| Co-Investigator(Kenkyū-buntansha) |
YASUDA Kazuki Faculty of Medicine, University of Tokyo, Assistant Medical staff, 医学部・附属病院, 医員
TAMEMOTO Hiroyuki Faculty of Medicine, University of Tokyo, Assistant Medical staff, 医学部・附属病院, 医員
TOBE Kazuyuki Faculty of Medicine, University of Tokyo, Assistant Medical staff, 医学部・附属病院, 助手 (30251242)
TERAUCHI Yasuo Faculty of Medicine, University of Tokyo, Lecturer, 医学部・附属病院, 医員
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| Research Abstract |
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.
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