Department of Biochemistry, Weill Cornell Medical College, New York, NY, 10065, USA.
Sci Rep. 2017 Aug 25;7(1):9536. doi: 10.1038/s41598-017-10209-0.
Type 2 diabetes results from defects in both insulin sensitivity and insulin secretion. Elevated cholesterol content within pancreatic β-cells has been shown to reduce β-cell function and increase β-cell apoptosis. Hyperglycemia and dyslipidemia contribute to glucolipotoxicity that leads to type 2 diabetes. Here we examined the capacity of glucolipotoxicity to induce free cholesterol accumulation in human pancreatic islets and the INS-1 insulinoma cell line. Glucolipotoxicity treatment increased free cholesterol in β-cells, which was accompanied by increased reactive oxygen species (ROS) production and decreased insulin secretion. Addition of AAPH, a free radical generator, was able to increase filipin staining indicating a link between ROS production and increased cholesterol in β-cells. We also showed the ability of stigmasterol, a common food-derived phytosterol with anti-atherosclerotic potential, to prevent the increase in both free cholesterol and ROS levels induced by glucolipotoxicity in INS-1 cells. Stigmasterol addition also inhibited early apoptosis, increased total insulin, promoted actin reorganization, and improved insulin secretion in cells exposed to glucolipotoxicity. Overall, these data indicate cholesterol accumulation as an underlying mechanism for glucolipotoxicity-induced defects in insulin secretion and stigmasterol treatment as a potential strategy to protect β-cell function during diabetes progression.
2 型糖尿病源于胰岛素敏感性和胰岛素分泌的双重缺陷。已有研究表明，胰腺β细胞内胆固醇含量升高会降低β细胞功能并增加β细胞凋亡。高血糖和血脂异常导致糖脂毒性，进而引发 2 型糖尿病。本研究旨在探讨糖脂毒性诱导人胰岛和 INS-1 胰岛素瘤细胞系游离胆固醇积累的能力。糖脂毒性处理增加了β细胞中的游离胆固醇，伴随着活性氧（ROS）产生增加和胰岛素分泌减少。添加 AAPH，一种自由基生成剂，能够增加 filipin 染色，表明 ROS 产生与β细胞中胆固醇增加之间存在联系。我们还表明，β-谷甾醇（一种具有抗动脉粥样硬化潜力的常见食物衍生植物甾醇）能够防止 INS-1 细胞中糖脂毒性诱导的游离胆固醇和 ROS 水平升高。β-谷甾醇的添加还抑制了早期细胞凋亡，增加了总胰岛素，促进了肌动蛋白的重组，并改善了暴露于糖脂毒性的细胞中的胰岛素分泌。总的来说，这些数据表明胆固醇积累是糖脂毒性诱导胰岛素分泌缺陷的潜在机制，而β-谷甾醇治疗可能是在糖尿病进展过程中保护β细胞功能的一种潜在策略。
