Reduction of Reactive Oxygen Species Ameliorates Metabolism-Secretion Coupling in Islets of Diabetic GK Rats by Suppressing Lactate Overproduction

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 beta-cells by exposure to tempol, a superoxide (O-2(-)) dismutase mimic, plus ebselen, a glutathione peroxidase mimic (TE treatment). In GK islets, both H2O2 and O-2(-) 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 1 alpha (HIF1 alpha). 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 beta-cells and suggest that ROS reduction can improve mitochondrial metabolism by suppressing lactate overproduction through the inhibition of HIF1 alpha stabilization.