| First Author | Ida S | Year | 2017 |
| Journal | Diabetologia | Volume | 60 |
| Issue | 9 | Pages | 1761-1769 |
| PubMed ID | 28642969 | Mgi Jnum | J:252014 |
| Mgi Id | MGI:5923820 | Doi | 10.1007/s00125-017-4327-y |
| Citation | Ida S, et al. (2017) Diverse metabolic effects of O-GlcNAcylation in the pancreas but limited effects in insulin-sensitive organs in mice. Diabetologia 60(9):1761-1769 |
| abstractText | 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-betaKO 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-betaKO 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. |
