Endothelial Dysfunction and Therapeutic Intervention in Type 2 Diabetes

Diabetes mellitus (DM) is a major risk factor for micro and macrovascular complications (Kannel & McGee, 1979; King & Sheetz, 2002), and is associated with endothelial dysfunction, premature atherosclerosis (Johnstone et al., 1993; Nathan et al., 2003; Williams et al., 2005), and a reduced capability of neovascularization in ischemic conditions (Abaci et al., 1999). Hyperglycemia increases the production of superoxide (O2-) and reduces the bioavailability of nitric oxide (NO) resulting in the development of endothelial dysfunction in diabetic patients (Creager et al., 2003; Loomans et al., 2005). Exposure to oxidative stress induces a pro-inflammatory response and increases endothelial cell apoptosis, which leads to a disturbance in the endothelial monolayer. The denuded vessel wall is highly proatherogenic, so fast regeneration of the endothelium is essential to prevent formation of atherosclerotic plaques (Dimmeler et al., 2002; Dimmeler & Zeiher, 2004). Patients with type 2 diabetes suffer disturbances in the intermediate metabolism of carbohydrates, proteins and lipids, caused by poor insulin secretion what leads to chronically sustained hyperglycemia. As a result, insulin-resistance develops in target organs and at peripheral sites, the main cause of the pathogenesis related to type 2 diabetes (Cerrato, 2004). Hyperinsulinemia promotes atherogenesis through cell proliferation at the vascular wall which produces endothelial damage (Mátthael & Stumvall, 2001). These endothelial alterations induce the early appearance of atherosclerosis, altering vascular homeostasis mainly due to the interaction of nitric oxide (NO) and free oxygen radicals. As a consequence of this interaction the endothelial anti-inflammatory and vasodilator properties are perturbed which leads to endothelial cell death, proliferation and inadequate restructuring of the vascular walls (Galle et al., 2003). While endothelial damage and the underlying inflammatory processes are often detected later, endothelial damage occurs before the atherosclerotic plate can be identified (Bots et al., 1997). There are many biomarkers for inflammation and early endothelial dysfunction that can be used to identify endothelial damage in order to prevent cardiovascular disease (CD), including: high sensitivity C reactive protein (hs-CRP), homocysteine, microalbuminuria, glycosylated hemoglobin (A1c), Von Willebrand factor and plasminogen-activator inhibitor type 1 (Reinhart et al., 2002). Elevated hs-CRP appears to be a strong predictor for future cardiovascular events (Tornel et al., 2003). On the other hand, much interest has been generated in determining serum homocysteine levels due to the relationship with CD (de Luis et al., 2004). Indeed, elevated serum homocysteine levels have been associated with a