Insulin is the key hormone regulating glucose homeostasis and has many cellular effects on metabolism, growth, and differentiation. Its action is mediated through a specific cell surface receptor. The first step following insulin binding consists of receptor autophosphorylation and stimulation of its tyrosine kinase activity. Among the multiple substrates the insulin receptor substrate-1 is the major cytoplasmic substrate. It binds several Src homology 2 proteins through its multiple tyrosine phosphorylation sites: phosphatidylinositol 3-kinase, the Ras guanine nucleotide-releasing complex growth factor receptor-bound protein-2/son of sevenless protein, the tyrosine phosphatase Syp, and the adapter protein Nek. Insulin receptor substrate-1 is essential for many, but not all of the insulin biological responses. Recently, a primary alternative substrate, insulin receptor substrate-2, was purified and cloned. Numerous biochemical abnormalities of the insulin signaling system lead to insulin resistance. The recent data about the molecular mechanisms of insulin action may provide new insights into the pathophysiology and therapy of diabetes mellitus and other insulin resistance states.
Biomedical Reviews 1996; 5: 47-55.
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