The effects of DPP-4 inhibitors on vascular endothelial function in diabetes
Creators: name: Salheen, Salheen
Publisher: name: RMIT University
Year: 2024

description: In diabetes mellitus, it is well known that hyperglycaemia causes overproduction of reactive oxygen species causing vascular endothelial dysfunction which plays a role in the initiation and development of cardiovascular complications. The aim of this thesis was to investigate the effects of a high concentration of glucose, hyperglycaemia in diabetes, and consumption of a western, high fat, diet on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric artery. Further, the effect of acute and chronic treatment with dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin was investigated on endothelium-dependent relaxation in normal and diabetic rat mesenteric artery. As oxidative stress plays a role in the initiation of endothelial dysfunction, it was hypothesised that drugs with antioxidant activity might be helpful in maintaining vascular function in diabetes. In the first study, the aim was to investigate the effects of DPP-4 inhibitors and a glucagon-like peptide 1 receptor agonist, exendin-4, on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric arteries exposed to a high concentration of glucose (40 mM). Exendin-4 and the DPP-4 inhibitor linagliptin, but not sitagliptin or vildagliptin, significantly reduced vascular superoxide and improved endothelium-dependent relaxation in the presence of high glucose. High glucose impaired endothelium-dependent relaxation can be improved by exendin-4 and linagliptin, due to their antioxidant activity and independently of any glucose lowering effect.<br><br> In the second study, the aim was to investigate the effect of the acute presence of linagliptin, a DPP-4 inhibitor, in vitro on the mechanism(s) of endothelium-dependent relaxation in rat mesenteric arteries isolated from type 1 diabetic rats. In This study endothelial dysfunction was due to a decreased contribution of both NO- and EDH to endothelium-dependent relaxation and acute treatment with linagliptin reduced the oxidative stress and improved endothelial function. Western diet (WD) may cause endothelial dysfunction as one of the earliest events in atherogenesis. In the third study, the aim was to examine whether consumption of a WD affected endothelium-dependent relaxation of rat mesenteric arteries and whether the DPP-4 inhibitor linagliptin improves endothelium-dependent relaxation. WD significantly increased superoxide and linagliptin significantly reduced the vascular superoxide production and improved the contribution of both NO and EDH. In the fourth study, we hypothesized that long-term chronic treatment with DPP-4 inhibitor linagliptin in vivo, would improve relaxation in mesenteric arteries from diabetic rats. Treatment with linagliptin did not affect plasma glucose but reduced the levels of superoxide production and improved endothelium-dependent relaxation in mesenteric arteries from type1 STZ-induced diabetic rats. In conclusion, this thesis extends our understanding of the pathological process underlying endothelial dysfunction in the microvasculature caused by exposure to high glucose concentrations, high fat diet and hyperglycaemia. Treatment with linagliptin in diabetic rats had no effect on plasma glucose levels, indicating that linagliptin exerted its improvement in vascular function via a mechanism independent of glucose lowering. These beneficial actions make linagliptin a potential adjunctive treatment for diabetic vascular complications in patients with both type 1 and type 2 diabetes and importantly expanding the range of patients able to benefit from the use of this drug.<br><br>