Telmisartan, an angiotensin II receptor blocker, has been widely used for hypertension. It has also been reported to improve insulin sensitivity in animal models of obesity and diabetic patients by targeting to the peroxisome proliferator-activated receptor (PPAR)-γ. High glucose/high lipid (HG/HL)-induced apoptosis of pancreatic β-cells impairs its function of insulin secretion and is generally believed to be the key factor in the development of diabetes. In this study, we investigated whether telmisartan exerted a protective effect against HG/HL-induced apoptosis and insulin secretion in vitro as well as in vivo; 10-μM telmisartan treatment significantly reduced HG (25 mM) or/and HL (0.4 mM palmitic acid) induced-cell apoptosis and greatly improved insulin secretion in INS-1 pancreatic β-cells, which is consistent in an obesity rat model induced by HG/HL diets. Furthermore, telmisartan treatment markedly reduced the protein level of GRP78, CHOP, and caspase 12, while increasing anti-apoptotic Bcl-2 protein expression. Moreover, telmisartan treatment significantly reduced intracellular ROS levels. Mechanistically, we demonstrated that PPARγ signaling pathway may be involved in the telmisartan protective effects, which were blocked by a PPARγ blocker, GW9662. In conclusion, the protective effect of telmisartan was mediated by an anti-ER stress-induced apoptotic and anti-oxidative pathway. SIGNIFICANCE OF THIS STUDY: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder worldwide pathologically characterized by hyperglycemia and insulin resistance. Long-term high glucose in the blood has been proposed to induce pancreatic β-cell loss and is generally believed to be the key factor in the development of diabetes. In the present study, we demonstrated that telmisartan, a common drug used for hypertension treatment, has a protective effect against high glucose/high lipid-induced cell apoptosis and greatly improves the insulin secretion function by inhibiting the oxidative stress and ER stress. Furthermore, this protective effect of telmisartan is mediated by the PPAR-γ signal pathway, which may provide a potential strategy against T2DM.
Keywords: ER stress; apoptosis; high glucose/high lipid; insulin secretion; oxidative stress; telmisartan.
© 2019 John Wiley & Sons, Ltd.