Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, UAE.
Biomolecules. 2020 Feb 5;10(2):239. doi: 10.3390/biom10020239.
Glucolipotoxicity caused by hyperglycemia and hyperlipidemia are the common features of diabetes-induced complications. Metabolic adaptation, particularly in energy metabolism; mitochondrial dysfunction; and increased inflammatory and oxidative stress responses are considered to be the main characteristics of diabetes and metabolic syndrome. However, due to various fluctuating endogenous and exogenous stimuli, the precise role of these factors under in vivo conditions is not clearly understood. In the present study, we used pancreatic β-cells, Rin-5F, to elucidate the molecular and metabolic changes in glucolipotoxicity. Cells treated with high glucose (25 mM) and high palmitic acid (up to 0.3 mM) for 24 h exhibited increased caspase/poly-ADP ribose polymerase (PARP)-dependent apoptosis followed by DNA fragmentation, alterations in mitochondrial membrane permeability, and bioenergetics, accompanied by alterations in glycolytic and mitochondrial energy metabolism. Our results also demonstrated alterations in the expression of mammalian target of rapamycin (mTOR)/5' adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptotic and autophagy markers. Furthermore, pre-treatment of cells with 10 mM -acetyl cysteine attenuated the deleterious effects of high glucose and high palmitic acid with improved cellular functions and survival. These results suggest that the presence of high energy metabolites enhance mitochondrial dysfunction and apoptosis by suppressing autophagy and adapting energy metabolism, mediated, at least in part, via enhanced oxidative DNA damage and mTOR/AMPK-dependent cell signaling.
高血糖和高血脂引起的糖脂毒性是糖尿病引起的并发症的共同特征。代谢适应，特别是在能量代谢中；线粒体功能障碍；以及增加的炎症和氧化应激反应被认为是糖尿病和代谢综合征的主要特征。然而，由于各种内源性和外源性刺激的波动，这些因素在体内条件下的确切作用尚不清楚。在本研究中，我们使用胰岛β细胞 Rin-5F 来阐明糖脂毒性中的分子和代谢变化。用高葡萄糖（25mM）和高棕榈酸（高达 0.3mM）处理 24 小时的细胞表现出增加的半胱天冬酶/聚 ADP 核糖聚合酶（PARP）依赖性细胞凋亡，随后是 DNA 片段化、线粒体膜通透性和生物能的改变，伴随着糖酵解和线粒体能量代谢的改变。我们的结果还表明，哺乳动物雷帕霉素靶蛋白（mTOR）/5' 腺苷单磷酸激活蛋白激酶（AMPK）依赖性凋亡和自噬标志物的表达发生改变。此外，用 10mM N-乙酰半胱氨酸预处理细胞可减轻高葡萄糖和高棕榈酸的有害作用，改善细胞功能和存活。这些结果表明，高能量代谢物的存在通过抑制自噬和适应能量代谢来增强线粒体功能障碍和细胞凋亡，这至少部分是通过增强氧化 DNA 损伤和 mTOR/AMPK 依赖性细胞信号传导来介导的。
