Sakai Koji, Matsumoto Kazuya, Nishikawa Takeshi, Suefuji Mihoshi, Nakamaru Kazuhiko, Hirashima Yoshiaki, Kawashima Junji, Shirotani Tetsuya, Ichinose Kenshi, Brownlee Michael, Araki Eiichi
Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Japan.
Biochem Biophys Res Commun. 2003 Jan 3;300(1):216-22. doi: 10.1016/s0006-291x(02)02832-2.
Pancreatic beta-cells exposed to hyperglycemia produce reactive oxygen species (ROS). Because beta-cells are sensitive to oxidative stress, excessive ROS may cause dysfunction of beta-cells. Here we demonstrate that mitochondrial ROS suppress glucose-induced insulin secretion (GIIS) from beta-cells. Intracellular ROS increased 15min after exposure to high glucose and this effect was blunted by inhibitors of the mitochondrial function. GIIS was also suppressed by H(2)O(2), a chemical substitute for ROS. Interestingly, the first-phase of GIIS could be suppressed by 50 microM H(2)O(2). H(2)O(2) or high glucose suppressed the activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme, and inhibitors of the mitochondrial function abolished the latter effects. Our data suggested that high glucose induced mitochondrial ROS, which suppressed first-phase of GIIS, at least in part, through the suppression of GAPDH activity. We propose that mitochondrial overwork is a potential mechanism causing impaired first-phase of GIIS in the early stages of diabetes mellitus.
暴露于高血糖环境下的胰腺β细胞会产生活性氧（ROS）。由于β细胞对氧化应激敏感，过量的ROS可能导致β细胞功能障碍。在此我们证明，线粒体ROS会抑制β细胞的葡萄糖诱导胰岛素分泌（GIIS）。暴露于高糖环境15分钟后，细胞内ROS增加，而线粒体功能抑制剂可减弱这种效应。H₂O₂（一种ROS的化学替代物）也会抑制GIIS。有趣的是，50微摩尔的H₂O₂可抑制GIIS的第一阶段。H₂O₂或高糖会抑制糖酵解酶甘油醛-3-磷酸脱氢酶（GAPDH）的活性，而线粒体功能抑制剂可消除后一种效应。我们的数据表明，高糖诱导线粒体ROS，其至少部分通过抑制GAPDH活性来抑制GIIS的第一阶段。我们提出，线粒体过度工作是糖尿病早期导致GIIS第一阶段受损的潜在机制。
