The Role Of Sitagliptin On Inflammatory Reaction On Pancreatic Beta Cell Of Diabetic Rats And The Relationship Of Keap1-Nrf2-ARE Passway

Objective: To observe the role of Sitagliptin(Sita) on inflammatory reaction on pancreatic beta cell of diabetic rats and the relationship of Keap1-Nrf2-ARE passway. Methods: Fourty Sprague Dawley(SD) rats were divided into two groups. One is normal diets group(NC group, n=10),another one is high sucrose-fat diets group(HSFD group, n=30). 8 weeks later, after fasting 12 hours the subjects in HSFD group were injected intraperitoneally with streptozotocin(STZ, 30mg/kg),while those in NC group were injected intraperitoneally with equal normal saline. Rats with FBG higher than 16.7mmol/L for three consecutive days were successfully modeled. 20 of the modeled rats were selected randomly and divided into two groups :untreated diabetes control group(DM group, n=10)and sitagliptin treated group(Sita group, Sita100mg/kg·d, n=10).NC group and DM group were given by gavage with a similar dose of normal saline. Body weight and fasting blood glucose were measured after 0,4, 8,12,16,20 weeks respectively, intraperitoneal glucose tolerance test(IPGTT) and insulin tolerance test(ITT) were conducted before sitagliptin treated and after treated for 20 weeks. To observe the histological changes, pancreatic tissue in rats of each group were detected by HE staining.The expression of inflammatory cytokines nuclear factor Kappa B(NF-κB)、Toll-like receptors 4(TLR4)and Keap1-Nrf2-ARE pass way related gene Kelch-like ECH-associated protein 1(Keap1)、nuclear factor erythroid-derived factor 2-related factor(Nrf2)、hemeoxygenase-1(HO-1) mRNA and protein were detected by Real-time Quantitative-polymerase chain reaction(Q-PCR) and western blot respectively. Results: 1)After treating with Sitagliptin for 8 weeks, FBG in Sita group was lower than that in DM group(P<0.05); body weight in Sita group had no significant difference with that in DM group(P>0.05). 2)After intervening with Sitagliptin for 20 weeks, FBG and AUC of IPGTT and ITT in Sita group decreased visibly(P<0.05) compared with DM group; body weight had no significant difference(P>0.05) in two groups. 3) The number of pancreatic islet in DM group was significantly reduced, as well as the volume of pancreatic islet. After intervening by Sita. There was no obvious reduction in the number of the pancreas islet or the volume of islet. 4) The expression of TLR4、NF-κB、Nrf2、 Keap1、HO-1 mRNA and protein in DM group increased obviously(P<0.05),but significantly decreased in Sita group(P<0.05). Conclusions: 1) Sita can reduce blood glucose in diabetic rats without affecting body weight. 2) Sita alleviate the damage of diabetic pancreas, reduce apoptosis of pancreatic beta cells, enhance islet architecture remodeling. 3) Sita has anti-inflammatory effect on pancreatic beta cells through inhibiting the expression of TLR4/NF- kappa B pathways which is inflammatory. 4) Sita can attenuates insulin resistance and increase insulin secretion through the inhibition of Nrf2-Keap1-ARE system,and the mechanisms are closely related with its anti-inflammatory properties.