Abnormal Insulin Signaling: Early Detection of Silent Coronary Artery Disease-Erectile Dysfunction?

Coronary Artery Disease (CAD) and erectile dysfunction (ED) are cardiovascular complications frequently occurring in patients with diabetes, obesity, and dyslipidemia. All these metabolic disorders are characterized by insulin resistance, defined as decreased sensitivity and/or responsiveness to metabolic actions of insulin promoting glucose disposal. Insulin resistance is not only a hallmark of metabolic abnormalities, but also a prominent feature of haemodynamic disorders. Indeed, insulin-stimulated release of endothelial factors takes part into the physiological regulation of vascular function, and altered insulin actions may profoundly affect cardiovascular homeostasis under metabolic derangement. The signpost of impaired vascular reactivity is endothelial dysfunction, a condition in which the endothelium loses its physiological ability to produce the vasodilator nitric oxide (NO). A number of molecular, cellular, physiological, and clinical studies have indicated that insulin resistance may impair NO release and damage endothelial function through several patho-physiological mechanisms reciprocally interconnected. Although considered the earliest marker of impaired vascular health, endothelial dysfunction is initially asymptomatic; additional changes in the vessel structure are usually required before vascular complications manifest. Nevertheless, endothelial dysfunction may become clinically evident when endothelial-mediated relaxation is necessary and sufficient to exert a specific effect. ED may be the first expression of endothelial dysfunction, and therefore represents a sentinel event in the clinical appearance of silent CAD. Thus, insulin resistance triggers endothelial dysfunction, and endothelial dysfunction may manifest as ED long before CAD or other vascular complications become clinically evident. This review briefly outlines the main characteristics of endothelial function and dysfunction, and describes the signaling pathways involved in cardiovascular actions of insulin under physiological and pathological conditions. Moreover, potential cellular and molecular mechanisms linking insulin resistance to early CAD-ED detection are also illustrated.