Mechanism of insulin action and its disorder

非胰岛素依赖性糖尿病mellitus （NIDDM）是一种常见的葡萄糖homeostasis影响-5%的普通人群。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。cDNA编码第185页是孤立的，并命名为胰岛素受体底物-1（IRS-1）。酪氨酸磷酸化IRS-1绑定的几种信号分子，包括85 kDa磷酸盐（PI）3-激酶、Grb 2·Sos复合体和SH PTP-2通过Src同源2 （SH 2）域。为了识别NIDDM的新候选基因，我们过度表达了中国仓鼠卵巢癌细胞过度表达胰岛素受体的85 kDa亚基的主要阴性类型，Grb 2·Sos复合体和SH PTP-2。这些信号分子的显性阴性类型的过度表达揭示了PI 3-激酶在胰岛素刺激的葡萄糖上提取和转运中的作用，但不是在Ras激活中。在另一只手上，Grb 2和SH PTP-2在胰岛素刺激的Ras激活中发生，但不在胰岛素刺激的葡萄糖上提取和转移中发生。这些数据建议PI 3-激酶是NIDM的一种新的候选基因。

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.