DEVELOPMENT OF NON-INSULIN-DEPENDENT DIABETES-MELLITUS IN THE DOUBLE KNOCKOUT MICE WITH DISRUPTION OF INSULIN-RECEPTOR SUBSTRATE-1 AND BETA-CELL GLUCOKINASE GENES - GENETIC RECONSTITUTION OF DIABETES AS A POLYGENIC DISEASE

Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polyge nic 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 ass ociated with insulin resistance and compensatory hyperinsulinemia. Het erozygous mice with beta cell glucokinase (GK) gene knockout showed im paired glucose tolerance due to decreased insulin secretion to glucose . To elucidate the interplay between insulin resistance and insulin se cretory defect for the development of NIDDM, we generated double knock out mice with disruption of IRS-1 and beta cell GK genes by crossing t he mice with each of the single gene knockout. The double knockout mic e developed overt diabetes, Blood glucose levels 120 min after intrape ritoneal glucose load (1.5 mg/g body wt) were 108+/-24 (wild type), 95 +/-26 (IRS-1 knockout), 159+/-68 (GK knockout), and 210+/-38 (double k nockout) mg/dl (mean+/-SD) (double versus wild type, IRS-1, or GK; P < 0.01), The double knockout mice showed fasting hyperinsulinemia and s elective hyperplasia of the beta cells as the IRS-1 knockout mice (fas ting insulin levels: 0.38+/-0.30 [double knockout], 0.35+/-0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of area s of insulin-positive cells to the pancreas: 1.18+/-0.68%; P < 0.01 [d ouble knockout], 1.20+/-0.93%; P < 0.05 [IRS-1 knockout] versus 0.54+/ -0.26% [wild type]), but impaired insulin secretion to glucose (the ra tio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reco nstitution of NIDDM as a polygenic disorder in mice.