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Science 7 March 2008:
Vol. 319. no. 5868, pp. 1402 - 1405
DOI: 10.1126/science.1151363
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Reports

Hepatic Glucose Sensing via the CREB Coactivator CRTC2

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

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}salk.edu

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