Medical Pharmacology Chapter 29:  Diabetes

• 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)

     

  • Endocrine Effects of Insulin on the Liver, Muscle and Adipose Tissue

    Hepatic Effects	Catabolic features associated with insulin deficiency: reversal Glycogenolysis: inhibited Conversion of fatty acids/amino acids to ketoacids: inhibited Conversion of amino acids to glucose: inhibited Anabolic actions: Glucose storage increased Triglyceride synthesis: increased VLDL synthesis: increased Phosphorylase activity: decreased
    Muscle Effects	Protein synthesis: increased Amino acid transport: increased Ribosomal protein synthesis: increased Glycogen synthesis: increased Glucose transport: increased Glycogen synthase:increased Phosphorylase activity: decreased
    Adipose Tissue Effects	Triglyceride storage: increased Lipoprotein lipase: induced; activated Triglyceride (from lipoproteins) hydrolysis: increased Glucose transport: increased(providing glycerophosphate -- permitting fatty acids esterification) Intracellular lipase: inhibited
    	attribution:   Karam, J. H., Pancreatic Hormones and Antidiabetic Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 688.

   

  • 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

  • Muscle

    • Insulin enhances:

      1. Protein synthesis (increasing amino acid transport; stimulation of ribosyl action)

      2. Gycogen synthesis

         • By increasing glucose transport to the muscle

         • Inducing glycogen synthase

         • Inhibiting phosphorylase

  • 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)

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