Endothelial dysfunction in diabetes: pathogenesis, significance, and treatment

Abstract

Type 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

Figures

Figure 1

A: Nitric oxide (NO) is produced from L-arginine and molecular oxygen (O2) by endothelial nitric oxide synthase (eNOS) in a tightly ‘coupled’ process involving tetrahydrobiopterin (BH4) and nicotinamide adenine dinucleotide phosphate (NADPH). B: In diabetes, increased redox imbalance (due to increased NADH/NADPH) and decreased availability of BH4 (due to oxidation) leads to 'uncoupling' of NO production. This results in transfer of electrons to O2 to form superoxide (O2˙). Superoxide in turn reacts with and consumes NO, forming the oxidant species peroxynitrite (OONO-). Hence, oxidative stress and endothelial dysfunction are further increased [39, 41]. Abbreviations: NADH - reduced nicotinamide adenine dinucleotide, H2O2 - hydrogen peroxide.

Figure 2

Mechanism whereby hyperglycemia and elevated fatty acids induce uncoupling of mitochondrial oxidative phosphorylation and increased oxidative stress in diabetes. Abbreviations: ATP - adenosine triphosphate, NADH - reduced nicotinamide adenine dinucleotide [12].

Figure 3. Pathogenesis and consequences of endothelial dysfunction in type 2 diabetes mellitus

Oxidative stress contributes to endothelial dysfunction by activating protein kinase C, polyol, hexosamine, and NF kappa B pathways, as well as increasing asymmetric dimethylarginine and advanced glycation end-products [4].