The importance of endothelin-1 for microvascular dysfunction in diabetes

Abstract

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET(A) receptor antagonists are discussed.

Keywords: ETA-receptor antagonist; diabetes mellitus; diabetic microangiopathy; endothelin-1; microcirculation.

Figure 1

Pathogenesis of diabetic skin microangiopathy.

Figure 2

Effect of BQ123 on resting capillary blood cell velocity (CBV) (a) and peak capillary blood cell velocity following a 1-min arterial occlusion (b) in patients with type 2 diabetes (n = 10) and nondiabetic controls (n = 8). Data are shown as the mean and SEM. A significant difference between groups in the change in resting CBV and peak CBV, respectively, following a 60-min infusion of BQ123 is shown. Copyright © 2008. Reproduced with the kind permission of Karger AG, Basel from Settergren M, Pernow J, Brismar K, et al 2008. Endothelin-A receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and albuminuria. J Vasc Res, 45:295–302.

Figure 3

Effects of a 60-min infusion of a selective ET_A receptor antagonist (BQ123) on transcutaneous oxygen tension (TcPO₂) and toe blood pressure (TBP) in six patients with type 2 diabetes and critical limb ischemia.