Mechanisms of Glucose- and Diabetes-Induced Vascular Dysfunction

Abstract

Vascular dysfunction manifested by increased vascular permeability, impaired autoregulation of blood flow, and increased glomerular filtration rate develops early after the onset of poorly controlled diabetes in humans and animals. Several lines of evidence are consistent with the hypothesis that these functional changes predispose the vasculature to injury by risk factors independent of diabetes (such as hypertension and hyperlipemia), and it is the interaction between vascular injury by these risk factors and diabetes-induced vascular dysfunction that culminates in the vascular complications of diabetes. A corrolary of this hypothesis is that elucidation of the metabolic imbalances that mediate glucose/diabetes—induced vascular dysfunction is pivotal to understanding the pathogenesis of diabetic vascular disease. Recent observations in animal models (which will be discussed in this chapter) suggest the following sequence of events (Fig. 6.1). Elevated glucose levels increase flux of glucose via the sorbitol pathway, which increases the ratio of NADH/NAD± (as a consequence of increased oxidation of sorbitol to fructose). This change in cytoplasmic redox state causes an elevation of triose phosphates (which are among the most reactive naturally occurring nonenzymatic glycation agents) and has an impact on two pathways of lipid metabolism, resulting in accumulation of amphipathic lipids—i.e. 1,2-diacyl-sn-glycerol (DAG) and long-chain fatty acyl esters, which modulate the activity of several important enzymes (i.e. Na+K+ATPase, Cat±-ATPase, and protein kinase C) linked to glucose-and diabetes-induced vascular dysfunction.