The pathobiology of diabetic vascular complications--cardiovascular and kidney disease

Abstract

With the increasing incidence of obesity and type 2 diabetes, it is predicted that more than half of Americans will have diabetes or pre-diabetes by 2020. Diabetic patients develop vascular complications at a much faster rate in comparison to non-diabetic individuals, and cardiovascular risk is increased up to tenfold. With the increasing incidence of diabetes across the world, the development of vascular complications will become an increasing medical burden. Diabetic vascular complications affect the micro- and macro-vasculature leading to kidney disease often requiring dialysis and transplantation or cardiovascular disease increasing the risk for myocardial infarction, stroke and amputations as well as leading to premature mortality. It has been suggested that many complex pathways contribute to the pathobiology of diabetic complications including hyperglycaemia itself, the production of advanced glycation end products (AGEs) and interaction with the receptors for AGEs such as the receptor for advanced glycation end products (RAGE), as well as the activation of vasoactive systems such as the renin-angiotensin aldosterone system (RAAS) and the endothelin system. More recently, it has been hypothesised that reactive oxygen species derived from NAD(P)H oxidases (Nox) may represent a common downstream mediator of vascular injury in diabetes. Current standard treatment of care includes the optimization of blood glucose and blood pressure usually including inhibitors of the renin-angiotensin system. Although these interventions are able to delay progression, they fail to prevent the development of complications. Thus, there is an urgent medical need to identify novel targets in diabetic vascular complications which may include the blockade of Nox-derived ROS formation, as well as blockade of AGE formation and inhibitors of RAGE activation. These strategies may provide superior protection against the deleterious effects of diabetes on the vasculature.