| First Author | Jo S | Year | 2022 |
| Journal | Front Endocrinol (Lausanne) | Volume | 13 |
| Pages | 1040014 | PubMed ID | 36387851 |
| Mgi Jnum | J:331440 | Mgi Id | MGI:7385507 |
| Doi | 10.3389/fendo.2022.1040014 | Citation | Jo S, et al. (2022) Pancreatic beta-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo. Front Endocrinol (Lausanne) 13:1040014 |
| abstractText | Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in beta-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and beta-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from beta-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive beta-cell OGA ablation (betaOGAKO) to specifically increase O-GlcNAcylation in beta-cells. Under normal chow diet, young male and female betaOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in beta-cell mass was observed between betaOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in betaOGAKO islets. betaOGAKO mice showed deficit in insulin secretion <i>in vivo and in vitro.</i> When young animals were subjected to HFD, both male and female betaOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable beta-cell mass was found between betaOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in beta-cells reduces beta-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the beta-cell. |
