Elevation of Global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis

Chem Biol. 2010 Sep 24;17(9):949-58. doi: 10.1016/j.chembiol.2010.07.005.


The O-GlcNAc modification is proposed to be a nutrient sensor with studies suggesting that global increases in O-GlcNAc levels cause insulin resistance and impaired glucohomeostasis. We address this hypothesis by using a potent and selective inhibitor of O-GlcNAcase, known as NButGT, in a series of in vivo studies. Treatment of rats and mice with NButGT, for various time regimens and doses, dramatically increases O-GlcNAc levels throughout all tissues but does not perturb insulin sensitivity or alter glucohomeostasis. NButGT also does not affect the severity or onset of insulin resistance induced by a high-fat diet. These results suggest that pharmacological increases in global O-GlcNAc levels do not cause insulin resistance nor do they appear to disrupt glucohomeostasis. Therefore, the protective benefits of elevated O-GlcNAc levels may be achieved without deleteriously affecting glucohomeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylglucosamine / metabolism*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • G(M2) Ganglioside / metabolism
  • Glucose / metabolism*
  • Insulin Resistance*
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • beta-N-Acetylhexosaminidases / antagonists & inhibitors*
  • beta-N-Acetylhexosaminidases / metabolism


  • 1,2-dideoxy-2'-propylglucopyranoso(2,1-d)-delta 2'-thiazoline
  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • G(M2) Ganglioside
  • hexosaminidase C
  • beta-N-Acetylhexosaminidases
  • Glucose
  • Acetylglucosamine