Diabetes mellitus is increasing worldwide, resulting from the interaction of
obesity,
inflammation, and
hyperglycemia. Activated immunity and
cytokine production lead to
insulin resistance and other components of the
metabolic syndrome, establishing the link between diabetes and
atherosclerosis.
Hyperglycemia-induced endothelial dysfunction is mediated by increased oxidative stress, a promoter of adventitial
inflammation and vasa vasorum neovascularization in experimental models of diabetic
atherosclerosis. Recent studies have documented increased
inflammation, neovascularization, and intraplaque
hemorrhage in human diabetic
atherosclerosis. This inflammatory microangiopathic process is independently associated with plaque
rupture, leading to
coronary thrombosis.
Tissue factor, the most potent trigger of the coagulation cascade, is increased in diabetic patients with poor
glycemic control. Circulating
tissue factor microparticles are also associated with apoptosis of plaque macrophages, closing the link among
inflammation, plaque
rupture, and blood thrombogenicity.
High-density lipoproteins, responsible for free
cholesterol removal, are reduced in patients with
insulin resistance and diabetes.
High-density lipoprotein therapy leads to a significant decrease in plaque macrophages and increase in smooth-muscle cells. These beneficial effects may be responsible for coronary plaque stabilization in patients treated with recombinant
Apolipoprotein A-I Milano/
phospholipid complex. Finally, peroxisomal proliferator-activated receptors (PPARs) are now considered the nuclear transcriptional regulators of
atherosclerosis. Three subfamilies, including
PPAR-alpha, -delta, and -gamma, have been identified with crucial roles in lipid metabolism, plaque
inflammation, expression of adhesion molecules and
cytokines, and regulation of
matrix metalloproteinases. Multiple experimental studies have documented plaque stabilization with
PPAR-gamma agonists, a group of medications holding great promise in the treatment of diabetes
atherosclerosis.