Peking University Fifth School of Clinical Medicine (Beijing Hospital), Beijing, China.
FEBS J. 2010 Dec;277(24):5061-71. doi: 10.1111/j.1742-4658.2010.07911.x. Epub 2010 Nov 12.
Defects in insulin secretion by pancreatic cells and/or decreased sensitivity of target tissues to insulin action are the key features of type 2 diabetes. It has been shown that excessive generation of reactive oxygen species (ROS) is linked to glucose-induced β-cell dysfunction. However, cellular mechanisms involved in ROS generation in β-cells and the link between ROS and glucose-induced β-cell dysfunction are poorly understood. Here, we demonstrate a key role of NADPH oxidase 2 (NOX2)-derived ROS in the deterioration of β-cell function induced by a high concentration of glucose. Sprague-Dawley rats were fed a high-fat diet for 24 weeks to induce diabetes. Diabetic rats showed increased glucose levels and elevated ROS generation in blood, but decreased insulin content in pancreatic β-cells. In vitro, increased ROS levels in pancreatic NIT-1 cells exposed to high concentrations of glucose (33.3 mmol·L(-1)) were associated with elevated expression of NOX2. Importantly, decreased glucose-induced insulin expression and secretion in NIT-1 cells could be rescued via siRNA-mediated NOX2 reduction. Furthermore, high glucose concentrations led to apoptosis of β-cells by activation of p38MAPK and p53, and dysfunction of β-cells through phosphatase and tensih homolog (PTEN)-dependent Jun N-terminal kinase (JNK) activation and protein kinase B (AKT/PKB) inhibition, which induced the translocation of forkhead box O1 and pancreatic duodenal homeobox-1, followed by reduced insulin expression and secretion. In conclusion, NOX2-derived ROS could play a critical role in high glucose-induced β-cell dysfunction through PTEN-dependent JNK activation and AKT inhibition.
胰岛细胞胰岛素分泌缺陷和/或靶组织对胰岛素作用的敏感性降低是 2 型糖尿病的主要特征。已经表明，活性氧（ROS）的过度产生与葡萄糖诱导的β细胞功能障碍有关。然而，β细胞中 ROS 产生的细胞机制以及 ROS 与葡萄糖诱导的β细胞功能障碍之间的联系还知之甚少。在这里，我们证明了 NADPH 氧化酶 2（NOX2）衍生的 ROS 在高浓度葡萄糖诱导的β细胞功能恶化中起关键作用。Sprague-Dawley 大鼠用高脂肪饮食喂养 24 周以诱导糖尿病。糖尿病大鼠表现出血糖升高和血液中 ROS 生成增加，但胰腺β细胞中胰岛素含量降低。在体外，暴露于高浓度葡萄糖（33.3mmol·L（-1））的胰腺 NIT-1 细胞中 ROS 水平升高与 NOX2 表达升高有关。重要的是，通过 siRNA 介导的 NOX2 减少可以挽救 NIT-1 细胞中葡萄糖诱导的胰岛素表达和分泌减少。此外，高葡萄糖浓度通过激活 p38MAPK 和 p53 导致β细胞凋亡，并通过磷酸酶和张力同源物（PTEN）依赖性 Jun N-末端激酶（JNK）激活和蛋白激酶 B（AKT/PKB）抑制导致β细胞功能障碍，这诱导了叉头框 O1 和胰腺十二指肠同源盒-1 的易位，随后胰岛素表达和分泌减少。总之，NOX2 衍生的 ROS 可能通过 PTEN 依赖性 JNK 激活和 AKT 抑制在高葡萄糖诱导的β细胞功能障碍中发挥关键作用。
