Effect of sitagliptin on cardiomyocyte pyroptosis induced by type 2 diabetes mellitus and underlying mechanism

AIM: To explore the effect of sitagliptin (SLT) on cardiomyocyte pyroptosis induced by type 2 diabetes mellitus (T2DM) and the underlying mechanism. METHODS: The T2DM rat model was established by high-fat diet and intraperitoneal injection of streptozotocin (35 mg/kg). The model rats were treated with SLT at 3, 10 and 30 mg/kg and nicotinamide[NAM; an non-specific inhibitor of sirtuin (SIRT) family] at 500 mg/kg for 4 weeks. Fasting blood glucose was measured, and the tissue proteins were determined by the methods of Western blot and immunochemistry. RESULTS: Compared with control group, the pyroptosis of cardiomyocytes and NLRP3 expression were significantly induced, while the protein level of SIRT3 was downregulated by T2DM (P<0.05). SLT inhibited the pyrpotosis of diabetic rat cardiomyocytes, downregulated the expression of NLRP3, and upregulated the expression of SIRT3 in a dose-dependent manner (P<0.05). All the function of SLT (30 mg/kg) was reversed by the treatment with NAM (500 mg/kg). Compared with control group, the pyroptosis of cardiomyocytes and NLRP3 expression were significantly induced, while the protein level of SIRT3 was not regulated by NAM (500 mg/kg). CONCLUSION: SLT exerts the inhibitory effect on the pyroptosis of cardiomyocytes induced by diabetes, and the mechanism is related to the SIRT3/NLRP3 signaling pathway.     

Effect of sitagliptin on autopaghy in mesangial cells induced by AGEs

AIM: To investigate the effect of sitagliptin on the autopaghy and the expression of extracellular matrix in mesangial cells induced by advanced glycation end products (AGEs). METHODS: The cells were divided into 5 groups:control group, AGE group, and sitagliptin (5, 10 and 20 μmol/L) groups. After 48 h, the cell viability was measured by MTT assay, and the content of collagen (Col) Ⅳ in the supernatant of the cell culture was detected by ELISA. The protein levels of beclin-1, adenosine monophosphate-activated protein kinase (AMPK), p-AMPK, p70S6K and p-p70S6K were determined by Western blot. RESULTS: Compared with control group, the viability and the expression of Col IV induced by AGEs in the cultured mesangial cells were significantly increased (P<0.01). Sitagliptin decreased the viability and the expression of Col IV induced by AGEs in the mesangial cells in a dose-dependent manner. AGEs significantly inhibited the protein levels of beclin-1 and p-AMPK, but significantly increased the protein level of p-p70S6K. Compared with AGE group, sitagliptin significantly reversed the above results in a dose-dependent manner. CONCLUSION: Autophagy may mediate the protective effect of sitagliptin on mesangial cells induced by AGEs.