Preface [Hot topic: Insulin Resistance and Impaired Coronary Endothelial Function (Guest Editor: Teruo Inoue)]

The insulin resistance syndrome is described as a clinical syndrome in which there is clustering of insulin resistance together with factors such as hypertension, dyslipidemia and obesity leads to a substantial increase in cardiovascular risk. In the United States, almost one quarter of adult population is now believed to have this syndrome. Insulin resistance is a state of dysregulation of glucose-insulin homeostasis in which the ability of insulin to stimulate glucose uptake in peripheral tissues is reduced. Insulin resistance is a crucially important metabolic abnormality in type 2 diabetes, where coronary artery disease is the most significant cause of morbidity and mortality. Diagnosis of diabetes is thought to be preceded by a long term insulin resistance state, during which blood glucose level is maintained near normal levels by compensatory hyperinsulinemia. Cardiovascular risk is increased in this euglycemic prediabetic state, suggesting that insulin resistance per se is atherogenic. Insulin resistance has often been associated with the other known cardiovascular risk factors. Hyperinsulinemia induces hypertension, which may be caused by increased renal sodium retention, increased Na+-H+ exchange on vascular wall cells, or increased sympathetic activity. Hyperinsulinemia also induces abnormalities of lipid metabolism. In addition to this atherogenic proclivity, insulin itself may initiate vascular smooth muscle cell proliferation mediated by stimulating insulinlike growth factor receptors, leading to atherosclerosis. More recently, insulin resistance has been shown to be associated with the impairment of vascular endothelial function, which is believed to be an initial step toward atherosclerosis. In insulin resistant humans, there is evidence that the acetylcholine-induced coronary artery vasodilatory response is impaired. Acetylcholine stimulates the release of nitric oxide (NO) from endothelial cells and diffuses to the underlying smooth muscle cells to cause relaxation. Thus, impaired vascular relaxation in response to acetylcholine is thought to reflect endothelial dysfunction. Insulin resistance may be linked to endothelial dysfunction by a number of mechanisms, including disturbances of subcellular signaling pathways common to both insulin action and NO production, oxidant stress, endothelin, the reninangiotensin system and the secretion of hormones and cytokines. The long predrome of insulin resistance in the development of type 2 diabetes cause the vascular endothelium to be exposed to a potentially atherogenic environment for many years before the onset of coronary artery disease. In the near future, early intervention to improve insulin resistance will be a powerful therapeutic strategy to ameliorate coronary endothelial function, leading to prevention of coronary artery disease. The articles in this issue provide a valuable overview of insulin resistance, impaired coronary endothelial function and new paradigms for prevention of coronary artery disease based upon targeting the endothelial dysfunction in the molecular level as well as the clinical setting.