Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Biomolecules. 2021 Oct 6;11(10):1474. doi: 10.3390/biom11101474.
Chronic hyperglycemia and hyperlipidemia hamper beta cell function, leading to glucolipotoxicity. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies reactive aldehydes, such as methylglyoxal (MG) and 4-hydroxynonenal (4-HNE), derived from glucose and lipids, respectively. We aimed to investigate whether ALDH2 activators ameliorated beta cell dysfunction and apoptosis induced by glucolipotoxicity, and its potential mechanisms of action. Glucose-stimulated insulin secretion (GSIS) in MIN6 cells and insulin secretion from isolated islets in perifusion experiments were measured. The intracellular ATP concentrations and oxygen consumption rates of MIN6 cells were assessed. Furthermore, the cell viability, apoptosis, and mitochondrial and intracellular reactive oxygen species (ROS) levels were determined. Additionally, the pro-apoptotic, apoptotic, and anti-apoptotic signaling pathways were investigated. We found that Alda-1 enhanced GSIS by improving the mitochondrial function of pancreatic beta cells. Alda-1 rescued MIN6 cells from MG- and 4-HNE-induced beta cell death, apoptosis, mitochondrial dysfunction, and ROS production. However, the above effects of Alda-1 were abolished in knockdown MIN6 cells. In conclusion, we reported that the activator of ALDH2 not only enhanced GSIS, but also ameliorated the glucolipotoxicity of beta cells by reducing both the mitochondrial and intracellular ROS levels, thereby improving mitochondrial function, restoring beta cell function, and protecting beta cells from apoptosis and death.
慢性高血糖和高血脂会损害β细胞功能，导致糖脂毒性。线粒体乙醛脱氢酶 2（ALDH2）可以清除来自葡萄糖和脂质的反应性醛，如甲基乙二醛（MG）和 4-羟基壬烯醛（4-HNE）。我们旨在研究 ALDH2 激活剂是否可以改善糖脂毒性诱导的β细胞功能障碍和细胞凋亡，及其潜在的作用机制。通过 MIN6 细胞的葡萄糖刺激胰岛素分泌（GSIS）实验和离体胰岛的灌注实验来测量胰岛素分泌。评估 MIN6 细胞的细胞内 ATP 浓度和耗氧量。此外，还测定了细胞活力、细胞凋亡、线粒体和细胞内活性氧（ROS）水平。同时，还研究了促凋亡、凋亡和抗凋亡信号通路。我们发现 Alda-1 通过改善胰腺β细胞的线粒体功能来增强 GSIS。Alda-1 可挽救 MIN6 细胞免受 MG 和 4-HNE 诱导的β细胞死亡、凋亡、线粒体功能障碍和 ROS 产生。然而，在 knockdown MIN6 细胞中，Alda-1 的上述作用被消除。总之，我们的研究结果表明，ALDH2 激活剂不仅可以增强 GSIS，还可以通过降低线粒体和细胞内 ROS 水平来改善β细胞的糖脂毒性，从而改善线粒体功能，恢复β细胞功能，并防止β细胞凋亡和死亡。
