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Mechanism of insulin action and its disorder

胰岛素作用机制及其紊乱

基本信息

批准号：
06404038
负责人：
KASUGA Masato
金额：
$ 18.75万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06404038/
关键词：
IRS-1 PI 3-kinase Grb2・Sos complex SH PTP-2 glucose transporters Ras Ras SH PTP-1 インスリン

项目摘要

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.

非胰岛素依赖型糖尿病（NIDDM）是一种常见的葡萄糖稳态紊乱，约占总人口的5%。NIDDM的特征是胰腺β细胞分泌胰岛素和/或外周组织胰岛素作用的缺陷。胰岛素处理各种完整细胞导致一个高分子量蛋白（Mr= 16000 - 185000） pp185快速酪氨酸磷酸化。分离到pp185编码的cDNA，并将其命名为胰岛素受体底物-1 （insulin receptor substrate-1, IRS-1）。酪氨酸磷酸化的IRS-1通过Src同源性2 （SH2）结构域结合多个信号分子，包括磷酸肌苷（PI） 3-激酶的85kDa亚基、Grb2·Sos复合物和SH PTP-2。为了寻找新的NIDDM候选基因，我们在过表达胰岛素受体的中国仓鼠卵巢细胞中过表达PI 3-激酶85kDa亚基、Grb2·Sos复合物和SH PTP-2的显性阴性型。这些显性负型信号分子的过表达表明，PI 3-激酶参与胰岛素刺激的葡萄糖摄取和葡萄糖转运体的易位，但不参与Ras的激活。另一方面，Grb2和SH PTP-2参与胰岛素刺激的Ras激活，但不参与胰岛素刺激的葡萄糖摄取和葡萄糖转运体的易位。这些数据表明PI 3-激酶是NIDDM的一个新的候选基因。