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Glucose suppresses superoxide generation in metabolically responsive pancreatic β cells

par Martens, Geert Antoine;Cai, Ying ;Hinke, Simon;Stangé, Geert;Van De Casteele, Christine ;Pipeleers, Daniel
Référence The Journal of biological chemistry, 280, 21, page (20389-20396)
Publication Publié, 2005-05

Article révisé par les pairs

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Résumé :

High rates of glucose metabolism and mitochondrial electron transport have been associated with increased mitochondrial production of reactive oxygen species (ROS). This mechanism was also proposed as a possible cause for dysfunction and death of pancreatic β cells exposed to high glucose levels. We examined whether high rates of glucose metabolism increase ROS production in purified rat β cells. Glucose up to 20 mM did not stimulate H 2O2 or superoxide production, whereas it dose-dependently increased cellular NAD(P)H and FADH2 levels with an EC50 around 8 mM. On the contrary, glucose concentration-dependently suppressed H2O2 and superoxide formation, with a major effect between O and 5 mM, parallel to an increase in cellular NAD(P)H levels. This suppressive effect was more marked in β cells with higher NAD(P)H responsiveness to glucose; it was not observed in glucagon-containing α cells, which lacked a glucose-induced increase in NAD(P)H. Suppression was also induced by the mitochondrial substrates leucine and succinate. Experiments with electron transport chain inhibitors indicate a role of respiratory complex I in ROS production at low mitochondrial activity and low NADH levels. Superoxide production at low glucose is potentially cytotoxic, because scavenging by the superoxide dismutase mimetic agent manganese(III)tetrakis(4-benzoic acid)porphyrin was found to reduce the rate of β cell apoptosis. Analysis of islets cultured at 20 mM glucose confirmed that this condition does not induce ROS production in β cells as a result of their increased rates of glucose metabolism. Our study indicates the need of β cells for basal nutrients maintaining mitochondrial NADH production at levels that suppress ROS accumulation from an inadequate respiratory complex I activity and thus inhibit a potential apoptotic pathway. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.