Approach to the Pathogenesis of Non-Insulin-Dependent Diabetes Mellitus by Gene Targeting.

概要

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Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polygenic disoder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1 (IRS-1) gene knockout showed insulin resistance, but nomal glucose tolerance due to compensatory hyperinsulinemia. Heterozygous mice with β-cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and β-cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes and showed fasting hyperinsulinemia and selective hyperplasia of the β-cells as the IRS-1 knockout mice, but impaired insulin secretion to glucose as the GK knockout mice. In conclusion, the genetic abnormalities, each of which is non-diabetogenic by itself, can cause overt diabetes if they coexist. This study provides the first genetic reconstitution of NIDDM as a poly genic disorder in mice.
公益社団法人日本実験動物学会の論文