Sulfonylurea as well as elevated glucose levels stimulate reactive oxygen species production in the pancreatic beta-cell line, MIN6-a role of NAD(P)H oxidase in beta-cells.
Increased oxidative stress may play a key role in the progressive deterioration of pancreatic beta-cells and the development of diabetes. However, the underlying mechanism is not well understood. Exposure of pancreatic beta-cell line, MIN6 cells, to elevated glucose level for 2h induced an increase in reactive oxygen species (ROS) production, as evaluated by the staining of 2',7'-dichlorofluorescein diacetate. This effect was completely blocked by NAD(P)H oxidase inhibitor (diphenylene iodonium) and protein kinase C (PKC) inhibitor (calphostin C), but not affected by other flavoprotein inhibitors (rotenone, oxypurinol, or l-N-monomethyl arginine). Glibenclamide also stimulated ROS production in a dose-dependent manner. This effect was again blocked by diphenylene iodonium and calphostin C. In conclusion, insulin secretagogues, both glibenclamide and elevated glucose level, stimulated ROS production in beta-cells through a PKC-dependent activation of NAD(P)H oxidase. This mechanism may be a novel therapeutic target for preventing the progression of beta-cell deterioration.
Tsubouchi
Hirotaka
H
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Inoguchi
Toyoshi
T
Inuo
Mieko
M
Kakimoto
Maiko
M
Sonta
Toshiyo
T
Sonoda
Noriyuki
N
Sasaki
Shuji
S
Kobayashi
Kunihisa
K
Sumimoto
Hideki
H
Nawata
Hajime
H
D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009249:NADP / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D017382:Reactive Oxygen Species; D013453:Sulfonylurea Compounds; D009249:NADP; D005947:Glucose; D005905:Glyburide