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-cell mass and altered glucose sensing impair insulin-secretory function in IRKO mice
1Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110; 2Research Division, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215; and 3Laboratory of Metabolic Diseases, Rockefeller University, New York, New York 10021
Submitted 27 November 2001 ; accepted in final form 13 September 2003
Pancreatic 
-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 -cell insulin receptor knockout (IRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, 
7-mo-old IRKO 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 -cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic IRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic IRKOs and to a lesser degree in the nondiabetic IRKO group. Pancreatic islets of nondiabetic IRKO 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 -cells leads primarily to profound defects in postnatal -cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.
-cell insulin receptor knockout; insulin secretion; insulin resistance; glucose transporter 2; glucokinase
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