Jaquet D, Deghmoun S, Chevenne D, Czernichow P, Lévy-Marchal ...


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Jaquet D, Deghmoun S, Chevenne D, Czernichow P, Lévy-Marchal ...

  1. 1. PROPOSAL FOR A 2 YR MEDICAL POST-DOCTORAL FELLOWShIP IN TRANSLATIONAL RESEARCH IN DIABETOLOGY/ENDOCRINOLOGY Fetal programming of insulin resistance and metabolic syndrome Role of ante and postnatal growth : the case of the CASyMIR cohort The CASyMIR cohort A large body of research has addressed the association of fetal and early growth with type 2 diabetes, insulin resistance and the metabolic syndrome. The mechanisms of this association are still unknown. The concept of “fetal programming” has been suggested to explain this phenomenon. According to this theory, the events that affect fetal life would “set” the fetal epigenetic code with long- term consequences. Fetal under-nutrition, taken in the broad sense of the word that would occur during specific periods of development in subjects with unfavorable genetic predisposition could alter growth and metabolism in the fetus, and later in the child and then the young adult. Adipose tissue could play here a critical role in the development of the metabolic disease in this situation. Data from our prospective cohort of adults born small for gestational age show that function and growth of this tissue are altered (adipokin secretion, insulin sensitivity, cathecholamines secretion…). We have also evidenced an interaction between intra-uterine growth and genetic polymorphisms of important components of adipose tissue (PPAR, adrenergic receptors). However
  2. 2. only a limited proportion of subjects born small for gestational age are affected by long term consequences. In our study the degree of thinness at birth as well as pattern of fat catch up are important risks factors of early development of insulin resistance. Moreover birth weight doesn’t well reflect fetal growth. Indeed one could distinguish fetuses with steady growth rate and small size at birth from fetuses with restricted growth leading to a low birth weight. We hypothesize that children with restricted fetal growth that leads to thinness at birth are those who will experience catch up growth during the four first years of life; consequently delayed and abnormal growth of adipose tissue would be associated with the development of an insulin resistance and metabolic troubles. The objectives of our study are to monitor the different types of fetal growth of fetus at risk of low birth weight, to determine the relation between restricted fetal growth and post natal catch up growth, to assess consequences on body composition, on insulin sensitivity and on parameters of the metabolic syndrome. This study is based on a prospective cohort including 600 carefully monitored pregnancies at increased risk of SGA and the prospective follow-up of 200 children up to 4 years of age, period of the adiposity rebound. We will be able to link ante and postnatal growth, changes in body composition, insulin resistance and development of the metabolic syndrome. The CASyMIR NRJ project The working hypothesis Most of the SGA newborns experience catch-up growth, which is a period of accelerated growth aimed at compensating the previous growth deficit. This period would encompass changes in substrates flux and utilization in order to promote storage, with a prevailing accretion of fat mass. During the period of catch-up fatty acids would become primary energy substrates inducing a decrease in insulin sensitivity. At the end of the phase of catch-up, energy expenditure would b back to normal but the excess of fat mass would not be corrected inducing the metabolic disorders.
  3. 3. We hypothesize that SGA-infants born after fetal growth restriction would experience catch-up growth during the first months of life with decreased energy expenditure together with increased body fat content, which will induce persisting changes in substrate utilization (decreased glucose oxidation and increased lipids oxidation). Methods Non-invasive methods have been selected (double labeled water, 13C-palmitate, indirect calorimetry). Three groups of subjects will be compared at the ages of 2, 4 mth and 1 yr. • SGA newborns with regular fetal growth (n=25) • SGA newborns with fetal growth restriction (n= 25) • AGA newborns with fetal growth restriction (n= 25) Expected results This project should yield physiological information on the nutritional regulatory process in relation with what is called metabolic programming. List of publications of the group on the subject over the past five years 1. Jaquet D, Trégouët DA, Godefroy T, Nicaud V, Chevenne D, Tiret L, Czernichow P, Lévy-Marchal C. Combined effects of genetic and environmental factors on the insulin-resistance associated with reduced fetal growth. Diabetes 2002; 51: 3472-3478 2. Jaquet D, Collin D, Lévy-Marchal C, Czernichow P. Adult height distribution in subjects born small for gestational age. Hormone Research 2004; 62: 92-96 3. Stefan N, Weyer C, Lévy-Marchal C, Stumvoll M, Knowler WC, Tataranni PA, Bogardus C, Pratley RE. Endogenous glucose production, insulin sensitivity, and insulin secretion in normal glucose-tolerant Pima
  4. 4. Indians with low birth weight. Metabolism 2004; 53: 904-911. 4. Jaquet D, Swaminathan S, Alexander GR, Czernichow P, Collin D, Salihu HM, Kirby RS, Lévy-Marchal C. Significant paternal contribution to the risk of small-for-gestational-age. British Journal of Obstetrics and Gynaecology 2005; 112: 153-159. 5. Jaquet D, Deghmoun S, Chevenne D, Collin D, Czernichow P, Lévy-Marchal C. . Dynamic change in adiposity from foetal to post-natal life is involved in the metabolic syndrome associated with reduced foetal growth. Diabetologia 2005; 48: 849-855 6. Boiko J, Jaquet D, Chevenne D, Rigal O, Czernichow P, Lévy Marchal C. In situ lipolysis regulation in subjects born small for gestational age. International Journal of Obesity 2005; 29: 565-570 7. Ezzahir N, Alberti C, Deghmoun S, Zaccaria I, Czernichow P, Lévy-Marchal C, Jaquet D. Time course of catch-up in adiposity influences adult anthropometry in individuals who were born small for gestational age. Pediatric Research 2005; 58 : 243-247. 8. Verkauskiene R, Jaquet D, Deghmoun S, Chevenne D, Czernichow P, Lévy-Marchal C. Smallness for gestational age is associated with permanent change in insulin-like growth factor-I(IGF-I) and the ratio IGF-I/IGF binding protein-3 in adulthood. Journal of Clinical Endocrinology and Metabolism 2005; 90; 5672-5676 9. Beltrand J, Guilmin-Crepon S, Castanet M, Peuchmaur M, Czernichow P and Lévy-Marchal C. Insulin Allergy and Extensive Lipoatrophy in Child with Type 1 Diabetes. Hormone Research 2006; 65: 253-260 10. Jaquet D, Deghmoun S, Chevenne D, Czernichow P, Lévy-Marchal C. Low serum adiponectin levels in subjects born small for gestational age: impact on insulin-sensitivity. International Journal of Obesity 2006; 30; 1-5 11. Vu-Hong TA, Durand E, Deghmoun S, Boutin P, Meyre D, Chevenne D, Czernichow P, Froguel P, Lévy-Marchal C.The INS VNTR locus does not associate with Smallness for Gestational Age (SGA), but interacts with SGA to increase insulin resistance in young adults. Journal of Clinical Endocrinology and Metabolism 2006; 91: 2437-2440 12. Verkauskiene R, Beltrand J, Claris O, Chevenne D, Deghmoun S, Dorgeret S, Alison M, Gaucherand P, Sibony O and Levy-Marchal C. Impact of fetal growth restriction on body composition and hormonal status at birth in infants of small and appropriate weight for gestational age. European Journal of Endocrinology 207; 157: 605-612 13. S Cauchi, D Meyre, H Choquet, S Deghmoun, E Durand, S Gaget, C Lecoeur, P Froguel and C Levy- Marchal. TCF7L2 rs7903146 variant does not associate with Smallness for Gestational Age (SGA) in the French population. BMC Medical Genetics 2007, 8:37 14. Verkauskiene R, Figueras F, Deghmoun S, Chevenne D, Czernichow P, Gardosi J, Levy-Marchal C. Birth weight and long-term metabolic outcomes: does the definition of smallness matter? Hormone Research (in press) 15. Verkauskiene R, Figueras F, Deghmoun S, Chevenne D, Czernichow P, Gardosi J, Levy-Marchal C. Birth weight and long-term metabolic outcomes: does the definition of smallness matter? Hormone Research (in press)
  5. 5. 16. J Beltrand, M Alison, R Nicolescu, R Verkauskiene, S Deghmoun, O Sibony, G Sebag, C Lévy Marchal. Bone mineral content at birth is determined both by birth weight and fetal growth. Pediatric Research (sous presse) 17. J Beltrand, R Verkauskiene, R Nicolescu, O Sibony, P Gaucherand, D Chevenne, O Claris And C Lévy Marchal. Adaptive changes In neonatal hormonal and metabolic profiles induced by fetal growth restriction. Soumis Conditions and required expertise • Application for a Pediatrician with interest and some experience in Nutrition and Diabetology or Endocrinology. • Experience in Clinical Research welcome • French language not mandatory but preferred ; should be learned if not fluent (interaction with the subjects and the hospital staff) • The proposal is for two years (at least). • A salary or fellowship is provided in part but a contribution from the country of origin will be extremely valuable. • Possibility for graduation with a French University Diploma of subspecialty of Pediatric Endocrinology Setting The group is dedicated to translational research in Pediatric Diabetlogy sponsored by INSERM and in close connection wit the Department of Pediatric Endocrinology and Diabetology of the Robert Debré hospital (Prof Jean-Claude Carel). The group welcomes each year 4-6 post-graduate students with a medical background or not and a technical staff members. The projects research benefit from the Clinical Investigation Centre in the same hospital wher we have developed a unique setting for the metabolic investigation in children. CONTACT Claire LEVY-MARCHAL, MD INSERM U690 Robert Debré hospital – 75019 PARIS Send CV and letter of motivation claire.Levy-marchal@inserm.fr