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J. Biol. Chem., Vol. 282, Issue 20, 15228-15237, May 18, 2007

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Glucose Is Necessary for Embryonic Pancreatic Endocrine Cell Differentiation^*

Ghislaine Guillemain¹, Gaëlle Filhoulaud², Gabriela Da Silva-Xavier³, Guy A. Rutter⁴, and Raphaël Scharfmann

From the University Paris-Descartes, Faculty of Medicine, INSERM, Necker Hospital, EMI 363 and U845, 75730 Paris cedex 15, France and the Department of Cell Biology, Division of Medicine, Imperial College London, Exhibition Road, SW7 2AZ, United Kingdom

Mature pancreatic cells develop during embryonic life from endodermal progenitors, and this developmental process depends on activation of a hierarchy of transcription factors. While information is available on mesodermal signals controlling pancreas development, little is known about environmental factors, such as the levels of nutrients including glucose, that may control this process. Here, we studied the effects of glucose on pancreatic cells development. We used an in vitro model where both endocrine and acinar cells develop from early pancreatic and duodenal homeobox-1 (PDX1)-positive embryonic pancreatic progenitors. We first showed that glucose does not have a major effect on global pancreatic cell proliferation, survival, and acinar cell development. On the other hand, glucose controlled both alpha and beta cell development. Specifically, the surface occupied by insulin-positive cells was 20-fold higher in pancreases cultured in presence than in absence of glucose, and this effect was dose-dependent over the range 0.5-10 mM. Glucose did not appear to control beta cell development by activating the proliferation of early progenitors or beta cells themselves but instead tightly regulated cell differentiation. Thus, glucose did not modify the pattern of expression of Neurogenin3, the earliest marker of endocrine progenitor cells, but was necessary for the expression of the transcription factor NeuroD, a direct target of Neurogenin3 known to be important for proper pancreatic endocrine cell development. We conclude that glucose interferes with the pancreatic endocrine cells development by regulating the transition between Ngn3 and upstream NeuroD.

Received for publication, November 29, 2006 , and in revised form, March 20, 2007.

^* This work was supported in part by INSERM-JDRF Grant (AIP Cellules souches A03139MS), the Sixth European Union Framework Program (Beta-Cell Therapy Integrated Project), the Institut National de la Sante et de la Recherche Medicale/Fondation pour la Recherche Medicale/Juvenile Diabetes Research Foundation (Grant 4DA03H), the French National Program of Research on Diabetes/Association of Research on Diabetes, and the Association Française des Diabetiques. 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.

² Supported by a CIFRE grant from Servier and the Ministère de l'Education Nationale de la Recherche et de la Technologie.

³ Supported by a Juvenile Diabetes Research Foundation Postdoctoral Fellowship.

⁴ Supported by the Wellcome Trust (Programme Grant and Research Leave Fellowship), the Medical Research Council and the Juvenile Diabetes Research Foundation.

¹ To whom correspondence should be addressed: INSERM E363 Faculté Necker, 156 Rue de Vaugirard, 75015 Paris, France. Tel.: 33-1-40-61-55-84; Fax: 33-1-43-06-04-43; E-mail: guillemain{at}necker.fr.

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