title: Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice.
abstract: Pancreatic beta-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in beta-cell insulin receptor knockout (betaIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, approximately 7-mo-old betaIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced beta-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic betaIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic betaIRKOs and to a lesser degree in the nondiabetic betaIRKO group. Pancreatic islets of nondiabetic betaIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in beta-cells leads primarily to profound defects in postnatal beta-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D003920:Diabetes Mellitus / Q000378:metabolism*; D004195:Disease Models, Animal; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011972:Receptor, Insulin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D011972:Receptor, Insulin