The insulin receptor: signalling mechanism and contribution to the pathogenesis of insulin resistance.
The insulin receptor is a heterotetrameric structure consisting of two alpha-subunits of Mr 135 kilodalton on the outside of the plasma membrane connected by disulphide bonds to beta-subunits of Mr 95 kilodalton which are transmembrane proteins. Insulin binding to the alpha-subunit induces conformational changes which are transduced to the beta-subunit. This leads to the activation of a tyrosine kinase activity which is intrinsic to the cytoplasmatic domains of the beta-subunit. Activation of the tyrosine kinase activity of the insulin receptor represents an essential step in the transduction of an insulin signal across the plasma membrane of target cells. Signal transduction on the post-kinase level is not yet understood in detail, possible mechanisms involve phosphorylation of substrate proteins at tyrosine residues, activation of serine kinases, the interaction with G-proteins, phospholipases and phosphatidylinositol kinases. Studies in multiple insulin-resistant cell models have demonstrated that an impaired response of the tyrosine kinase to insulin stimulation is one potential mechanism causing insulin resistance. An impairment of the insulin effect on tyrosine kinase activation in all major target tissues of insulin, in particular the skeletal muscle was demonstrated in Type 2 (non-insulin-dependent) diabetic patients. There is no evidence that the impaired tyrosine kinase response in the skeletal muscle is a primary defect, however, it is likely that this abnormality of insulin signal transduction contributes significantly to the pathogenesis of the insulin-resistant state in Type 2 diabetes.
Häring
H U
HU
Institute for Diabetes Research, Munich, FRG.
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D006801:Humans; D007333:Insulin Resistance; D046911:Macromolecular Substances; D008954:Models, Biological; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D046911:Macromolecular Substances; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin