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Am J Physiol Endocrinol Metab (September 30, 2003). doi:10.1152/ajpendo.00533.2001
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Submitted on November 27, 2001
Accepted on September 13, 2003

Reduced {beta}-cell mass and altered glucose sensing impairs insulin secretory function in mice with pancreatic {beta}-cell knockout of the insulin receptor

Kenichi Otani1, Rohit N. Kulkarni2, Aaron C. Baldwin1, Jan Krutzfeldt3, Kohjiro Ueki2, Markus Stoffel3, C. Ronald Kahn2, and Kenneth S. Polonsky1*

1 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
2 Research Division, Department of Medicine, Harvard Medical School, Joslin Diabetes Center, Boston, MA, USA
3 Laboratory of Metabolic Diseases, Rockefeller University, New York, NY, USA

* To whom correspondence should be addressed. E-mail: polonsky{at}im.wustl.edu.

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 ({beta}IRKO) mice to define the mechanisms underlying the defect in insulin secretion. Based on responses to intraperitoneal glucose, ~7 month-old {beta}IRKO mice were either diabetic (25%) or normal glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared to 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 {beta}IRKO mice compared to controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic {beta}IRKOs and to a lesser degree in the non-diabetic {beta}IRKO group. Pancreatic islets of non-diabetic {beta}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 non-diabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in {beta}-cells leads primarily to profound defects in post-natal {beta}-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.




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