IRS proteins and beta-cell function

Insulin receptor substrate (IRS) proteins mediate a variety of the metaboli c and growth-promoting actions of insulin and IGF-1. After phosphorylation by activated receptors, these intracellular signaling molecules recruit var ious downstream effector pathways including phosphatidylinositol 3-kinase a nd Grb2. Ablation of the IRS-2 gene produces a diabetic phenotype; mice lac king IRS-2 display peripheral insulin resistance and beta -cell dysfunction characterized by a 50% reduction in beta -cell mass. In contrast, deletion of IRS-1 retards somatic growth and enhances beta -cell mass. IRS1(-/-) mi ce are 50% smaller than controls but have a twofold increase in pancreatic beta -cell mass. Thus, observations from these recently developed animal mo dels implicate the IRS signaling systems in the response of classical insul in target tissues, and they suggest a critical role for these proteins in t he regulation of beta -cell function. In humans, type 2 diabetes generally occurs when insulin-secretory reserves fail to compensate for peripheral in sulin resistance. Study and identification of the signals downstream of IRS proteins in beta -cells may provide unique insights into the compensatory mechanisms by which these cells respond to insulin resistance. Therefore, t he intent of this review is to summarize recent observations regarding the regulation of beta -cell function by members of the IRS protein family.