Mechanism of insulin action and its disorder

Non-insulin-dependent diabetes mellitus(NIDDM)is common disorder of glucose homeostasis affecting-5%of the general population。NIDDM is characterized by defects in the insulin secretion from pancreatic beta-cells and/or the insulin action in peripheral tissues.Insulin treatment of various intact cells causes rapid tyrosine phosphorylation of a high molecular weight protein(Mr=16，000-185，000)designated pp 185.A cDNA encoding pp185was isolated and the predicted protein was named insulin receptor substrate-1(IRS-1)。Tyrosinphosphorylated IRS-1binds several signaling molecules，including the 85 kDa subunit of phosphoinositide(PI)3-kinase，Grb2·Sos complex and SH PTP-2via their Src homology2(SH2)domain。To identify new candidate genes for NIDDM，we overexpressed the dominant negative type of 85 kDa subunit of PI3-kinase，Grb2·Sos complex and SH PTP-2in Chinese hamster ovary cells overexpressing the insulin receptor。Overexpression of dominant negative type of these signaling molecules revealed that PI3-kinase involves in insulin-stimulated glucose uptake and translocation of glucose transporters，but not in Ras activation。On the other hand，Grb2 and SH PTP-2involves in insulin-stimulated Ras activation，but not in insulin-stimulated glucose uptake and translocation of glucose transporters.These data suggest that PI3-kinase is a new candidate gene for NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) is common disorder of glucose homeostasis affecting -5% of the general population. NIDDM is characterized by defects in the insulin secretion from pancreatic beta-cells and/or the insulin action in peripheral tissues.Insulin treatment of various intact cells causes rapid tyrosine phosphorylation of a high molecular weight protein (Mr=16,000-185,000) designated pp185. A cDNA encoding pp185 was isolated and the predicted protein was named insulin receptor substrate-1 (IRS-1). Tyrosinphosphorylated IRS-1 binds several signaling molecules, including the 85kDa subunit of phosphoinositide (PI) 3-kinase, Grb2・Sos complex and SH PTP-2 via their Src homology 2 (SH2) domain. To identify new candidate genes for NIDDM,we overexpressed the dominant negative type of 85kDa subunit of PI 3-kinase, Grb2・Sos complex and SH PTP-2 in Chinese hamster ovary cells overexpressing the insulin receptor. Overexpression of dominant negative type of these signaling molecules revealed that PI 3-kinase involves in insulin-stimulated glucose uptake and translocation of glucose transporters, but not in Ras activation. On the other hand, Grb2 and SH PTP-2 involves in insulin-stimulated Ras activation, but not in insulin-stimulated glucose uptake and translocation of glucose transporters. These data suggest that PI 3-kinase is a new candidate gene for NIDDM.