Investigation of the effect of oral antidibetic agent Sitagliptin on oxidant-antioxidant balance in rats with type 2 diabetes mellitus

Diabetes is a chronic metabolic disorder and increasing rapidly worldwide. Many underlying mechanisms have been suggested in the pathogenesis and complications of diabetes. Free radicals that are main cause of the complications most accepted mechanisms. For this reason used drug for therapy, should support the antioxidant balance while providing the antidiabetic effect. In this context, the purpose of study is to investigate the effect of oral antidiabetic agent Sitagliptin on oxidant-antioxidant balance in rats with type 2 diabetes mellitusSitagliptin is a potent and an orally-active inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme. Inhibition of DPP-4 as a recent therapy for type 2 diabetes is based on inactivation process of bioactive peptides. Glucagon-like peptide-1 (GLP-1) is the most important bioactive peptide for diabetes. Recent studies have been shown that inhibition of DPP-4 with sitagliptin improves glycemic control in patients with type 2 Diabetes by effecting on GLP-1.In this thesis a combination of twice low-dose streptozotocin (STZ, 30 ?g/kg) injection and high-fat diet (HFD, % 57,3 of energy as fat) were used for generating a model mimicking human type 2 diabetes. Rats were divided into 5 groups as follows: Control group (rats fed regular diet for 24 weeks), HFD group (rats fed with high-fat diet for 24 weeks), HFD-SIT group (rats fed with high-fat diet for 12 weeks and then treated sitagliptin for 12 weeks), DYB-Control group (rats fed with high-fat diet for 8 weeks and then of low-dose streptozotocin by twice intraperitoneal injection) and the last group DYB-SIT (diabetic rats were treated with sitagliptin for last 12 weeks). Rat weight gains were recorded every week and plasma glucose levels were measured every four week during the study (24 weeks). At the end of the study HbA1c, insulin, ALT, AST, LDH, total protein, TAS and TOS were assessed in plasma. Total protein, TAS and TOS were also evaluated in samples obtained from pancreas of rats. Additionally the effect of sitagliptin on insulin resistance (IR) was determined by insulin tolerance test.Moreover for effect of sitagliptin on oxidant-antioxidant balance in the streptozotocin-induced diabetic rat liver tissues were determined by assessing antioxidant enzymes (SOD, CAT, GPx), NFkB and iNOS on mRNA expression level.In this study sitagliptin in diabetic rats promoted decreases in the level of glucose, HbA1c and IR. It was found that sitagliptin did not effect on oxidative stress at diabetic rat plasma and it increases oxidative stress while decreasing levels of TAS in pancreas tissue.Moreover, present study showed sitagliptin supression in mRNA expressions of antioxidant enzymes while stimulating NFkB and iNOS gen expressions, it was found also that stagliptin increases oxidative stress liver of diabetic rats as well.