Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
FASEB J. 2010 May;24(5):1497-505. doi: 10.1096/fj.09-136572. Epub 2009 Dec 23.
Patients with type 2 diabetes lose beta cells, but the underlying mechanisms are incompletely understood. Glucose-6-phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reductant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic beta cells are highly sensitive to increased ROS. This study aimed to determine whether G6PD and NADPH play central roles in beta-cell survival. Human and mouse islets, MIN6 cell line, and G6PD deficient mice were studied. High glucose inhibited G6PD expression and activity. Inhibition of G6PD with siRNA led to increased ROS and apoptosis, decreased proliferation, and impaired insulin secretion. High glucose decreased insulin secretion, which was improved by overexpressing G6PD. G6PD-deficient mice had smaller islets and impaired glucose tolerance compared with control mice, which suggests that G6PD deficiency per se leads to beta-cell dysfunction and death. G6PD plays an important role in beta-cell function and survival. High-glucose-mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of beta cells in patients with diabetes.
2 型糖尿病患者会损失β细胞，但其中的潜在机制尚不完全清楚。葡萄糖-6-磷酸脱氢酶（G6PD）是主要的细胞内还原剂 NADPH 的主要来源，许多酶都需要 NADPH，包括抗氧化途径的酶。我们实验室之前的研究表明，高葡萄糖会损害内皮细胞和肾脏细胞中的 G6PD 活性，从而导致细胞存活率降低。胰腺β细胞对增加的 ROS 非常敏感。本研究旨在确定 G6PD 和 NADPH 是否在β细胞存活中起核心作用。研究了人胰岛、鼠胰岛、MIN6 细胞系和 G6PD 缺陷小鼠。高葡萄糖抑制 G6PD 的表达和活性。用 siRNA 抑制 G6PD 会导致 ROS 和细胞凋亡增加、增殖减少以及胰岛素分泌受损。高葡萄糖会降低胰岛素分泌，而过表达 G6PD 则可以改善胰岛素分泌。与对照组小鼠相比，G6PD 缺陷小鼠的胰岛更小，葡萄糖耐量受损，这表明 G6PD 缺陷本身会导致β细胞功能障碍和死亡。G6PD 在β细胞功能和存活中发挥重要作用。高葡萄糖介导的 G6PD 活性降低可能为糖尿病患者β细胞逐渐丧失提供了一种机制解释。
