In Utero Origins of Adult Insulin Resistance and Vascular Dysfunction

Jennifer A Thompson; Timothy R.H. Regnault

doi:10.1055/s-0031-1275522

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2011; 29(3): 211-224
DOI: 10.1055/s-0031-1275522

In Utero Origins of Adult Insulin Resistance and Vascular Dysfunction

Jennifer A. Thompson¹ , Timothy R.H. Regnault¹

¹Departments of Obstetrics and Gynaecology and Physiology and Pharmacology, Children's Health Research Institute and Lawson Research Institute, University of Western Ontario, London, Ontario, Canada

Abstract

ABSTRACT

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.

KEYWORDS

Fetus - programming - adult - muscle - insulin resistance - vessels - vascular dysfunction - endothelial dysfunction

Full Text

References

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Timothy R.H. RegnaultPh.D.

Department of Obstetrics and Gynaecology

The University of Western Ontario, London, ON, Canada N6A 5C1

Email: tim.regnault@uwo.ca