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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Blood Glucose / metabolism
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Cell Nucleus / metabolism
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Cells, Cultured
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cytoplasm / metabolism
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Diabetes Mellitus / metabolism
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Gluconeogenesis*
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Glucose / metabolism*
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Glycosylation
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Glycosyltransferases / metabolism
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Hepatocytes / metabolism
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Humans
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Insulin / metabolism
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Liver / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Phosphorylation
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RNA Interference
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Signal Transduction
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors
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beta-N-Acetylhexosaminidases / metabolism
Substances
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Blood Glucose
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Crtc2 protein, mouse
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Cyclic AMP Response Element-Binding Protein
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Insulin
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Trans-Activators
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Transcription Factors
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Glycosyltransferases
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hexosaminidase C
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beta-N-Acetylhexosaminidases
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Glucose