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Rana K. Gupta, Marko Z. Vatamaniuk, Catherine S. Lee, Reed C. Flaschen, James T. Fulmer, Franz M. Matschinsky, Stephen A. Duncan, Klaus H. Kaestner
J Clin Invest. 2005;
115(4):1006
doi:10.1172/JCI22365
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utations in the gene encoding hepatocyte nuclear factor-4α (HNF-4α) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4α to the maintenance of glucose homeostasis by the β cell in vivo, we derived a conditional knockout of HNF-4α using the Cre-loxP system. Surprisingly, deletion of HNF-4α in β cells resulted in hyperinsulinemia in fasted and fed mice but paradoxically also in impaired glucose tolerance. Islet perifusion and calcium-imaging studies showed abnormal responses of the mutant β cells to stimulation by glucose and sulfonylureas. These phenotypes can be explained in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. We demonstrate using cotransfection assays that the Kir6.2 gene is a transcriptional target of HNF-4α. Our data provide genetic evidence that HNF-4α is required in the pancreatic β cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.
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