| First Author | Lockridge A | Year | 2020 |
| Journal | Cell Rep | Volume | 31 |
| Issue | 5 | Pages | 107609 |
| PubMed ID | 32375037 | Mgi Jnum | J:300223 |
| Mgi Id | MGI:6489015 | Doi | 10.1016/j.celrep.2020.107609 |
| Citation | Lockridge A, et al. (2020) Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2. Cell Rep 31(5):107609 |
| abstractText | During early obesity, pancreatic beta cells compensate for increased metabolic demand through a transient phase of insulin hypersecretion that stabilizes blood glucose and forestalls diabetic progression. We find evidence that beta cell O-GlcNAcylation, a nutrient-responsive post-translational protein modification regulated by O-GlcNAc transferase (OGT), is critical for coupling hyperlipidemia to beta cell functional adaptation during this compensatory prediabetic phase. In mice, islet O-GlcNAcylation rises and falls in tandem with the timeline of secretory potentiation during high-fat feeding while genetic models of beta-cell-specific OGT loss abolish hyperinsulinemic responses to lipids, in vivo and in vitro. We identify the endoplasmic reticulum (ER) Ca(2+) ATPase SERCA2 as a beta cell O-GlcNAcylated protein in mice and humans that is able to rescue palmitate-stimulated insulin secretion through pharmacological activation. This study reveals an important physiological role for beta cell O-GlcNAcylation in sensing and responding to obesity, with therapeutic implications for managing the relationship between type 2 diabetes and its most common risk factor. |
