ursing Pharmacology Chapter 29:  Diabetes

• Insulin is a small protein, composed of two chains, A and 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 where proteases proinsulin is hydrolyzed to insulin and C-peptide

  • Pancreatic B cell granules store insulin in crystals, 2 atoms of zinc six molecules of insulin.

• 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

• 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)

    • Further degradation: proteolysis

Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 684-703

Foster, D. W., Diabetes Mellitus, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2060-2080