title: Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells.
abstract: 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.
authors.affiliation: Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakai
authors.forename: Kazuya
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Mihoshi
authors.initials: M
authors.lastname: Suefuji
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakamaru
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hirashima
authors.forename: Junji
authors.initials: J
authors.lastname: Kawashima
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shirotani
authors.forename: Kenshi
authors.initials: K
authors.lastname: Ichinose
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Eiichi
authors.initials: E
authors.lastname: Araki
mesh_terms: D000818:Animals; D002460:Cell Line; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007461:Iodoacetates / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
chemical_list: D007328:Insulin; D007461:Iodoacetates; D017382:Reactive Oxygen Species; D013481:Superoxides; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005947:Glucose