Journal
CHEMISTRY & BIOLOGY
Volume 17, Issue 9, Pages 937-948Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2010.07.006
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Funding
- Canadian Institutes for Health Research
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- MSFHR
- NSERC
- University of York
- Royal Society
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council [BB/F007124/1] Funding Source: researchfish
- BBSRC [BB/F007124/1] Funding Source: UKRI
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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.
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