| First Author | Essawy A | Year | 2021 |
| Journal | J Biol Chem | Pages | 100297 |
| PubMed ID | 33460647 | Mgi Jnum | J:302171 |
| Mgi Id | MGI:6507065 | Doi | 10.1016/j.jbc.2021.100297 |
| Citation | Essawy A, et al. (2021) O-linked N-Acetylglucosamine Transferase (OGT) regulates pancreatic alpha-cell function in mice. J Biol Chem :100297 |
| abstractText | The nutrient sensor O-GlcNAc Transferase (OGT) catalyzes posttranslational addition of O-GlcNAc onto target proteins, influencing signaling pathways in response to cellular nutrient levels. OGT is highly expressed in pancreatic glucagon-secreting cells (alpha-cells), which secrete glucagon in response to hypoglycemia. The objective of this study was to determine whether OGT is necessary for the regulation of alpha-cell mass and function in vivo. We utilized genetic manipulation to produce two alpha-cell specific OGT-knockout models: a constitutive glucagon-Cre (alphaOGT(KO)), and an inducible glucagon-Cre (i-alphaOGT(KO)), that effectively delete OGT in alpha-cells. Using approaches including immunoblotting, immunofluorescent imaging, and metabolic phenotyping in vivo, we provide the first insight on the role of O-GlcNAcylation in alpha-cell mass and function. alphaOGT(KO) mice demonstrated normal glucose tolerance and insulin sensitivity but displayed significantly lower glucagon levels during both fed and fasted states. alphaOGT(KO) mice exhibited significantly lower alpha-cell glucagon content and alpha-cell mass at 6 months of age. In fasting, alphaOGT(KO) mice showed impaired pyruvate stimulated gluconeogenesis in vivo and reduced glucagon secretion in vitro. i-alphaOGT(KO) mice showed similarly reduced blood glucagon levels, defective in vitro glucagon secretion, and normal alpha-cell mass. Interestingly, both alphaOGT(KO) and i-alphaOGT(KO) mice had no deficiency in maintaining blood glucose homeostasis under fed or fasting conditions, despite impairment in alpha-cell mass and function, and glucagon content. In conclusion, these studies provide a first look at the role of OGT signaling in the alpha-cell, its effect on alpha-cell mass, and its importance in regulating glucagon secretion in hypoglycemic conditions. |
