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 β-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and β-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from β-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive β-cell OGA ablation (βOGAKO) to specifically increase O-GlcNAcylation in β-cells. Under normal chow diet, young male and female βOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in β-cell mass was observed between βOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in βOGAKO islets. βOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female βOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable β-cell mass was found between βOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in β-cells reduces β-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 β-cell.
|Original language||English (US)|
|Journal||Frontiers in Endocrinology|
|State||Published - Oct 26 2022|
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grant NIDDK (R21DK112144 and R01DK115720 to EUA; F31DK131860 to SJ, T32 DK007203 for SP; and T32GM140936 for AW). This work was also supported by the Department of Integrative Biology and Physiology Accelerator Program.
Copyright © 2022 Jo, Pritchard, Wong, Avula, Essawy, Hanover and Alejandro.
- O-GlcNAcase (OGA)
- O‐linked N‐acetylglucosamine (O‐GlcNAc)
- Streptozocin (STZ)
- beta cell (β‐cell)
- high fat diet (HFD)
- insulin secretion
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
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