Mitigation of Endothelial Dysfunction by Saxagliptin in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

摘要

Background and Aim Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that reduces postprandial plasma glucose associated with type 2 diabetes mellitus. It is a novel class of drugs for the treatment of diabetes mellitus. Diabetes mellitus is associated with an induction of vascular endothelial dysfunction (VED), an initial event that could lead to the pathogenesis of atherosclerosis and hypertension. Saxagliptin effects on endothelial dysfunction function have not been fully elucidated. This study was designed to assess the possible effect of saxagliptin on impaired endothelial function, oxidative stress, and inflammation beyond blood glucose control in type 2 diabetic rats. Material and Methods adult male Wistar rats were randomly divided into 3 equal groups. Group 1, Normal control group; rats were fed normal diet for 16 weeks; group 2 (diabetic group), rats were fed with a high fat diet for 8 weeks followed by administration of streptozotocin (100mg/kg body weight) by intraperitoneal injection and group 3, diabetic rats received saxagliptin (10mg/kg/day, orally) for 8 weeks. Fasting blood glucose and glucose tolerance test, blood pressure, nitric oxide (NO) bioavailability in the aortic tissue and soluble intracellular adhesion molecule -1 (sICAM-1) were determined in serum of the different groups. Results: high fat fed diabetic rats showed increased fasting glucose levels, systolic and diastolic blood pressure, and vascular oxidative stress. Saxagliptin treatment significantly decreased fasting blood glucose level, improved glucose tolerance test and decreased systolic blood and diastolic blood pressure. Saxagliptin also decreased serum sICAM-1 levels by 37% (p≤0.05), aortic NO was increased by 22% (p≤0.05) in diabetic treated rats compared with diabetic non treated group. Conclusion: The results of the present study support the concept of anti-inflammatory properties of saxagliptin through inhibition of the pro-inflammatory mediator, including sICAM-1, which are independent of its glucose-lowering properties. In addition, it reduces the vascular oxidative stress by increasing the NO vascular levels, which resulted in an improvement of endothelial function in a diabetic rat model. These beneficial effects of saxagliptin on vascular function with its hypotensive effects might serve it as a potential therapy for type 2 diabetes with endothelial dysfunction.