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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.

非胰岛素依赖型糖尿病（NIDDM）是由多个基因和环境因素相互作用引起的。我们一直采用基因敲除小鼠模型来剖析 NIDDM 的复杂分子机制。我们已经培育出了 IRS-1 和 IRS-2 的基因敲除小鼠，IRS-1 和 IRS-2 是胰岛素受体激酶的两种主要底物。 IRS-1 敲除小鼠表现出骨骼肌胰岛素抵抗，而 IRS-2 敲除小鼠则表现出肝脏胰岛素抵抗。尽管胰岛素抵抗程度相似，但 IRS-1 敲除小鼠表现出代偿性 β 细胞增生，而 IRS-2 敲除小鼠则表现出 β 细胞质量减少并发展为 NIDDM。这些结果表明IRS-1和IRS-2在骨骼肌、肝脏和β细胞中发挥不同的作用，并且胰岛素抵抗和β细胞缺陷是NIDDM的发生所必需的。我们还通过靶向破坏葡萄糖激酶 (GK) 和 NADH 穿梭系统研究了几种基因在 β 细胞功能中的作用。结果表明，通过经典途径（TCA 循环）和 NADH 穿梭系统进行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）中发挥调节作用。通过基因突变重建来发展NIDDM，每种基因突变单独不会导致重大代谢改变，验证了NIDDM的多基因概念，胰岛素分泌缺陷与胰岛素抵抗之间的相互作用，以β细胞bK/IRS-1双敲除小鼠和IRS-2敲除小鼠为例，似乎是NIDDM发生发展的共同途径。因此，通过靶向破坏对小鼠人类糖尿病基因缺陷进行遗传操作将为了解人类 NIDDM 的分子机制和实际生化途径提供重要见解。