Abstract：
Sodium 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.
摘要：
丁酸钠（NaB）改善糖尿病临床前模型的β细胞功能；然而，这些有益作用的潜在机制尚未完全阐明。在这项研究中,我们使用离体和体外糖尿病模型研究了NaB对β细胞功能和钙(Ca2+)信号传导的影响.我们的结果表明，NaB显着改善了2型糖尿病人体器官供体胰岛和细胞因子处理的INS-1β细胞中葡萄糖刺激的胰岛素分泌。始终如一，NaB改善了用促炎细胞因子处理的小鼠胰岛中葡萄糖刺激的Ca2振荡。由于β细胞中Ca2+的振荡表型受内质网(ER)Ca2+水平变化的支配,我们探索了NaB和储存操作钙进入(SOCE)之间的关系，一种通过STIM1介导的质膜Orai通道门控来补充ERCa2水平的救援机制。我们发现NaB处理保留了IL-1β处理的INS-1细胞的基础ERCa2水平并恢复了SOCE。此外，我们将这些变化与细胞因子处理的INS-1细胞和小鼠胰岛中STIM1水平的恢复联系起来，我们发现NaB治疗足以防止响应IL-1β治疗的β细胞死亡。机制实验表明，NaB通过抑制组蛋白去乙酰化酶（HDAC）在β细胞中介导这些有益作用，iNOS抑制,和AKT-GSK-3信号的调制。一起来看,这些数据支持以下模型:NaB治疗通过与SOCE维持相关的多效性作用促进促炎条件下的β细胞功能和Ca2+稳态.这些结果还表明β细胞SOCE与肠道微生物组来源的丁酸之间的关系，这可能与糖尿病的治疗和预防有关。
