Medical 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).

    •  

      Insulin Receptor Ectodomain (Extracellular Portion)

      The dimeric insulin receptor ectodomain (residing outside the cell membrane surface) colored to demonstrate L1 (blue), CR (cyan), L2 (green), FnIII-1 (yellow), FNIII-2 (orange), FnIII-3 (red) domains with foreground and background monomers represented as cartoon and sphere projections respectively.  "Image generated by Pymol, derived from structure PDB:3LOH" Caption and structure attribution:  Fletcher01 February 2011:  http://en.wikipedia.org/wiki/File:IR_Ectodomain_mod3LOH.png

    • 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.

    •  

      Representations of Insulin monomeric and dimeric forms and combinations

      "Colour coded Schematic of the Insulin Receptor featuring each domain with black lines representing disulphide linkages." Attribution:  Fletcher01 http://en.wikipedia.org/wiki/File:Colour_coded_Schematic_of_the_Insulin_Receptor.png

     

  • Receptor Activation

    •  

      Monomeric Interactions and Activation of the Insulin Receptor

      "Depiction of the insulin receptor ectodomain (PDB 3LOH) and putative binding sites on the first (green) and second (blue) monomer alpha chains as well as a schmatic representation of receptor activation via crosslinking of binding sites.  Modified from 'Harmonic oscillator model of the insulin and IFG1 receptors' allosteric binding and activation.'" Attribution:  Kiselyouv VV Versteyhe S Gauguin L De Meyts P http://en.wikipedia.org/wiki/File:IR-binding-site-scheme.png and (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657531/).

    • 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