Hepatocyte nuclear factor-4α is essential for glucose-stimulated insulin secretion by pancreatic β-cells

Atsuko Miura, Kazuya Yamagata, Masafumi Kakei, Hiroyasu Hatakeyama, Noriko Takahashi, Kenji Fukui, Takao Nammo, Kazue Yoneda, Yusuke Inoue, Frances M. Sladek, Mark A. Magnuson, Haruo Kasai, Junichiro Miyagawa, Frank J. Gonzalez, Iichiro Shimomura

Research output: Contribution to journalArticlepeer-review

116 Citations (Scopus)

Abstract

Mutations in the hepatocyte nuclear factor (HNF)-4α gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose-stimulated insulin secretion by pancreatic β-cells. HNF-4α, a transcription factor belonging to the nuclear receptor superfamily, is expressed in pancreatic islets as well as in the liver, kidney, and intestine. However, the role of HNF-4α in pancreatic β-cell is unclear. To clarify the role of HNF-4α in β-cells, we generated β-cell-specific HNF-4α knock-out (βHNF-4αKO) mice using the Cre-LoxP system. The βHNF-4αKO mice exhibited impairment of glucose-stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, β-cell mass, and insulin content were normal in the HNF-4α mutant mice. Insulin secretion by βHNF-4αKO islets and the intracellular calcium response were impaired after stimulation by glucose or sulfonylurea but were normal after stimulation with KCl or arginine. Both NAD(P)H generation and ATP content at high glucose concentrations were normal in the βHNF-4αKO mice. Expression levels of Kir6.2 and SUR1 proteins in the βHNF-4αKO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in βHNF-4αKO mice compared with control mice. These results are suggestive of the dysfunction of KATP channel activity in the pancreatic β-cells of HNF-4α-deficient mice. Because the KATP channel is important for proper insulin secretion in β-cells, altered KATP channel activity could be related to the impaired insulin secretion in the βHNF-4αKO mice.

Original languageEnglish
Pages (from-to)5246-5257
Number of pages12
JournalJournal of Biological Chemistry
Volume281
Issue number8
DOIs
Publication statusPublished - 2006 Feb 24

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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