Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice

Aims/hypothesis O- GlcNAcylation is characterised by the addition of N -acetylglucosamine to various proteins by O -GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O -GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O -GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions. Methods Tamoxifen-inducible global Ogt -knockout ( Ogt -KO) mice were generated by crossbreeding Ogt -flox mice with R26 -Cre-ER T2 mice. Liver, skeletal muscle, adipose tissue and pancreatic beta cell-specific Ogt -KO mice were generated by crossbreeding Ogt -flox mice with Alb -Cre, Mlc1f -Cre, Adipoq -Cre and Pdx1 PB -CreER™ mice, respectively. Glucose metabolism was evaluated by i.p. glucose and insulin tolerance tests. Results Tamoxifen-inducible global Ogt -KO mice exhibited a lethal phenotype from 4 weeks post injection, suggesting that O -GlcNAcylation is essential for survival in adult mice. Tissue-specific Ogt deletion from insulin-sensitive organs, including liver, skeletal muscle and adipose tissue, had little impact on glucose metabolism under physiological conditions. However, pancreatic beta cell-specific Ogt -KO mice displayed transient hypoglycaemia ( Ogt -flox 5.46 ± 0.41 vs Ogt -βKO 3.88 ± 0.26 mmol/l) associated with about twofold higher insulin secretion and accelerated adiposity, followed by subsequent hyperglycaemia ( Ogt -flox 6.34 ± 0.32 vs Ogt -βKO 26.4 ± 2.37 mmol/l) with insulin depletion accompanied by beta cell apoptosis. Conclusions/interpretation These findings suggest that O -GlcNAcylation has little effect on glucose metabolism in insulin-sensitive tissues but plays a crucial role in pancreatic beta cell function and survival under physiological conditions. Our results provide novel insight into O -GlcNAc biology and physiology in glucose metabolism.