NDLI: Elevated nucleocytoplasmic glycosylation by O-GlcNAc results ininsulin resistance associated with defects in Akt activation in3T3-L1 adipocytes

Content Provider	PubMed Central
Author	Keith, Vosseller Wells, Lance Lane, M. Daniel Hart, Gerald W.
Copyright Year	2002
Abstract	Increased flux of glucose through the hexosamine biosyntheticpathway (HSP) is believed to mediate hyperglycemia-induced insulinresistance in diabetes. The end product of the HSP,UDPβ-N-acetylglucosamine (GlcNAc), is a donorsugar nucleotide for complex glycosylation in the secretorypathway and for O-linked GlcNAc (O-GlcNAc) addition tonucleocytoplasmic proteins. Cycling of the O-GlcNAc posttranslationalmodification was blocked by pharmacological inhibition of O-GlcNAcase,the enzyme that catalyzes O-GlcNAc removal from proteins, withO-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate(PUGNAc). PUGNAc treatment increased levels of O-GlcNAc and causedinsulin resistance in 3T3-L1 adipocytes. Insulin resistance inducedthrough the HSP by glucosamine and chronic insulin treatment correlatedwith increased O-GlcNAc levels on nucleocytoplasmic proteins. Whereasinsulin receptor autophosphorylation and insulin receptorsubstrate 2 tyrosine phosphorylation were not affected by PUGNAcinhibition of O-GlcNAcase, downstream phosphorylation of Akt at Thr-308and glycogen synthase kinase 3β at Ser-9 was inhibited.PUGNAc-induced insulin resistance was associated with increasedO-GlcNAc modification of several proteins including insulin receptorsubstrate 1 and β-catenin, two important effectors of insulinsignaling. These results suggest that elevation of O-GlcNAc levelsattenuate insulin signaling and contribute to the mechanism by whichincreased flux through the HSP leads to insulin resistance inadipocytes.
Related Links	http://dx.doi.org/10.1073/pnas.072072399
Ending Page	5318
Page Count	6
Starting Page	5313
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	8
Volume Number	99
Language	English
Publisher	National Academy of Sciences
Publisher Date	2002-04-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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