Approach to the pathogenesis of NIDDM using knockout mouse models.

非胰岛素依赖型糖尿病（NIDDM）是多基因和环境因素相互作用的结果。我们一直采用基因敲除小鼠模型来剖析NIDDM复杂的分子机制。我们已经产生了IRS-1和IRS-2的敲除小鼠，IRS-1和IRS-2是胰岛素受体激酶的两种主要底物。IRS-1敲除小鼠显示骨骼肌胰岛素抵抗，而IRS-2敲除小鼠显示肝脏胰岛素抵抗。尽管胰岛素抵抗程度相似，但IRS-1敲除小鼠显示代偿性β细胞增生，而IRS-2敲除小鼠显示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，胰岛素抵抗和β细胞缺陷是NIDDM发生发展的必要条件。我们还通过靶向破坏葡萄糖激酶（GK）和NADH穿梭系统研究了几个基因在β细胞功能中的作用。结果表明，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PI 3-激酶似乎在β细胞功能如葡萄糖诱导的胰岛素分泌中起调节作用。通过基因突变的重建而发生的NIDDM，每一种单独的基因突变都不会导致主要的代谢改变，验证了NIDDM的多基因概念，胰岛素分泌缺陷和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发生的共同途径。因此，通过靶向破坏对小鼠中的人致糖尿病基因中的缺陷进行遗传操作将为人类NIDDM的分子机制和实际生化途径提供重要的见解。

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.