Diabetic Vascular Disease

Diabetes mellitus affects approximately 100 million persons worldwide. Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity. Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively.

Pathophysiology of Diabetic Vascular Disease

Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.  Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of L-arginine. The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.  In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell proliferation and migration.   Conversely, the loss of endothelium-derived NO permits increased activity of the proinflammatory transcription factor nuclear factor kappa B (NF-κΒ), resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines.. These actions promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, characterizing the initial morphological changes of atherosclerosis..  Endothelial dysfunction, as represented by impaired endothelium-dependent, NO-mediated relaxation, occurs in cellular and experimental models of diabetes..  Similarly, many, but not all, clinical studies have found that endothelium-dependent vasodilation is abnormal in patients with type 1 or type 2 diabetes.  Thus, decreased levels of NO in diabetes may underlie its atherogenic predisposition.

The bioavailability of NO reflects a balance between its production via NOS and its degradation, particularly by oxygen-derived free radicals.  Many of the metabolic derangements known to occur in diabetes, including hyperglycemia, excess free fatty acid liberation, and insulin resistance, mediate abnormalities in endothelial cell function by affecting the synthesis or degradation of NO

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