Inhibition of O-GlcNAcase Using a Potent and Cell-Permeable Inhibitor Does Not Induce Insulin Resistance in 3T3-L1 Adipocytes

Matthew S. Macauley, Yuan He, Tracey M. Gloster, Keith A. Stubbs, Gideon J. Davies, David J. Vocadlo

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

To probe increased O-GlcNAc levels as an independent mechanism governing insulin resistance in 3T3-L1 adipocytes, a new class of O-GlcNAcase (OGA) inhibitor was studied. 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas) is a potent inhibitor of OGA. The structure of 6-Ac-Cas bound in the active site of an OGA homolog reveals structural features contributing to its potency. Treatment of 3T3-L1 adipocytes with 6-Ac-Cas increases O-GlcNAc levels in a dose-dependent manner. These increases in O-GlcNAc levels do not induce insulin resistance functionally, measured using a 2-deoxyglucose (2-DOG) uptake assay, or at the molecular level, determined by evaluating levels of phosphorylated IRS-1 and Akt. These results, and others described, provide a structural blueprint for improved inhibitors and collectively suggest that increased O-GlcNAc levels, brought about by inhibition of OGA, does not by itself cause insulin resistance in 3T3-L1 adipocytes.

Original languageEnglish
Pages (from-to)937-948
Number of pages12
JournalChemistry and Biology
Volume17
Issue number9
DOIs
Publication statusPublished - 24 Sept 2010

Keywords

  • BETA-N-ACETYLGLUCOSAMINIDASE
  • PROTEIN MODIFICATION
  • GLYCOSYL HYDROLASES
  • NAG-THIAZOLINE
  • IN-VIVO
  • GLUCOSE
  • PHOSPHORYLATION
  • PUGNAC
  • STATE
  • GLCNACYLATION

Fingerprint

Dive into the research topics of 'Inhibition of O-GlcNAcase Using a Potent and Cell-Permeable Inhibitor Does Not Induce Insulin Resistance in 3T3-L1 Adipocytes'. Together they form a unique fingerprint.

Cite this