Insulin

Overview:

• small protein,composed of two chains and( A & B)
• Pancreatic B cells produced proinsulin, the insulin precursor, which consists of a single-chain protein
• Proinsulin, following Golgi apparatus processing, is packaged into granules -- that hydrolyzes insulin and C-peptide
• Pancreatic B cell granules store insulin in crystals (2 atoms of zinc six molecules of insulin)
• 28 units of insulin per milligram

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• Secretion:
  • normally low basal rate from pancreatic B cells
  • higher stimulated rate in response to:
    1. glucose
    2. other sugars (e.g. mannose)
    3. certain amino acids (e.g. leucine, arginine)
    4. vagal nerve activity
  • Proposed secretion mechanism:
    1. hyperglycemia
    2. increased intracellular ATP concentration
    3. higher intracellular ATP closes ATP-dependent potassium channels
    4. decreased outward potassium current causes pancreatic B cell depolarization and opens voltage-gated calcium channels
    5. increased intracellular calcium promotes insulin secretion
    6. intracellular second messengers modulate release:
       • cyclic AMP
       • inositol triphosphate
       • diacylglycerol

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• Insulin Degradation:
  • circulating insulin is removed by: liver and kidney
    • Liver: clears 60% of insulin released from the pancreas
    • Kidney: clears about 35-40% of endogenous insulin (in insulin-treated diabetics -- subcutaneous injections -- the kidney may clear as much as 60%.)
  • catabolism:
    • Cleavage of sulfide linkage between A and B chains space for (catalyzed by glutathione insulin transhydrogenase and (insulinase)than
    • Further degradation: proteolysis

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•  Insulin Receptor:
  • Insulin binds to target receptors (high affinity, high specificity) and liver, muscle, and fat tissue
  • Insulin receptor: -- composition
    • two heterodimers;
      1. each containing an alpha subunit (extracellular: recognition site) and
      2. a beta subunit which spans the membrane and contains a tyrosine kinase
  • Receptor Activation:
    1.  insulin binds to alpha subunit
    2.   beta subunit increases tyrosine kinase activity, resulting in auto- phosphorylation
    3.   Phosphorylated beta subunit promotes aggregation of heterodimers and stabilizes the receptor tyrosine kinase activated state
    4.   docking protein (insulin receptor substrate-1, IRS-1) is then phosphorylated
    5.   phosphorylated IRS-1 activates other kinases, promoting further phosphorylation reactions
    6.   Insulin's second messenger's: these phosphorylation products
       • Consequence: glucose transporter translocation from sequestered sites to exposure on the cell surface
    7.   Insulin-receptor complex is then internalized
  • Alteration in Insulin receptor affinity:
    • Decrease affinity: some hormonal agents (e.g. hydrocortisone)
    • Increase affinity: (excess growth hormone)

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• Action of Insulin: Target Sites
  • Glucose Transporters
    • GLUT 4: most important lowering blood glucose
      • found in muscle and adipose cell membranesto
      • inserted from storage vesicles
    • GLUT-2: abnormalities in GLUT-2 transport into pancreatic B cells: may contribute to reduced insulin secretion (NIDDM)

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  • Table summary: Effects of Insulin on: Liver, Muscle and Adapose Tissue
  • Liver:
    • Endogenous insulin reaches the liver first (portal circulation)
    • Hepatic Insulin Actions:
      • increases glucose storage as glycogen
      • resets liver to "fed" state -- influencing:
        1. glycogenolysis
        2. ketogenesis
        3. gluconeogenesis
      • Mechanisms for insulin-hepatic actions results, in part, from:
        • insulin-induced phosphorylations activating:
          1. pyruvate kinase
          2. phophofructokinase
          3. glucokinase
        • in the "fed" state repression of gluconeogenic enzymes occurs:
          1. pyruvate carboxylase
          2. phosphoenolpyruvate carboxykinase
          3. fructose bisphosphatase
          4. glucose 6-phosphatase
      • Insulin also decreases hepatic:
        • urea production
        • protein catabolism
        • cyclic AMP
      • Insulin promotes:
        • triglyceride synthesis
        • increases hepatic phosphate and potassium uptake

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  • Muscle:
    • Insulin enhances:
      1. protein synthesis (increasing amino acid transport; stimulation of ribosyl action)
      2. glycogen synthesis
         • by increasing glucose transport to the muscle
         • inducing glycogen synthase
         • inhibiting phosphorylase

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  • Adipose Tissue:
    • Insulin: reduces free fatty acids in the circulation, promoting adipocytes triglyceride storage -- three main mechanisms-- which involves cAMP production suppression and suppression of fat cell lipases:
      1. lipoprotein lipases induction
         • promotes triglyceride hydrolysis from circulating lipoproteins
      2. enhances glucose transport, promotes glycerophosphate generation: permitting fatty acids esterification
      3. reduces adipocytes intracellular lipolysis of stored triglyceride (inhibits intracellular lipase)

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