Cardiovascular disease affects approximately 60% of the adult population over the age of 65 and represents the number one cause of death in the United States.
Coronary atherosclerosis is responsible for the vast majority of the cardiovascular events, and a number of cardiovascular risk factors have been identified. In recent years, it has become clear that
insulin resistance and endothelial dysfunction play a central role in the pathogenesis of
atherosclerosis. Much evidence supports the presence of
insulin resistance as the fundamental pathophysiologic disturbance responsible for the cluster of metabolic and cardiovascular disorders, known collectively as the
metabolic syndrome. Endothelial dysfunction is an important component of the metabolic or
insulin resistance syndrome and this is demonstrated by inadequate vasodilation and/or paradoxical vasoconstriction in coronary and peripheral arteries in response to stimuli that release
nitric oxide (NO). Deficiency of endothelial-derived NO is believed to be the primary defect that links
insulin resistance and endothelial dysfunction. NO deficiency results from decreased synthesis and/or release, in combination with exaggerated consumption in tissues by high levels of reactive
oxygen (ROS) and
nitrogen (RNS) species, which are produced by cellular disturbances in
glucose and lipid metabolism. Endothelial dysfunction contributes to impaired
insulin action, by altering the transcapillary passage of
insulin to target tissues. Reduced expansion of the capillary network, with attenuation of microcirculatory blood flow to metabolically active tissues, contributes to the impairment of
insulin-stimulated
glucose and lipid metabolism. This establishes a reverberating negative feedback cycle in which progressive endothelial dysfunction and disturbances in
glucose and lipid metabolism develop secondary to the
insulin resistance. Vascular damage, which results from
lipid deposition and oxidative stress to the vessel wall, triggers an inflammatory reaction, and the release of
chemoattractants and
cytokines worsens the
insulin resistance and endothelial dysfunction.From the clinical standpoint, much experimental evidence supports the concept that
therapies that improve
insulin resistance and endothelial dysfunction reduce cardiovascular morbidity and mortality. Moreover, interventional strategies that reduce
insulin resistance ameliorate endothelial dysfunction, while interventions that improve tissue sensitivity to
insulin enhance vascular endothelial function. There is general agreement that aggressive
therapy aimed simultaneously at improving
insulin-mediated
glucose/lipid metabolism and endothelial dysfunction represents an important strategy in preventing/delaying the appearance of
atherosclerosis. Interventions that 1 correct
carbohydrate and lipid metabolism, 2 improve
insulin resistance, 3 reduce blood pressure and restore vascular reactivity, and 4 attenuate procoagulant and inflammatory responses in adults with a high risk of developing
cardiovascular disease reduce cardiovascular morbidity and mortality. Whether these benefits hold when the same prevention strategies are applied to younger, high-risk individuals remains to be determined.