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Insulin

Insulin

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INSULIN
  • Peptide hormone secreted by pancreatic beta cells
  • Promotes anabolic (synthetic pathways): energy requiring
  • Binds receptor tyrosine kinases (liver, muscle, adipose tissue, etc.)
PANCREAS
Islets of Langerhans (1-2% of pancreatic beta cells)
  • Beta cell: secretes insulin
  • Alpha cell: secretes glucagon (opposes insulin)
INSULIN SYNTHESIS AND STRUCTURE
Components of insulin
  • N-terminal signal peptide: targets preproinsulin to endoplasmic reticulum
  • B chain: portion of final hormone
  • C peptide: marker of endogenously synthesized insulin
  • A chain: portion of final hormone
  • Two disulfide bonds: 1 within A chain, another between B and A chains
Synthesis
  • Signal peptide cleaved from preproinsulin in ER of beta cells to form proinsulin
  • C peptide cleaved from proinsulin in Golgi apparatus
  • Two products: C peptide and insulin
C peptide
  • Longer half-life than insulin: marker of insulin synthesis and secretion
Insulin
  • Half-life ~ 6 min.
INSULIN SECRETION
Pancreatic beta cell surface
  • Voltage-dependent Ca2+ channel (closed)
  • ATP-sensitive K+ channel (open): K+ flows down concentration gradient out of cell
  • GLUT2: tissue-specific glucose transporter (beta cells and liver cells)
Steps of secretion
1. Eat carbohydrate rich meal: plasma glucose is high 2. Glucose enters beta cell via GLUT2 3. Glucokinase phosphorylates/sequesters glucose in cell (glucose --> glucose 6P)
  • Glucokinase: tissue specific (beta cells and liver cells), high Km and high Vmax
4. Glycolysis: Glucose 6P --> ATP 5. ATP binds K+ channel and closes it: depolarizes membrane & activates Ca2+ channel 6. Ca2+ influx promotes exocytosis and release of insulin secretory granules
Pancreatic beta cells: most important glucose-sensing cells
  • GLUT2: high Km, only bind glucose when plasma glucose is high
  • Glucokinase: High Km, high Vmax & no product inhibition (can continue trapping glucose even when intracellular glucose concen. rise)
INSULIN MECHANISM OF ACTION
Key insulin-sensitive tissues: liver, muscle & adipose tissue
1. Insulin binds receptor tyrosine kinase: activates intracellular RTK beta subunits 2. Autophosphorylation: activated RTK phosphorylates other intracellular proteins 3. Initiates signaling cascade 4. Muscle & adipose: signaling cascade mobilizes GLUT4 transporters from intracellular storage to cell surface
  • Increases glucose absorption
  • Seconds after insulin binding
  • Does not occur in hepatocytes
5. Activates anabolic enzymes: glycogen, protein and lipid synthesis (~minutes/hours)
  • Promotes glucose storage when glucose is abundant
6. Inhibits catabolic enzymes: glycogen & lipid breakdown (~minutes/hours) 7. Inhibits gluconeogenesis(~minutes/hours) 8. Long-term response: transcriptional control (~hours/days)

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