Hepatic glucose sensing via the CREB coactivator CRTC2

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.