Generation of Animal Models for Diabetes by Transgenic and Gene Targeting Technology

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Non-insulin-dependent diabetes mellitus(NIDDM)is considered a polygenic disorder 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 normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with beta-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 a double knockout mouse with ***ption of IRS-1 and beta-cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120min after intraperitoneal glucose load(1.5mg/ g body weight)were 108(]SY.+-。[)24(wide-type), 95(]SY.+-。[)26(IRS-1 knockout), 159(]SY.+-。[)68(GK knockout), and 210(]SY.+-。[)38(double knockout) mg/dl(mean(]SY.+-。[)SD)(double vs. wild-type, IRS-1, or GK ; P<0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta-cells as the IRS-1 knockout mice(fasting insulin levels : 0.38(]SY.+-。[)0.30(double knockout), 0.35(]SY.+-。[)0.27(IRS-1 knockout)vs. 0.25(]SY.+-。[)0.12(wild-type)ng/ml)(proportion of areas of insulin-positive cells to the pancreas : 1.18(]SY.+-。[)0.68% ; P<0.01(double knockout), 1.20(]SY.+-。[)0.95% ; P<0.05(IRS-1 knockout)vs. 0.54(]SY.+-。[)0.26%(wild-type)), but impaired insulin secreation to glucose(the ratio of increment of insulin to that of glucose during the first 30min after load : 31(double knockout)vs. 163(wild-type)or 183(IRS-1 knockout)ng insulin/mg glucose x 103). In conclusions, the genetic abnormalities, each of which is non-diabetogenic by itself, cause overtdiabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.