The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Gupta, RK; Vatamaniuk, MZ; Lee, CS; Flaschen, RC; Fulmer, JT; Matschinsky, FM; Duncan, SA; Kaestner, KH

Published Date

  • April 2005

Published In

Volume / Issue

  • 115 / 4

Start / End Page

  • 1006 - 1015

PubMed ID

  • 15761495

Pubmed Central ID

  • PMC1059446

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI22365

Language

  • eng

Conference Location

  • United States