2210-LB: Mitigating ER Stress Improves Vitamin D Action and β-Cell Function

Introduction and Objective: ER stress contributes to β-cell dysfunction and loss in T1D and T2D. Vitamin D plays a critical role in systemic physiology, and its deficiency increases T2D risk. VDR SNPs are associated with diabetes risk, and β-cell-specific VDR overexpression protects against diabetes. However, vitamin D supplementation failed in the D2d trial. Our preliminary data suggest sustained ER stress reduces VDR expression and activity, potentially explaining this failure. We aim to explore the relationship between vitamin D and ER stress in β-cells, investigating whether reducing ER stress can restore VDR activity and improve β-cell function. Methods: Mouse primary islets were used for the study and cultured variously with ER stressors (thapsigargin (Tg) or Grp78 knockdown), vitamin D, and/or the ER stress-reducing chemical chaperone TUDCA. UPR activation and VDR activity were evaluated by qPCR. β-cell death and function were evaluated using immunostaining and static glucose-stimulated insulin secretion (GSIS), respectively. Results: Endoplasmic reticulum (ER) stressors such as Tg and Grp78 loss significantly activated all three arms of the UPR(ATF6a, sXBP1, ATF4), reduced VDR and induced β-cell death. Vitamin D treatment prior to the ER stress challenge reduced UPR activation and β-cell death, as shown by TUNEL-positive cells. Since ER stress reduces VDR expression and activity, TUDCA pretreatment before the ER stress challenge prevented the loss of β-cell VDR expression, activity, and function. Conclusion: Vitamin D is a potent agent that protects β-cells against overactive ER stress. ER stress mitigation could provide a new therapeutic strategy to restore vitamin D action and prevent diabetes. Disclosure C. Darko: None. Y. Wang: None. T. Lama: None. L.C. Alonso: None. R.B. Sharma: None. Funding Institutional startup funds