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Science 325 (5940): 607-610

Copyright © 2009 by the American Association for the Advancement of Science

The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs

Chang-Liang Zhang,1 Megumi Katoh,1 Tadao Shibasaki,1 Kohtaro Minami,1 Yasuhiro Sunaga,1,* Harumi Takahashi,1 Norihide Yokoi,1 Masahiro Iwasaki,1 Takashi Miki,1 Susumu Seino1,2,3,{dagger}

Abstract: Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1, is activated by adenosine 3',5'-monophosphate. Fluorescence resonance energy transfer and binding experiments revealed that sulfonylureas, widely used antidiabetic drugs, interact directly with Epac2. Sulfonylureas activated Rap1 specifically through Epac2. Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, and the glucose-lowering effect of the sulfonylurea tolbutamide was decreased in these mice. Epac2 thus contributes to the effect of sulfonylureas to promote insulin secretion. Because Epac2 is also required for the action of incretins, gut hormones crucial for potentiating insulin secretion, it may be a promising target for antidiabetic drug development.

1 Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
2 Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
3 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 4 - 1- 8, Hon-cho,Kawaguchi, Saitoma 332-0012, Japan.

* Present address: Cell Scale Team, Integrated Simulation of Living Matter Group, Computational Science Research Program, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.

{dagger} To whom correspondence should be addressed. E-mail: seino{at}

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