Year: 2005
Type: article
Abstract: Mutations in the gene encoding hepatocyte nuclear factor-4alpha (HNF-4alpha) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4alpha to the maintenance of glucose homeostasis by the beta cell in vivo, we derived a conditional knockout of HNF-4alpha using the Cre-loxP system. Surprisingly, deletion of HNF-4alpha in beta 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 beta 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-4alpha. Our data provide genetic evidence that HNF-4alpha is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.
DOI: 10.1172/jci22365
Institutions: University of Pennsylvania, Medical College of Wisconsin
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G135863467, FUNCTIONAL GENOMICS OF THE DEVELOPING ENDOCRINE PANCREAS, Transcriptional Control of Pancreatic Development, FUNCTIONAL GENOMICS OF THE BETA-CELL, Transcriptional Regulation of Mammalian Hepatic Development, Regulation of Fetal Liver Growth, The Role of Neurogenin 3 in Pancreas Development, University of Pennsylvania Diabetes Research Center, Center for Molecular Studies in Digestive and Liver Diseases
OpenAlex ID: W2069271978