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Science 319 (5868): 1402-1405

Copyright © 2008 by the American Association for the Advancement of Science

Hepatic Glucose Sensing via the CREB Coactivator CRTC2

Renaud Dentin,1 Susan Hedrick,1 Jianxin Xie,2 John Yates, III,3 Marc Montminy1*

Abstract: Chronic hyperglycemia contributes to the development of diabetes-associated complications. Increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway (HBP) and promote the O-glycosylation of proteins by O-glycosyl transferase (OGT). We show that OGT triggered hepatic gluconeogenesis through the O-glycosylation of the transducer of regulated cyclic adenosine monophosphate response element–binding protein (CREB) 2 (TORC2 or CRTC2). CRTC2 was O-glycosylated at sites that normally sequester CRTC2 in the cytoplasm through a phosphorylation-dependent mechanism. Decreasing amounts of O-glycosylated CRTC2 by expression of the deglycosylating enzyme O-GlcNAcase blocked effects of glucose on gluconeogenesis, demonstrating the importance of the HBP in the development of glucose intolerance.

1 The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.
3 The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

* To whom correspondence should be addressed. E-mail: montminy{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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A. Gautier-Stein, M. Soty, J. Chilloux, C. Zitoun, F. Rajas, and G. Mithieux (2012)
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   Abstract »    Full Text »    PDF »
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W. Yi, P. M. Clark, D. E. Mason, M. C. Keenan, C. Hill, W. A. Goddard III, E. C. Peters, E. M. Driggers, and L. C. Hsieh-Wilson (2012)
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   Abstract »    Full Text »    PDF »
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S.-H. Yu, M. Boyce, A. M. Wands, M. R. Bond, C. R. Bertozzi, and J. J. Kohler (2012)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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