DYNAMIC CHANGES IN ADIPOSITY FROM FETAL TO POST-NATAL LIFE ARE INVOLVED IN THE ADULT METABOLIC SYNDROME ASSOCIATED WITH REDUCED FETAL GROWTH

DYNAMIC CHANGES IN ADIPOSITY FROM FETAL TO POST-NATAL LIFE ARE

INVOLVED IN THE ADULT METABOLIC SYNDROME ASSOCIATED WITH REDUCED FETAL GROWTH

D. Jaquet MD, PhD

, S. Deghmoun

, D. Chevenne PhD

, D. Collin MD

, P. Czernichow MD

, C. Lévy-Marchal MD

1

INSERM U 457, Robert Debré Hospital, 75019 Paris;

Maternity Department, M M Municipality Hospital, Haguenau, France

Introduction: The association between a low birth weight and the metabolic syndrome (dyslipidemia, hypertension and cardio-vascular diseases, insulin- resistance and type-2 diabetes) or with one of its components has been substantially documented in various populations. The metabolic syndrome was originally described in man to cluster with insulin-resistance. It has been postulated that insulin-resistance also plays a central and primary role in the metabolic complications associated with reduced fetal growth, but this has never been clearly demonstrated and the natural history of the metabolic syndrome in subjects born with a low birth weight remains poorly documented. Therefore, the question arises as to when and how the metabolic syndrome emerges in this particular clinical situation. Our previous data have shown that insulin- resistance is detectable as early as 20y. However, one third of young adults born small for gestational age (SGA) seem to be affected. In these individuals insulin-resistance could not be explained by family history of metabolic diseases or obesity. Therefore the reason for this variable predisposition for insulin- resistance might be sought either in specific aspects of SGA, or among post- natal events directly linked to SGA.

Objectives: The aim of the present study was therefore to investigate the origins and mechanisms of this association. The study population is based on a regional cohort of young adults, precisely selected on birth data from a population-based registry located in the city of Haguenau (eastern France). This cohort includes 735 subjects born small for gestational age (SGA: birth weight < 10th percentile t of the local distribution corrected for gestational age and gender) and 886 subjects born appropriate for gestational age (25th-75th percentile) in whom clinical and metabolic parameters of the MS were measured at a mean age of 22 years. Analyses of the metabolic syndrome components were performed after

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adjustment for BMI, age, gender, smoking, family history of diabetes and oral contraception at the time of the study.

Results: Mean values of all components of the metabolic syndrome significantly differed between the two groups. In SGA subjects, the upper tertile of fasting insulinemia (reflecting the more insulin-resistant subjects) was associated with the highest values of systolic (p=0.001) and diastolic (p=0.02) blood pressure, triglyceridemia (p=0.005) and glycemia at fasting (p=0.0001) and during OGTT (p=0.0001), emphasizing therefore the key role of insulin-resistance in the development of the metabolic syndrome associated with reduced fetal growth.

However, whether the risk for IR is already determined at birth or influenced by the post-natal growth is not clarified. To address this question, we studied in the 735 subjects born SGA the effect of characteristics at birth and catch-up growth on the insulin-to-glucose ratio (I/G) taken as a surrogate marker for insulin- resistance. Neither gestational age (32-42 wks, p=0.62) nor birthweight (1130- 3080 g, p=0.26) had a significant effect on the I/G, but BMI at birth was inversely related to the adult I/G. Catch-up height had no effect on the adult I/G (p=0.35). In contrast, catch-up in BMI was significantly associated with an increased I/G even when adjusted for adult BMI (p=0.004). As expected, catch- up in BMI was inversely related to BMI at birth, but subjects who experienced the larger BMI catch-up were not obese as young adults.

Conclusion: We have shown that all components of the insulin-resistant

syndrome are clustered with insulin-resistance in subjects born SGA as early as

22 years. Additionally, our results demonstrate that thinness at birth, but not

birth weight, influences the pots-natal growth and risk for the metabolic

syndrome associated with SGA, suggesting therefore that fetal dynamic changes

in adiposity are involved in the long-term metabolic consequences of reduced

fetal growth. Thus a better knowledge of fetal growth patterns leading to SGA

seems critical in order to unravel the mechanisms responsible for the post-natal

outcome.