Nursing Pharmacology Chapter 29:  Diabetes

•  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.

    • "Structure of the insulin receptor, a heterotetramer consisting of two extracellular insulin-binding subunits linked by a disulfide bonds to tow transmembrane beta subunits. The beta subunits contain an intrinsic tyrosine kinase activity that is activated upon insulin binding to the alpha subunit. " courtesy of Robert H. Parsons, Ph.D., Rensselaer Polytechnic Institute, used with permission

     

    • The insulin receptor (IR) belongs to the tyrosine kinase receptor class and is activated by insulin, IGF-I and IGF-II (insulin-like growth factor I and insulin-like growth factor II).

      • The receptor is encoded by a single gene (INSR) and during transcription alternate splicing results in either IR-A or IR-B isoforms.

      • Downstream from this step these isoforms undergo reactions that form proteolytically cleaved α and β subunits.

      • The subunits combine to form either homodimers or heterodimers, resulting in the disulfide-linked transmembrane insulin receptor.

        • Attribution:  Belifore A Frasca F "Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hydrids in physiology and disease" Endocr Rev 30(6): 586-623.

       

  • Receptor Activation

    • Insulin binds to alpha subunit

    • Beta subunit increases tyrosine kinase activity, resulting in auto- phosphorylation

    • Phosphorylated beta subunit promotes aggregation of heterodimers and stabilizes the receptor tyrosine kinase activated state

    • Docking protein (insulin receptor substrate-1, IRS-1) is then phosphorylated

    • Phosphorylated IRS-1 activates other kinases, promoting further phosphorylation reactions

    • Insulin's second messengers: these phosphorylation products

    • Consequence: glucose transporter translocation from sequestered sites to exposure on the cell surface

    • Insulin-receptor complex is then internalized

  • Alteration in Insulin receptor affinity

    • Decrease affinity caused by some hormonal agents (e.g. hydrocortisone).

    • Increase affinity caused by excess growth hormone.

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