Reduction of reactive oxygen species ameliorates metabolism-secretion coupling in islets of diabetic GK rats by suppressing lactate overproduction.
Reduction of reactive oxygen species ameliorates metabolism-secretion coupling in islets of diabetic GK rats by suppressing lactate overproduction.
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作者：
Sasaki M;Fujimoto S;Sato Y;Nishi Y;Mukai E;Yamano G;Sato H;Tahara Y;Ogura K;Nagashima K;Inagaki N
我们之前已经证明，在非肥胖糖尿病模型Goto-Kakizaki （GK）大鼠的胰岛中，葡萄糖诱导的胰岛素分泌（IS）和ATP升高受损，可以通过抑制内源性活性氧（ROS）过量产生30 - 60分钟显着恢复。在这项研究中，我们通过暴露于tempol（一种超氧化物（O2−）歧化酶模拟物）和ebselen（一种谷胱甘肽过氧化物酶模拟物）（TE治疗），研究了更长时间（12小时）ROS抑制对β细胞代谢-分泌偶联的影响。在GK型胰岛中，H2O2和O2−均被充分降低，TE治疗改善了葡萄糖诱导的IS和ATP升高。在高糖条件下，TE处理也改善了葡萄糖氧化（克雷布斯循环速度的指标），而决定糖酵解速度的葡萄糖激酶活性不受影响。GK胰岛的乳酸产量显著增加，TE处理降低了乳酸产量以及乳酸脱氢酶和缺氧诱导因子1α (HIF1α)的蛋白表达。这些结果表明，Warburg-like效应是癌细胞有氧代谢的特征，其中乳酸过量产生，与线粒体代谢的联系减少，在糖尿病β细胞代谢-分泌偶联受损中起重要作用，并表明ROS减少可以通过抑制HIF1α稳定来抑制乳酸过量产生，从而改善线粒体代谢。
We previously demonstrated that impaired glucose-induced insulin secretion (IS) and ATP elevation in islets of Goto-Kakizaki (GK) rats, a nonobese model of diabetes, were significantly restored by 30–60-min suppression of endogenous reactive oxygen species (ROS) overproduction. In this study, we investigated the effect of a longer (12 h) suppression of ROS on metabolism-secretion coupling in β-cells by exposure to tempol, a superoxide (O2−) dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE treatment). In GK islets, both H2O2 and O2− were sufficiently reduced and glucose-induced IS and ATP elevation were improved by TE treatment. Glucose oxidation, an indicator of Krebs cycle velocity, also was improved by TE treatment at high glucose, whereas glucokinase activity, which determines glycolytic velocity, was not affected. Lactate production was markedly increased in GK islets, and TE treatment reduced lactate production and protein expression of lactate dehydrogenase and hypoxia-inducible factor 1α (HIF1α). These results indicate that the Warburg-like effect, which is characteristic of aerobic metabolism in cancer cells by which lactate is overproduced with reduced linking to mitochondria metabolism, plays an important role in impaired metabolism-secretion coupling in diabetic β-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressing lactate overproduction through the inhibition of HIF1α stabilization.
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影响因子：
56.9
作者：
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7.7
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