Glucagon-like peptide–1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells

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• 作者：Hong-Wei Wang^a ; Masanari Mizuta^a ; Yukie Saitoh^a ; Kenji Noma^a ; Hiroaki Ueno ; ^a ; ^{intron@med.miyazaki-u.ac.jp"" rel=""nofollow} ; Masamitsu Nakazato^a
• 刊名：Metabolism
• 出版年：2011
• 出版时间：August 2011
• 年：2011
• 卷：60
• 期：8
• 页码：1081-1089
• 全文大小：658 K

文摘

Glucagon-like peptide–1 (GLP-1) and angiotensin II type 1 receptor blocker reduce β-cell apoptosis in diabetes, but the underlying mechanisms are not fully understood. We examined the combination effects of GLP-1 and candesartan, an angiotensin II type 1 receptor blocker, on glucolipotoxicity-induced β-cell apoptosis; and we explored the possible mechanisms of the antiapoptotic effects. The effects of GLP-1 and/or candesartan on glucolipotoxicity-induced apoptosis and the phosphorylation of insulin receptor substrate–2 (IRS-2), protein kinase B (PKB), and forkhead box O1 (FoxO1) were evaluated by using MIN6 cells and isolated mouse pancreatic islets. Although palmitate significantly enhanced the high-glucose–induced apoptosis in both islets and MIN6 cells, GLP-1 and candesartan significantly inhibited apoptosis; and combination treatment additively prevented apoptosis. Whereas palmitate significantly decreased the phosphorylation of IRS-2, PKB, and FoxO1 in MIN6 cells, these changes were significantly inhibited by treatment with GLP-1 and/or candesartan. In addition, wortmannin, an inhibitor of phosphoinositide 3-kinase, markedly inhibited GLP-1– and/or candesartan-mediated PKB and FoxO1 phosphorylation. The present results suggest that GLP-1 and candesartan additively prevent glucolipotoxicity-induced apoptosis in pancreatic β-cells through the IRS-2/phosphoinositide 3-kinase/PKB/FoxO1 signaling pathway.