Diabetes mellitus, increasing rapidly on a world-wide basis, is linked strongly to atherothrombosis (143,144). The linkage of glucose (glycosylation) to proteins produces an insoluble product known as advanced glycation end-products (AGEs) (145), which promote atherosclerosis through several unique mechanisms. AGE has been shown to deplete nitric oxide, thereby impairing endothelium-dependent dilation. It also binds specific macrophage receptors, stimulating cytokine release and smooth muscle cell proliferation. AGE increases the secretion of platelet-derived growth factor and enhances chemotaxis of blood monocytes (146).
Glycosylation of lipoproteins contributes to atherosclerosis through the following sequence of events. Glycosylated LDL, not being recognizing by LDL receptors, increases cholesteryl ester synthesis and accumulation in macrophages. In addition, gly-cosylation of LDL impairs its own degradation and permits more LDL to be bound by local matrix proteins, where oxidation can take place (147) (Fig. 16).
The glycosylation of HDL increases its clearance and decreases the physiologic HDL receptor-mediated cholesterol removal process (148).
Hyperinsulinemia is recognized as an important contributor to atherogenesis in the sitting of Type II diabetes. High fasting insulin concentrations are an independent predictor of ischemic heart disease-related events in men (149).
TNF-a is increased in the insulin-resistant state (150) and decreases the expression of nitric oxide synthase and increases the expression of ICAM-1 (151).
Diabetes is associated with a heightened thrombotic capacity that is multifactorial in origin. Endothelial dysfunction with impaired thromboresistance, increased sympathetic tone, reduced fibrinolytic potential, elevated coagulation factor concentrations (VII, IX, X, XII, fibrinogen), and enhanced platelet aggregation in response to a variety of biochemical mediators contribute collectively (152).
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