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J. Biol. Chem., Vol. 281, Issue 8, 5246-5257, February 24, 2006

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Hepatocyte Nuclear Factor-4 Is Essential for Glucose-stimulated Insulin Secretion by Pancreatic -Cells^*

Atsuko Miura, Kazuya Yamagata¹, 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^**, and Iichiro Shimomura

From the Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan, the Department of Internal Medicine, Division of Endocrinology, Metabolism, and Geriatric Medicine, Akita University School of Medicine, Hondo, Akita 010-8543, Japan, the ^¶Department of Cell Physiology, National Institute for Physiological Sciences and Graduate University of Advanced Studies, Okazaki 444-8787, Japan, the ^||Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan, the Department of Cell Biology and Neuroscience, University of California, Riverside, California 92521-0314, the Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and the ^**Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

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

Received for publication, July 11, 2005 , and in revised form, December 9, 2005.

^* This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Metabolic Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-3732; Fax: 81-6-6879-3739; E-mail: kazu{at}imed2.med.osaka-u.ac.jp.

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