In utero origins of adult insulin resistance and vascular dysfunction.

The metabolic syndrome (or syndrome X) is a constellation of risk factors including insulin resistance, hypertension, dyslipidemia, and central obesity that predispose to the development of cardiovascular disease and type 2 diabetes in adult life. Insulin resistance is believed to be a critical pathophysiological event early in the disease process, impacting both skeletal muscle metabolic function and vascular responses. Adverse changes in insulin sensitivity have been found to originate in utero; for instance, prenatal events such as placental insufficiency/oxidative stress leading to altered fetal growth trajectories are associated with increased rates of metabolic syndrome in adult life. Such intrauterine insults result in reduced skeletal muscle mass in conjunction with altered insulin signaling, decreased oxidative fibers, and impaired mitochondrial function. These developmental disturbances set the stage for development of muscle triglyceride accumulation and depressed insulin sensitivity in childhood. Abnormalities of vascular structure and function arising from deprived intrauterine conditions that are exacerbated by insulin resistance account for the progression of hypertension from childhood to adulthood. Arterial changes initiated in utero include reduced endothelial nitric oxide (NO) bioavailability, vascular smooth muscle cell proliferation and inflammation, events leading to endothelial dysfunction, and atherosclerosis that are present in those destined for metabolic syndrome. In addition, the hypertensive phenotype that is a hallmark of metabolic syndrome may also be traced to blunted kidney development and renin-angiotensin system activation in growth-restricted offspring. The summative impact of these intrauterine programmed changes in terms of influencing adult health and disease encompasses dietary and lifestyle factors introduced postnatally. Establishing novel therapeutic interventions aimed at preventing and/or reducing in utero-induced insulin resistance and vascular dysfunction warrants investigation because the numbers of low birthweight babies continue to increase. © Thieme Medical Publishers.