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.