Glucose enters the endothelium via a non-insulin sensitive GLUT-1 facilitated transporter that transports glucose continuously. Extracellular hyperglycemia is positively correlated with intracellular glucose. As the glucose levels increase, several changes in the glycolytic pathway, tricarboxilic acid cycle and the pentose phosphate pathway occur, all of them leading to an increase of oxygen reactive species (ROS). ROS are capable not only of directly impairing endothelial cells, but also indirectly by activating poly(ADPribose) polymerase, which inhibits glyceraldehyde 3-phosphate dehydrogenase. Further increase in glycloytic intermediates is followed by activation or overexpression of the main pathological pathways of hyperglycemia induced vascular damage: upregulation of glycation end-products, activation of protein kinase C, increased hexosamine pathway, and increased flux through polyol pathway, finally leading to the progressive narrowing and occlusion of the vessels.
Endothelium, the inner layer of the vasculature, represents the interface between blood and organ systems and it is active in the process of contraction and relaxation of vascular smooth muscle and in functions like secretion of vasoactive substances. Endothelial dysfunction is an important cause of cardiovascular disease. The function of the endothelium can be assessed by invasive and noninvasive methods. Endothelial cells produce vasoactive substances like endothelium derived relaxing factor, prostacyclin, nitric oxide, and endothelium derived hyperpolarizing factor. Diabetes mellitus is associated with an increased risk of cardiovascular diseases. Hyperglycemia leads to cardiovascular damage through different pathways, including the polyol and hexosamine pathways, generation of advanced glycation end products, and activation of protein kinase C. Together with hyperglycemia induced mitochondrial dysfunction and endoplasmic reticulum stress, all these can promote the accumulation of reactive oxygen species. The oxidative stress induced by hyperglycemia promotes endothelial dysfunction with an important role in micro and macro vascular disease. Insulin-resistance could be independently predictive of cardiovascular disease. Life style modification and pharmacotherapy could possibly ameliorate the effect of insulin resistance