Approach to the pathogenesis of NIDDM using knockout mouse models.

使用基因敲除小鼠模型探讨 NIDDM 的发病机制。

基本信息

批准号：
09470215
负责人：
KADOWAKI Takashi
金额：
$ 9.79万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Non-insulin dependent diabetes mellitus (NIDDM) is caused by interactions of multiple genes and environmental factors. We have been employing knockout mice models to dissect the complex molecular mechanisms of NIDDM. We have generated knockout mice of both IRS-1 and IRS-2, two major substrates for the insulin receptor kinase. IRS-1 knockout mice show skeletal muscle insulin resistance, whereas IRS-2 knockout mice show liver insulin resistance. Despite a similar degree of insulin resistance, IRS-1 knockout mice show compensatory β-cell hyperplasia, whereas IRS-2 knockout mice, show decreased β-cell mass and develop NIDDM. These results suggest that IRS-1 and IRS-2 play distinct roles in skeletal muscle, liver and β-cell, and that both insulin resistance and a defect in.β-cell are required for the development of NIDDM. We have also investigated the role of several genes in theβ-cell functions by targeted disruption of glucokinase (GK) and NADH shuttle system. The results show that glucose metabolism via the classical pathway (TCA cycle) and the NADH shuttle system are both required for glucose-induced insulin secretion. Moreover, IRS-1, IRS-2 and PI3-kinase appear to play regulatory roles inβ-cell functions such as glucose-induced insulin secretion. The development of NIDDM by reconstitution of genetic mutations, each of which alone does not lead to major metabolic alterations, validated the polygenic concept of NIDDM, Interplay between insulin secretory defect and insulin resistance, exemplified byβ-cell bK/IRS-1 double-knockout mice and IRS-2-knockout mice, appears to be a common pathway in the development of NIDDM. Thus, the genetic manipulation of defects in human diabetogenic genes in mice via targeted disruption will provide important insights into the molecular mechanisms and actual biochemical pathways of human NIDDM.

非胰岛素依赖性糖尿病（NIDDM）是由多个基因和环境因素的相互作用引起的。我们一直在使用基因敲除小鼠模型来剖析NIDDM的复杂分子机制。我们已经产生了IRS-1和IRS-2的敲除小鼠，这是胰岛素受体激酶的两个主要底物。 IRS-1敲除小鼠表现出骨骼肌胰岛素抵抗，而IRS-2敲除小鼠显示肝胰岛素抵抗。尽管具有相似程度的胰岛素耐药性，但IRS-1基因敲除小鼠表现出代偿性β细胞增生，而IRS-2敲除小鼠显示出β细胞质量降低并发展为NIDDM。这些结果表明，IRS-1和IRS-2在骨骼肌，肝脏和β细胞中起着不同的作用，并且胰岛素抵抗和a不缺陷。β细胞的发展需要NIDDM的发展。我们还通过针对性破坏葡萄糖激酶（GK）和NADH班车系统来研究了几个基因在β细胞功能中的作用。结果表明，通过经典途径（TCA循环）和NADH穿梭系统的葡萄糖代谢都是葡萄糖诱导的胰岛素分泌所必需的。此外，IRS-1，IRS-2和PI3-激酶似乎在β细胞功能（例如葡萄糖诱导的胰岛素分泌）中扮演调节作用。 The development of NIDDM by reconstitution of generic mutations, each of which alone does not lead to major metabolic alterations, validated the polygenic concept of NIDDM, Interplay between insulin secretory defect and insulin resistance, exemplified byβ-cell bK/IRS-1 double-knockout mice and IRS-2-knockout mice, appears to be a common pathway in the development of NIDDM.这是，通过靶向破坏，小鼠人类糖尿病基因缺陷的遗传操纵将为人类NIDDM的分子机制和实际生化途径提供重要的见解。