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In mammals, insulin is the principal hormone controlling blood glucose and acts by stimulating glucose influx and metabolism in muscle and adipocytes and inhibiting gluconeogenesis by the liver. In addition, insulin modifies the expression or activity of a variety of enzymes and transport systems in nearly all cels. Insulin action is mediated through the insulin receptor, a transmembrane glycoprotein with intrinsic protein tyrosine kinase activity. The level of tyrosine kinase activity reflects the serum concentration of insulin and appears to mediate the insulin response through tyrosine phosphorylation of the receptor itself and substrates like insulin recep-tor substrate-1 (IRS-l). l Non-insulin-dependent diabetes mellitus is due in large part to insulin resistance, a state when the target cells no longer respond to ordinary levels of circulating insulin. To understand the mechanisms of control of normal metabolism, as well as the pathogenesis of non-insulin-dependent diabetes mellitus, it is critical to understand the signaling pathways used by the insulin receptor.

Many plasma membrane receptors regulate cellular processes through protein tyrosine kinases. The receptor for insulin, like the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), contains intrinsic tyrosine kinase activity (1). The antigen receptor on T and B cells, as well as receptors for growth hormone, erythropoietin, and several cytokines, do not have intrinsic tyrosine kinase activity but stimulate tyrosine phosphorylation by association with cytoplasmic tyrosine kinases like Fyn, Tyk-2, or Jak-1 and-2 (2, 3). In each case, ligand binding activates the associated …