Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells.
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.
Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
Hong-Wei
HW
Wang
Masanari
M
Mizuta
Yukie
Y
Saitoh
Kenji
K
Noma
Hiroaki
H
Ueno
Masamitsu
M
Nakazato
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000378:metabolism / Q000494:pharmacology*; D001713:Biphenyl Compounds; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D013777:Tetrazoles; D052216:Glucagon-Like Peptide 1; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose; C081643:candesartan