title: Candesartan attenuates fatty acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic beta-cells.
abstract: Angiotensin II receptor blockers (ARBs) have been shown to decrease insulin resistance in obese diabetic animal models and reduce the risk of new-onset diabetes in hypertensive patients. In the present study, we studied whether candesartan, an ARB, can exert a direct effect against fatty acid-induced oxidative stress in pancreatic beta-cells. The effect of candesartan on lipotoxicity was evaluated using mouse insulin-secreting clonal cell, MIN6 and isolated mouse pancreatic islets. Intracellular insulin and triglyceride content, uncoupling protein-2 (UCP-2) mRNA expression, reactive oxygen species, protein kinase C (PKC) and NAD(P)H oxidase activity were examined. Candesartan recovered decreased insulin content in MIN6 exposed to 25mM glucose with 0.5mM palmitate (P<0.01). Candesartan tended to decrease intracellular triglyceride accumulation in cells exposed to 25mM glucose with 0.5mM palmitate. Palmitate-induced up-regulation of UCP-2 mRNA levels was suppressed by candesartan in a dose-dependent manner. Candesartan decreased palmitate-induced reactive oxygen species accumulation in MIN6 cells by 23% and in mouse islets by 59%. Candesartan also decreased palmitate-induced PKC activity by 21% and NAD(P)H oxidase activity by 37% in MIN6 cells. These findings indicated that candesartan attenuated fatty acid-induced oxidative stress and NAD(P)H oxidase activity in pancreatic beta-cells.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Miyazaki, Faculty of Medicine, Kiyotake, Miyazaki, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Wang
authors.initials: W
authors.lastname: Hongwei
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ueno
authors.forename: Masanari
authors.initials: M
authors.lastname: Mizuta
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002460:Cell Line; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006943:Hyperglycemia / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects*; D019308:Palmitic Acid / Q000633:toxicity; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000975:Antioxidants; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014280:Triglycerides; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D019308:Palmitic Acid; D019255:NADPH Oxidases; D011493:Protein Kinase C; C081643:candesartan