Development of Non–insulin-dependent Diabetes Mellitus in the Double Knockout Mice with Disruption of Insulin Receptor Substrate-1 and b Cell Glucokinase Genes Genetic Reconstitution of Diabetes as a Polygenic Disease
نویسندگان
چکیده
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 b 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 b cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120 min after intraperitoneal glucose load (1.5 mg/g body wt) were 108 6 24 (wild type), 95 6 26 (IRS-1 knockout), 159 6 68 (GK knockout), and 210 6 38 (double knockout) mg/dl (mean 6 SD) (double versus wild type, IRS-1, or GK; P , 0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the b cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 6 0.30 [double knockout], 0.35 6 0.27 [IRS-1 knockout] versus 0.25 6 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 6 0.68%; P , 0.01 [double knockout], 1.20 6 0.93%; P , 0.05 [IRS-1 knockout] versus 0.54 6 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio 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 3 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 reconstitution of NIDDM as a polygenic disorder in mice. ( J. Clin. Invest. 1997. 99:861– 866.)
منابع مشابه
Genetic engineering in mice: impact on insulin signalling and action.
The expression of a number of genes encoding key players in insulin signalling and action, including insulin, insulin receptor (IR), downstream signalling molecules such as insulin receptor substrate-1 (IRS-1) and IRS-2, glucose transporters (GLUT4, GLUT2) and important metabolic enzymes such as glucokinase, has now been altered in transgenic or knockout mice. Such mice presented with phenotype...
متن کاملDevelopment of a Novel Polygenic Model of NIDDM in Mice Heterozygous for IR and IRS-1 Null Alleles
NIDDM is a polygenic disease characterized by insulin resistance in muscle, fat, and liver, followed by a failure of pancreatic beta cells to adequately compensate for this resistance despite increased insulin secretion. Mice double heterozygous for null alleles in the insulin receptor and insulin receptor substrate-1 genes exhibit the expected approximately 50% reduction in expression of these...
متن کاملPolygenic models of non-insulin-dependent diabetes mellitus.
Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by peripheral insulin resistance and insulin secretory dysfunction (1, 2). These abnormalities are either genetically defined or augmented by hyperglycemia itself, and may interact in a complex manner to cause and sustain hyperglycemia. Previous prospective studies have demonstrated that both insulin resistance/ hyperinsulinemia a...
متن کاملTransgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout.
A series of recent studies in humans and the NOD mouse model have highlighted the central role that autoimmunity directed against insulin, in particular the insulin B chain 9-23 peptide, may play in the pathogenesis of type 1 diabetes. Both pathogenic and protective T-cell clones recognizing the B:9-23 peptide have been produced. This report describes the successful creation of BDC12-4.1 T-cell...
متن کاملImpact of genetic background on development of hyperinsulinemia and diabetes in insulin receptor/insulin receptor substrate-1 double heterozygous mice.
Type 2 diabetes is a complex disease in which genetic and environmental factors interact to produce alterations in insulin action and insulin secretion, leading to hyperglycemia. To evaluate the influence of genetic background on development of diabetes in a genetically susceptible host, we generated mice that are double heterozygous (DH) for knockout of the insulin receptor and insulin recepto...
متن کامل