Involvement of Telmisartan on the Protective Effects Mediated by the Peroxisome Proliferator-Activated Receptor-γ Pathway in Mice

Abstract

Aims: The aim of this study is to further elaborate the improving effects of telmisartan on insulin resistance, beta-cell dysfunction and islet inflammation in a PPAR-γ signaling-dependent manner. Methods: The mRNA levels of renin-angiotensin system components were detected. We compared the effects of telmisartan and telmisartan combined with GW9662 (a PPAR-γ antagonist) in mice fed a high-fat diet or isolated non-diabetic mouse islets. Immunofluorescence or real-time PCR was used to determine changes in islet structure, function and inflammation as well as PPAR-γ expression. Results: Telmisartan reduced body weight, especially the visceral adipose tissue weight, which may be due to enhancing PPAR-γ expression and reshaping the RAS balance, including increased ACE2 and decreased ACE/ATR1 mRNA expression levels. IPGTT and HOMA-IR showed that telmisartan attenuated insulin resistance in a manner dependent on the duration of high-fat diet fed, which could be offset by GW9662. In addition, telmisartan normalized beta-cell function (including the increase in PDX1, GLUT2 and insulin mRNA expression levels) and islet structure (such as the maintenance of islet cell distribution, decrease in the alpha/beta ratio and alpha-cell mass and the inhibition of beta-cell apoptosis) via the activation of PPAR-γ signaling in mice fed a high-fat diet. Moreover, telmisartan inhibited the high fat diet-induced activation of p65 expression and inflammatory factors (including IL-1beta and TNF-alpha) which were stimulated by chronic palmitate exposure in pancreatic islets, while GW9662 had the reverse effect. Discussions: Our novel results exhibit critical roles for PPARγ activation in the biological effects of telmisartan and suggest a therapeutic potential for telmisartan in the prevention of type 2