Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic beta-cells.
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.
Sakai
Koji
K
Department of Metabolic Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Japan.
Matsumoto
Kazuya
K
Nishikawa
Takeshi
T
Suefuji
Mihoshi
M
Nakamaru
Kazuhiko
K
Hirashima
Yoshiaki
Y
Kawashima
Junji
J
Shirotani
Tetsuya
T
Ichinose
Kenshi
K
Brownlee
Michael
M
Araki
Eiichi
E
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
D007328:Insulin; D007461:Iodoacetates; D017382:Reactive Oxygen Species; D013481:Superoxides; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005947:Glucose