State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing Key Laboratory of Tumor Systems Biology, Peking University, 38 Xueyuan Road, Beijing, 100191, People's Republic of China.
Apoptosis. 2015 Nov;20(11):1420-32. doi: 10.1007/s10495-015-1150-0.
Lipotoxicity plays a vital role in development and progression of type 2 diabetes. Prolonged elevation of free fatty acids especially the palmitate leads to pancreatic β-cell dysfunction and apoptosis. Curcumin (diferuloylmethane), a polyphenol from the curry spice turmeric, is considered to be a broadly cytoprotective agent. The present study was designed to determine the protective effect of curcumin on palmitate-induced apoptosis in β-cells and investigate underlying mechanisms. Our results showed that curcumin improved cell viability and enhanced glucose-induced insulin secretory function in MIN6 pancreatic β-cells. Palmitate incubation evoked chromatin condensation, DNA nick end labeling and activation of caspase-3 and -9. Curcumin treatment inhibited palmitate-induced apoptosis, relieved mitochondrial depolarization and up-regulated Bcl-2/Bax ratio. Palmitate induced the generation of reactive oxygen species and inhibited activities of antioxidant enzymes, which could be neutralized by curcumin treatment. Moreover, curcumin could promote rapid phosphorylation of Akt and nuclear exclusion of FoxO1 in MIN6 cells under lipotoxic condition. Phosphatidylinositol 3-kinase and Akt specific inhibitors abolished the anti-lipotoxic effect of curcumin and stimulated FoxO1 nuclear translocation. These findings suggested that curcumin protected MIN6 pancreatic β-Cells against apoptosis through activation of Akt, inhibition of nuclear translocation of FoxO1 and mitochondrial survival pathway.
脂毒性在 2 型糖尿病的发生和发展中起着至关重要的作用。游离脂肪酸（尤其是棕榈酸）的长期升高会导致胰岛β细胞功能障碍和细胞凋亡。姜黄素（二芳基甲烷）是咖喱香料姜黄中的一种多酚类物质，被认为是一种广泛的细胞保护剂。本研究旨在确定姜黄素对β细胞中棕榈酸诱导的细胞凋亡的保护作用，并探讨其潜在机制。我们的研究结果表明，姜黄素可提高 MIN6 胰岛β细胞的细胞活力和增强葡萄糖诱导的胰岛素分泌功能。棕榈酸孵育可引起染色质浓缩、DNA 缺口末端标记和 caspase-3 和 caspase-9 的激活。姜黄素处理可抑制棕榈酸诱导的细胞凋亡，减轻线粒体去极化并上调 Bcl-2/Bax 比值。棕榈酸诱导活性氧的产生并抑制抗氧化酶的活性，姜黄素处理可中和这种作用。此外，姜黄素可在脂毒性条件下促进 MIN6 细胞中 Akt 的快速磷酸化和 FoxO1 的核排除。磷脂酰肌醇 3-激酶和 Akt 特异性抑制剂可消除姜黄素的抗脂毒性作用，并刺激 FoxO1 的核转位。这些发现表明，姜黄素通过激活 Akt、抑制 FoxO1 的核转位和线粒体存活途径来保护 MIN6 胰岛β细胞免受凋亡。
