Nursing Pharmacology Chapter 29: Diabetes
Insulin binds to target receptors (high affinity, high specificity) and liver, muscle, and fat tissue
Each containing an alpha subunit (extracellular: recognition site) and
A beta subunit which spans the membrane and contains a tyrosine kinase.
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.
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
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