Review
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World J Diabetes. Jul 15, 2010; 1(3): 89-98
Published online Jul 15, 2010. doi: 10.4239/wjd.v1.i3.89
Mechanisms of developmental programming of the metabolic syndrome and related disorders
Zhong-Cheng Luo, Lin Xiao, Anne-Monique Nuyt
Zhong-Cheng Luo, Lin Xiao, Department of Obstetrics and Gynecology, CHU Sainte Justine, University of Montreal, Quebec H3T 1C5, Canada
Anne-Monique Nuyt, Department of Pediatrics, CHU Sainte Justine, University of Montreal, Quebec H3T 1C5, Canada
Author contributions: Luo ZC, Xiao L and Nuyt AM contributed to formulating the theoretic framework and offered critical comments to improve successive drafts of the manuscript; Luo ZC was responsible for drafting and finalizing the manuscript.
Supported by a Research Grant from the Canadian Institutes of Health Research (CIHR), Institute of Nutrition, Metabolism and Diabetes (CIHR Grant # 79896 - Luo ZC); partly by a Clinical Epidemiology Junior Scholar Award from the Fonds de la Recherche en Santé du Québec (FRSQ) (Luo ZC); and partly by a FRSQ Senior Scholar Award (Nuyt AM)
Correspondence to: Zhong-Cheng Luo, MD, PhD, Department of Obstetrics and Gynecology, Sainte Justine Hospital, University of Montreal, Bureau 4986A, 3175 Cote-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada. zhong-cheng.luo@recherche-ste-justine.qc.ca
Telephone: +1-514-3454931 Fax: +1-514-3452195
Received: April 20, 2010
Revised: June 22, 2010
Accepted: June 29, 2010
Published online: July 15, 2010
Abstract

There is consistent epidemiological evidence linking low birth weight, preterm birth and adverse fetal growth to an elevated risk of the metabolic syndrome (obesity, raised blood pressure, raised serum triglycerides, lowered serum high-density lipoprotein cholesterol and impaired glucose tolerance or insulin resistance) and related disorders. This “fetal or developmental origins/programming of disease” concept is now well accepted but the “programming” mechanisms remain poorly understood. We reviewed the major evidence, implications and limitations of current hypotheses in interpreting developmental programming and discuss future research directions. Major current hypotheses to interpret developmental programming include: (1) thrifty phenotype; (2) postnatal accelerated or catch-up growth; (3) glucocorticoid effects; (4) epigenetic changes; (5) oxidative stress; (6) prenatal hypoxia; (7) placental dysfunction; and (8) reduced stem cell number. Some hypothetical mechanisms (2, 4 and 8) could be driven by other upstream “driver” mechanisms. There is a lack of animal studies addressing multiple mechanisms simultaneously and a lack of strong evidence linking clinical outcomes to biomarkers of the proposed programming mechanisms in humans. There are needs for (1) experimental studies addressing multiple hypothetical mechanisms simultaneously; and (2) prospective pregnancy cohort studies linking biomarkers of the proposed mechanisms to clinical outcomes or surrogate biomarker endpoints. A better understanding of the programming mechanisms is a prerequisite for developing early life interventions to arrest the increasing epidemic of the metabolic syndrome, type 2 diabetes and other related disorders.

Keywords: Fetal origins; Developmental programming mechanisms; Metabolic syndrome; Insulin resistance; Type 2 diabetes