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Chem Biol. 2010 Sep 24;17(9):937-48. doi: 10.1016/j.chembiol.2010.07.006.

Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes.

Author information

1
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.

Erratum in

  • Chem Biol. 2010 Oct 29;17(10):1161.

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.

PMID:
20851343
PMCID:
PMC2954295
DOI:
10.1016/j.chembiol.2010.07.006
[Indexed for MEDLINE]
Free PMC Article

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