Sodium butyrate prevents cytokine‐induced β‐cell dysfunction through restoration of stromal interaction molecule 1 expression and activation of store‐operated calcium entry

Abstract

AbstractSodium butyrate (NaB) improves β‐cell function in preclinical models of diabetes; however, the mechanisms underlying these beneficial effects have not been fully elucidated. In this study, we investigated the impact of NaB on β‐cell function and calcium (Ca2+) signaling using ex vivo and in vitro models of diabetes. Our results show that NaB significantly improved glucose‐stimulated insulin secretion in islets from human organ donors with type 2 diabetes and in cytokine‐treated INS‐1 β cells. Consistently, NaB improved glucose‐stimulated Ca2+ oscillations in mouse islets treated with proinflammatory cytokines. Because the oscillatory phenotype of Ca2+ in the β cell is governed by changes in endoplasmic reticulum (ER) Ca2+ levels, we explored the relationship between NaB and store‐operated calcium entry (SOCE), a rescue mechanism that acts to refill ER Ca2+ levels through STIM1‐mediated gating of plasmalemmal Orai channels. We found that NaB treatment preserved basal ER Ca2+ levels and restored SOCE in IL‐1β‐treated INS‐1 cells. Furthermore, we linked these changes with the restoration of STIM1 levels in cytokine‐treated INS‐1 cells and mouse islets, and we found that NaB treatment was sufficient to prevent β‐cell death in response to IL‐1β treatment. Mechanistic experiments revealed that NaB mediated these beneficial effects in the β‐cell through histone deacetylase (HDAC) inhibition, iNOS suppression, and modulation of AKT‐GSK‐3 signaling. Taken together, these data support a model whereby NaB treatment promotes β‐cell function and Ca2+ homeostasis under proinflammatory conditions through pleiotropic effects that are linked with maintenance of SOCE. These results also suggest a relationship between β‐cell SOCE and gut microbiome‐derived butyrate that may be relevant in the treatment and prevention of diabetes.