Elevation of Global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis.
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.
Macauley
Matthew S
MS
Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada.
Shan
Xiaoyang
X
Yuzwa
Scott A
SA
Gloster
Tracey M
TM
Vocadlo
David J
DJ
D000117:Acetylglucosamine / Q000378:metabolism*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005678:G(M2) Ganglioside / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C555050:1,2-dideoxy-2'-propylglucopyranoso(2,1-d)-delta 2'-thiazoline; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005678:G(M2) Ganglioside; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D005947:Glucose; D000117:Acetylglucosamine