Fig. 5.

Hyperglycemia-induced Endothelial Dysfunction. High levels of glucose and fatty acids activate the polyol pathway, hexosamine, and glucose autooxidation pathway, PKC activation, and increase the levels of advanced glycation end products, stimulating the RAGE and its downstream pathways. Hyperglycemia activates PKC via DAG, leading to the upregulation of cell adhesion molecules (VCAMs and ICAMs), generation of ROS by NADPH oxidase, activation of the pro-inflammatory transcription factor NFkB and the uncoupling of endothelial nitric oxide synthase. The RAGE mediated pathway, glucose oxidation, hexosamine pathway, and polyol pathway all generate oxidative stress, leading to excessive ROS levels in the cell. NO reacts with superoxide anion, to form deleterious molecule peroxynitrite which is largely indicated in endothelial cell dysfunction. ROS also stimulates NFkB to express pro-inflammatory genes leading to systemic inflammation. These events lead to activated endothelium and vascular dysfunction in diabetes.