Inhibition of dipeptidyl peptidase IV by sitagliptin increases GLUT4 expression in insulin-sensitive tissues of SHR

Abstract

The goal of the present study was to investigate whether the dipeptidyl peptidase IV (DPPIV) inhibitor sitagliptin, which has been shown to exert both anti-hyperglycemic and anti-hypertensive actions, modulates GLUT4 expression in skeletal and cardiac muscles of SHR. To this end, male SHR at 5 and 20 weeks of age were treated with either sitagliptin (40 mg/kg twice daily) or vehicle for the period of ten days. Age-matched Wistar Kyoto (WKY) rats were used as normotensive controls. Sitagliptin treatment inhibited the activity of DPPIV in the plasma of both young and adult SHR and also decreased the circulating levels of the enzyme. Sitagliptin only suppressed blood pressure rising in Y-SHR. Levels of plasma insulin were not significantly different between the strains at young age. In contrast, adult SHR displayed enhanced plasma insulin concentration with fasting normoglycemia. Inhibition of DPPIV by sitagliptin restored plasma insulin levels of A-SHR. GLUT4 in the plasma membrane (PM) was lower in Y-SHR than in Y-WKY in the heart, the slow-twich oxidative soleus, the fast-twich glycolytic EDL and the fast-twich glycolytic-oxidative gastrocnemius. DPPIV inhibition normalized PM GLUT4 in myocytes from Y-SHR. Reduction of GLUT4 PM expression in the skeletal and cardiac myocytes was more pronounced in A-SHR vs. A-WKY than in Y-SHR vs. YWKY. Inhibition of DPPIV by sitagliptin increased GLUT4 PM, total protein and GLUT4-mRNA expression in the heart, soleus, EDL and gastrocnemius of treated-A-SHR to levels higher than those found in the A-WKY. Collectively, our data demonstrate that DPPIV inhibition upregulates GLUT4 in skeletal and cardiac muscles of SHR.