Hepatic glucose sensing via the CREB coactivator CRTC2

Science. 2008 Mar 7;319(5868):1402-5. doi: 10.1126/science.1151363.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Blood Glucose / metabolism
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytoplasm / metabolism
  • Diabetes Mellitus / metabolism
  • Gluconeogenesis*
  • Glucose / metabolism*
  • Glycosylation
  • Glycosyltransferases / metabolism
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • RNA Interference
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors
  • beta-N-Acetylhexosaminidases / metabolism

Substances

  • Blood Glucose
  • Crtc2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Insulin
  • Trans-Activators
  • Transcription Factors
  • Glycosyltransferases
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • Glucose