Hepatocyte Nuclear Factor-4α Is Essential for Glucose-stimulated Insulin Secretion by Pancreatic β-Cells

作者：Atsuko Miura, Kazuya Yamagata, Masafumi Kakei, Hiroyasu Hatakeyama, Noriko K. Takahashi, Kenji Fukui, Takao Nammo, Kazue Yoneda, Yusuke Inoue, Frances M. Sladek, Mark A. Magnuson, Haruo Kasai, Junichiro Miyagawa, Frank J. Gonzalez, Iichiro Shimomura · 发表于：Journal of Biological Chemistry · 年份：2005 · DOI：10.1074/jbc.m507496200 · 被引用次数：165 · 研究领域：Pancreatic function and diabetes、Hyperglycemia and glycemic control in critically ill and hospitalized patients、Aldose Reductase and Taurine

Mutations in the hepatocyte nuclear factor (HNF)-4alpha gene cause a form of maturity-onset diabetes of the young (MODY1) that is characterized by impairment of glucose-stimulated insulin secretion by pancreatic beta-cells. HNF-4alpha, 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-4alpha in pancreatic beta-cell is unclear. To clarify the role of HNF-4alpha in beta-cells, we generated beta-cell-specific HNF-4alpha knock-out (betaHNF-4alphaKO) mice using the Cre-LoxP system. The betaHNF-4alphaKO mice exhibited impairment of glucose-stimulated insulin secretion, which is a characteristic of MODY1. Pancreatic islet morphology, beta-cell mass, and insulin content were normal in the HNF-4alpha mutant mice. Insulin secretion by betaHNF-4alphaKO 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 betaHNF-4alphaKO mice. Expression levels of Kir6.2 and SUR1 proteins in the betaHNF-4alphaKO mice were unchanged as compared with control mice. Patch clamp experiments revealed that the current density was significantly increased in betaHNF-4alphaKO mice compared with control mice. These results are suggestive of the dysfunction of K(ATP) channel activity in the pancr...