The Main Determinants of Diabetes Mellitus Vascular Complications: Endothelial Dysfunction and Platelet Hyperaggregation

Abstract

Diabetes mellitus is a common disease that affects 3⁻5% of the general population in Italy. In some countries of northern Europe or in North America, it can even affect 6⁻8% of the population. Of great concern is that the number of cases of diabetes is constantly increasing, probably due to the increase in obesity and the sedentary nature of the population. According to the World Health Organization, in the year 2030 there will be 360 million people with diabetes, compared to 170 million in 2000. This has important repercussions on the lives of patients and their families, and on health systems that offer assistance to patients. In this review, we try to describe in an organized way the pathophysiological continuity between diabetes mellitus, endothelial dysfunction, and platelet hyperaggregation, highlighting the main molecular mechanisms involved and the interconnections.

Keywords: diabetes; endothelial dysfunction; molecular mechanisms; platelets activation.

Figure 1

Schematic representation of the main processes and molecules involved in the pathogenesis of endothelial dysfunction in diabetes. The sustained hyperglycemia during diabetes increases glycation through advanced glycation end products (AGEs); promotes the production of vasoconstrictive factors, such as asymmetric dimethyl arginine (ADMA); reduces the bioavailability of nitric oxide (NO) and BH4, increasing reactive oxygen species (ROS) formation through Rac1 and NOX recruitment and increasing the inflammatory status through the expression of several inflammatory molecules such as tumor necrosis factor (TNF)-α, P-selectin, vascular cell adhesion molecule (VCAM), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), C-reactive protein (CRP), and nF-Kβ.

Figure 2

Schematic of the main processes involved in platelet hyperaggregation in diabetes. The hyperglycemic condition regulates several molecular mechanisms both at endothelial and platelet levels. The high circulating levels of AGEs and the vessel wall damage lead to the increase of collagen exposition, von Willebrand factor (vWF), and tissue factor (TF). Concomitantly, the increased level of glycated hemoglobin (HbA1c) induces the expression on platelet surface of different glycoprotein receptors (GPIIb/IIIa), promoting platelet hyperactivation.