Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, Indianapolis, IN, USA.
Departments of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA.
Endocrinology. 2022 Jul 1;163(7). doi: 10.1210/endocr/bqac081.
Pancreatic islet beta cells require a fine-tuned endoplasmic reticulum (ER) stress response for normal function; abnormal ER stress contributes to diabetes pathogenesis. Here, we identified a small molecule, SW016789, with time-dependent effects on beta cell ER stress and function. Acute treatment with SW016789 potentiated nutrient-induced calcium influx and insulin secretion, while chronic exposure to SW016789 transiently induced ER stress and shut down secretory function in a reversible manner. Distinct from the effects of thapsigargin, SW016789 did not affect beta cell viability or apoptosis, potentially due to a rapid induction of adaptive genes, weak signaling through the eIF2α kinase PERK, and lack of oxidative stress gene Txnip induction. We determined that SW016789 acted upstream of voltage-dependent calcium channels (VDCCs) and potentiated nutrient- but not KCl-stimulated calcium influx. Measurements of metabolomics, oxygen consumption rate, and G protein-coupled receptor signaling did not explain the potentiating effects of SW016789. In chemical cotreatment experiments, we discovered synergy between SW016789 and activators of protein kinase C and VDCCs, suggesting involvement of these pathways in the mechanism of action. Finally, chronically elevated calcium influx was required for the inhibitory impact of SW016789, as blockade of VDCCs protected human islets and MIN6 beta cells from hypersecretion-induced dysfunction. We conclude that beta cells undergoing this type of pharmacological hypersecretion have the capacity to suppress their function to mitigate ER stress and avoid apoptosis. These results have the potential to uncover beta cell ER stress mitigation factors and add support to beta cell rest strategies to preserve function.
胰岛β细胞需要精细调节内质网（ER）应激反应才能正常发挥功能；异常的 ER 应激会导致糖尿病发病机制。在这里，我们鉴定了一种小分子 SW016789，它对β细胞 ER 应激和功能具有时间依赖性的影响。急性处理 SW016789 增强了营养诱导的钙内流和胰岛素分泌，而慢性暴露于 SW016789 以可逆的方式短暂诱导 ER 应激并关闭分泌功能。与他普西庚的作用不同，SW016789 不影响β细胞活力或凋亡，这可能是由于快速诱导适应性基因、通过 eIF2α 激酶 PERK 传递较弱的信号以及缺乏氧化应激基因 Txnip 诱导所致。我们确定 SW016789 作用于电压依赖性钙通道（VDCCs）上游，并增强了营养但不是 KCl 刺激的钙内流。代谢组学、耗氧量和 G 蛋白偶联受体信号的测量无法解释 SW016789 的增强作用。在化学共处理实验中，我们发现 SW016789 与蛋白激酶 C 和 VDCCs 的激活剂之间存在协同作用，表明这些途径参与了作用机制。最后，慢性升高的钙内流是 SW016789 抑制作用所必需的，因为 VDCC 阻断可保护人胰岛和 MIN6β细胞免受高分泌诱导的功能障碍。我们得出结论，经历这种类型的药理学高分泌的β细胞有能力抑制其功能以减轻 ER 应激并避免凋亡。这些结果有可能揭示β细胞 ER 应激缓解因素，并为保护β细胞功能的β细胞休息策略提供支持。
