On anti-diabetic agents and the vasculature

Abstract: Diabetes is rapidly increasing worldwide, and the number of patients suffering from diabetes is projected to rise with 50 % over the next 25 years, then affecting almost 600 million adults. Type 2 diabetes comprises 90-95 % of all people with diabetes, and they constitute a patient group that carries a high burden of cardiovascular disease. Patients with type 2 diabetes suffer a 2-4 times higher risk for myocardial infarction and stroke than healthy persons. In addition to this, diabetic patients have an increased atherosclerotic burden. Endothelial dysfunction is thought to be an early and important predictor of atherosclerosis and cardiovascular disease, and in people with type 2 diabetes endothelial dysfunction is a common finding. Also, diabetic patients have an increased risk of restenosis and late stent thrombosis upon surgical intervention to treat atherosclerosis, complications that are related to a defective re-growth of the endothelial cells. The relationship between hyperglycemia and macrovascular complications is still uncertain, at least in terms of the possibility of reducing cardiovascular events solely by improving glycemic control. The importance of finding other strategies to improve cardiovascular outcome in type 2 diabetes patients has consequently emerged. My aim with this thesis has therefore been to investigate how agents used for type 2 diabetes management directly affect the vasculature under normal and simulated diabetic conditions. We studied the effect of antidiabetic agents on endothelial cell viability, regeneration and apoptosis in three in vitro studies. We found that a number of agents could induce proliferation under normal and hyperglycemic conditions, and protect endothelial cells from free fatty acid-induced apoptosis. We studied two antihyperglycemic agents’, metformin and exendin-4, lipoprotective effects in more detail. We found that exendin-4 and metformin protected endothelial cells against lipoapoptosis by modulating pro-apoptotic kinases. Exendin-4 and metformin were also able to activate intracellular survival pathways and to improve endothelial nitric oxide synthase dysfunction. In our last study, we investigated the effect of exendin-4 on endothelial cells and smooth muscle cells in vivo by using a rat model of vascular injury, where the endothelium is denuded in the carotid artery; we found that exendin-4 selectively targeted the smooth muscle cells and decreased the injury-induced intimal hyperplasia. Treatment with exendin-4 did not affect the re-growth of the endothelial cells, but on the other hand improved arterial wall elasticity, suggesting that the re-grown endothelial cells were better functioning in exendin-4-treated animals. In conclusion, we show that drugs used in the management of type 2 diabetes exert direct positive effects on the vasculature. This might be of clinical benefit for patients suffering from diabetes by limiting the adverse consequences of the macrovascular complications of type 2 diabetes, as dysfunction of endothelial cells and smooth muscle cells is believed to contribute to premature development of atherosclerosis. Our findings might also be of therapeutic benefit for diabetic patients undergoing revascularization to treat atherosclerosis, since restenosis and late stent thrombosis are overrepresented and serious complications among these patients.