4EBPs is phosphorylated, freeing up the eIF-4E piece of the essential complex ♡
    • Without glucose, eIF-2α is phosphorylated and cannot form the essential Ternary Met tRNA complex.
    • With glucose, phosphorylation of eIF-2α is decreased ♡
  16. Distribution of Insulin
    • Insulin half-life: 5-6 min
    • Proinsulin half-life: 17 min
    • Normally, proinsulin ~10% of plasma insulin; if higher, then = marker of insulinoma
    • Since C peptide is secreted with insulin but not metabolized as rapidly, = measure of acute insulin secretion
    • After insulin binds to a receptor, it is internalized and degraded (50% liver)
  17. Insulin Receptor
    • Dimerization regulated tyrosine kinase
    • Insulin recognition at cysteine-rich area of alpha chain
    • Binds to all members of IGF-family signaling molecules
    • Binding is the key determinant of potency
  18. Glycogen Synthetase
    • Essential for glycogenesis
    • Insulin: activates
    • Glucagon: inhibits
  19. Glycogen Phosphorylase
    • Essential for glycogenolysis
    • Insulin: inhibits
    • Glucagon: activates
  20. Increased cAMP Effects in Liver cells
    • Stimulates glycogen breakdown (activates glycogen phosphorylase)
    • Inhibits glycogen synthesis (phosphorylates, and thus inhibits, glycogen synthase)
  21. α-Glucosidase inhibitors (Acarbose, Miglitol)
    Prevent digestion of carbohydrates, and thus limits absorption of dietary glucose
  22. Thiazolidinediones
    • PPARγ agonists
    • Promote conversion of glucose to triglycerides in adipose tissue
    • Thus increases glucose uptake by adipose tissue
  23. Biguanides
    Inhibit gluconeogenesis
  24. Diabetic Ketosis
    • Type I Diabetes
    • Low insulin levels = high levels of free fatty acids