Recent Advances in Growth Research: Nutritional, Molecular and Endocrine Perspectives

71st Nestlé Nutrition Institute Workshop, Vienna, October 2011

Editor(s): Gillman M.W. (Boston, Mass.) 
Gluckman P.D. (Auckland) 
Rosenfeld R.G. (Los Altos, Calif.) 
Table of Contents
Vol. 71, 2013
Section title: Drivers of Growth
Gillman MW, Gluckman PD, Rosenfeld RG (eds): Recent Advances in Growth Research: Nutritional, Molecular and Endocrine Perspectives. Nestlé Nutr Inst Workshop Ser. Nestec Ltd., Vevey/S. Karger AG., Basel, 2013, vol 71, pp 11–27
Drivers of Growth

Early Influences of Nutrition on Postnatal Growth

Koletzko B.a · Beyer J.a · Brands B.a · Demmelmair H.a · Grote V.a · Haile G.a · Gruszfeld D.b · Rzehak P.a · Socha P.b · Weber M.a · for The European Childhood Obesity Trial Study Group
aDr. von Hauner Children’s Hospital, University of Munich Medical Centre, Munich, Germany; bChildren’s Memorial Health Institute, Warsaw, Poland


Health and nutrition modulate postnatal growth. The availability of amino acids and energy, and insulin and insulin-like growth factor-I (IGF-I) regulates early growth through the mTOR pathway. Amino acids and glucose also stimulate the secretion of IGF-I and insulin. Postnatal growth induces lasting, programming effects on later body size and adiposity in animals and in human observational studies. Rapid weight gain in infancy and the first 2 years was shown to predict increased obesity risk in childhood and adulthood. Breastfeeding leads to lesser high weight gain in infancy and reduces obesity risk in later life by about 20%, presumably partly due to the lower protein supply with human milk than conventional infant formula. In a large randomized clinical trial, we tested the hypothesis that reduced infant formula protein contents lower insulin-releasing amino acid concentrations and thereby decrease circulating insulin and IGF-I levels, resulting in lesser early weight gain and reduced later obesity risk (the ‘Early Protein Hypothesis’). The results demonstrate that lowered protein in infant formula induces similar – but not equal – metabolic and endocrine responses and normalizes weight and BMI relative to breastfed controls at the age of 2 years. The results available should lead to enhanced efforts to actively promote, protect and support breastfeeding. For infants that are not breastfed or not fully breastfed, the use of infant formulas with lower protein contents but high protein quality appears preferable. Cows’ milk as a drink provides high protein intake and should be avoided in infancy.


  1. Michaelsen KF: Child growth. (eds) Koletzko B, Cooper P, Garza C, Makrides M, Uauy R, Wang W: Pediatric Nutrition - A Practical Reference Guide Basel, Karger, 2008;
  2. Szajewska H, Makrides M: Is early nutrition related to short-term health and long-term outcome?. Ann Nutr Metab 2011;58:(Suppl 1)38-48
  3. Patel MS, Srinivasan M: Metabolic programming in the immediate postnatal life. Ann Nutr Metab 2011;58:(Suppl 2)18-28
  4. Xiang L, He G: Caloric restriction and antiaging effects. Ann Nutr Metab 2011;58:42-48
  5. Karlberg J: A biologically-oriented mathematical model (ICP) for human growth. Acta Paediatr Scand Suppl 1989;350:70-94
  6. Hill DJ, Hogg J: Growth factors and the regulation of pre- and postnatal growth. Baillieres Clin Endocrinol Metab 1989;3:579-625
  7. Hogg J, Han VK, Clemmons DR, Hill DJ: Interactions of nutrients, insulin-like growth factors (IGFs) and IGF-binding proteins in the regulation of DNA synthesis by isolated fetal rat islets of Langerhans. J Endocrinol 1993;138:401-412
  8. Ketelslegers JM, Maiter D, Maes M, et al: Nutritional regulation of insulin-like growth factor-I. Metabolism 1995;44:(Suppl 4)50-57
  9. Baumann G: Growth hormone binding protein 2001. J Pediatr Endocrinol Metab 2001;14:355-375
  10. Ong KK, Elmlinger M, Jones R, et al: Growth hormone binding protein levels in children are associated with birth weight, postnatal weight gain, and insulin secretion. Metabolism 2007;56:1412-1417
  11. Newsholme P, Gaudel C, McClenaghan NH: Nutrient regulation of insulin secretion and beta-cell functional integrity. Adv Exp Med Biol 2010;654:91-114
  12. Muntoni S: Insulin resistance: pathophysiology and rationale for treatment. Ann Nutr Metab 2011;58:25-36
  13. de Oliveira CA, Latorraca MQ, de Mello MA, Carneiro EM: Mechanisms of insulin secretion in malnutrition: modulation by amino acids in rodent models. Amino Acids 2011;40:1027-1034
  14. Yang J, Chi Y, Burkhardt BR, et al: Leucine metabolism in regulation of insulin secretion from pancreatic beta cells. Nutr Rev 2010;68:270-279
  15. Polak P, Hall MN: mTOR and the control of whole body metabolism. Curr Opin Cell Biol 2009;21:209-218
  16. Polak P, Cybulski N, Feige JN, et al: Adiposespecific knockout of raptor results in lean mice with enhanced mitochondrial respiration. Cell Metab 2008;8:399-410
  17. Koletzko B, von Kries R, Monasterolo RC, et al: Infant feeding and later obesity risk. Adv Exp Med Biol 2009;646:15-29
  18. Hanley B, Dijane J, Fewtrell M, et al: Metabolic imprinting, programming and epigenetics - a review of present priorities and future opportunities. Br J Nutr 2010;104:(Suppl 1)S1-S25
  19. (eds) Koletzko B, Decsi T, Molnar D, de la Hunty A: Early Nutrition Programming and Health Outcomes in Later Life: Obesity and Beyond. New York, Springer, 2009;
  20. Dörner G: Perinatal hormone levels and brain organization. in Stumpf WE, Grant LD: Anatomical Neuroendocrinology Basel, Karger, 1975;245-252
  21. Ruemmele FM: Early programming effects of nutrition - life-long consequences?. Ann Nutr Metab 2011;58:(Suppl 2)5-6
  22. Tounian P: Programming towards childhood obesity. Ann Nutr Metab 2011;58:(Suppl 2)30-41
  23. Koletzko B, Symonds ME, Olsen SF: Programming research: where are we and where do we go from here?. Am J Clin Nutr 2011;94:2036S-2043S
  24. Koletzko B, von Kries R, Closa R, et al: Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. Am J Clin Nutr 2009;89:1836-1845
  25. McCance RA, Widdowson EM: The determinants of growth and form. Proc R Soc Lond B Biol Sci 1974;185:1-17
  26. Lamb MM, Dabelea D, Yin X, et al: Early-life predictors of higher body mass index in healthy children. Ann Nutr Metab 2010;56:16-22
  27. Koletzko B, von Kries R, Closa R, et al: Can infant feeding choices modulate later obesity risk?. Am J Clin Nutr 2009;89:1502S-1508S
  28. Toschke AM, Grote V, Koletzko B, von Kries R: Identifying children at high risk for overweight at school entry by weight gain during the first 2 years. Arch Pediatr Adolesc Med 2004;158:449-452
  29. Baird J, Fisher D, Lucas P, et al: Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ 2005;331:929
  30. Monteiro PO, Victora CG: Rapid growth in infancy and childhood and obesity in later life - a systematic review. Obes Rev 2005;6:143-154
  31. Ong KK, Loos RJ: Rapid infancy weight gain and subsequent obesity: systematic reviews and hopeful suggestions. Acta Paediatr 2006;95:904-908
  32. Druet C, Ong KK: Early childhood predictors of adult body composition. Best Pract Res Clin Endocrinol Metab 2008;22:489-502
  33. Adair LS: Child and adolescent obesity: epidemiology and developmental perspectives. Physiol Behav 2008;94:8-16
  34. Metcalfe NB, Monaghan P: Compensation for a bad start: grow now, pay later?. Trends Ecol Evol 2001;16:254-260
  35. (eds) Koletzko B, Akerblom H, Dodds PF, Ashwell M: Early nutrition and its later consequences: new opportunities New York, Springer, 2005;
  36. Wells JC: The programming effects of early growth. Early Hum Dev 2007;83:743-748
  37. Bansal N, Ayoola OO, Gemmell I, et al: Effects of early growth on blood pressure of infants of British European and South Asian origin at one year of age: the Manchester children's growth and vascular health study. J Hypertens 2008;26:412-418
  38. Stettler N: Nature and strength of epidemiological evidence for origins of childhood and adulthood obesity in the first year of life. Int J Obes (Lond) 2007;31:1035-1043
  39. Gonzalez DA, Nazmi A, Victora CG: Growth from birth to adulthood and abdominal obesity in a Brazilian birth cohort. Int J Obes (Lond) 2010;34:195-202
  40. Horta BL, Victora CG, Lima RC, Post P: Weight gain in childhood and blood lipids in adolescence. Acta Paediatr 2009;98:1024-1028
  41. Dunger DB, Salgin B, Ong KK: Session 7: early nutrition and later health early developmental pathways of obesity and diabetes risk. Proc Nutr Soc 2007;66:451-457
  42. Flaherman V, Rutherford GW: A meta-analysis of the effect of high weight on asthma. Arch Dis Child 2006;91:334-339
  43. Paul IM, Camera L, Zeiger RS, et al: Relationship between infant weight gain and later asthma. Pediatr Allergy Immunol 2010;21:(1 Pt 1)82-89
  44. Litonjua AA, Gold DR: Asthma and obesity: common early-life influences in the inception of disease. J Allergy Clin Immunol 2008;121:1075-1084, quiz 85-86
  45. Agency for Healthcare Research and Quality: Breastfeeding and maternal and infant health outcomes in developed countries. AHRQ Publication No 07-E0072007;524
  46. Dutch State Institute for Nutrition and Health: Van Rossum CMT, Büchner FL, Hoekstra J: Quantification of health effects of breastfeeding. Review of the literature and model situation. RIVM Report 350040001/2005
  47. Rebhan B, Kohlhuber M, Schwegler U, et al: Breastfeeding duration and exclusivity associated with infants’ health and growth: data from a prospective cohort study in Bavaria, Germany. Acta Paediatr 2009;98:974-980
  48. Victora CG, Morris SS, Barros FC, et al: Breast-feeding and growth in Brazilian infants. Am J Clin Nutr 1998;67:452-458
  49. Ong KK, Preece MA, Emmett PM, et al: Size at birth and early childhood growth in relation to maternal smoking, parity and infant breast-feeding: longitudinal birth cohort study and analysis. Pediatr Res 2002;52:863-867
  50. Dewey KG: Growth characteristics of breastfed compared to formula-fed infants. Biol Neonate 1998;74:94-105
  51. von Kries R, Koletzko B, Sauerwald T, et al: Breast feeding and obesity: cross sectional study. BMJ 1999;319:147-150
  52. Arenz S, Ruckerl R, Koletzko B, von Kries R: Breast-feeding and childhood obesity - a systematic review. Int J Obes Relat Metab Disord 2004;28:1247-1256
  53. Harder T, Bergmann R, Kallischnigg G, Plagemann A: Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol 2005;162:397-403
  54. Owen CG, Martin RM, Whincup PH, et al: Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 2005;115:1367-1377
  55. Kramer MS, Matush L, Vanilovich I, et al: A randomized breast-feeding promotion intervention did not reduce child obesity in Belarus. J Nutr 2009;139:417S-421S
  56. Beyerlein A, von Kries R: Breastfeeding and body composition in children: will there ever be conclusive empirical evidence for a protective effect against overweight?. Am J Clin Nutr 2011;Epub ahead of print
  57. Beyerlein A, Toschke AM, von Kries R: Breastfeeding and childhood obesity: shift of the entire BMI distribution or only the upper parts?. Obesity (Silver Spring) 2008;16:2730-2733
  58. Koletzko B: Marketing of dietetic products for infants and young children in Europe three decades after adoption of the International Code of Marketing of Breast Milk Substitutes. Ann Nutr Metab 2011;59:70-72
  59. Koletzko B, Hartmann W, Albring C: fur die Deutsche Gesellschaft fur Kinder- und Jugendmedizin, den Berufsverband der Kinder- und Jugendärzte, den Berufsverband der Frauenarzte: , et alUnakzeptable Werbemaßnahmen für Säuglingsnahrungen. Dtsch Arztebl 2011;108:A2268-A2269
  60. Alexy U, Kersting M, Sichert-Hellert W, et al: Macronutrient intake of 3- to 36-month-old German infants and children: results of the DONALD Study. Dortmund Nutritional and Anthropometric Longitudinally Designed Study. Ann Nutr Metab 1999;43:14-22
  61. Heinig MJ, Nommsen LA, Peerson JM, et al: Energy and protein intakes of breast-fed and formula-fed infants during the first year of life and their association with growth velocity: the DARLING Study. Am J Clin Nutr 1993;58:152-161
  62. Koletzko B, Broekaert I, Demmelmair H, et al: Protein intake in the first year of life: a risk factor for later obesity? The E.U. Childhood Obesity Project. Adv Exp Med Biol 2005;569:69-79
  63. Baird J, Poole J, Robinson S, et al: Milk feeding and dietary patterns predict weight and fat gains in infancy. Paediatr Perinat Epidemiol 2008;22:575-586
  64. Parizkova J, Rolland-Cachera MF: High proteins early in life as a predisposition for later obesity and further health risks. Nutrition 1997;13:818-819
  65. Gunther AL, Remer T, Kroke A, Buyken AE: Early protein intake and later obesity risk: which protein sources at which time points throughout infancy and childhood are important for body mass index and body fat percentage at 7 y of age?. Am J Clin Nutr 2007;86:1765-1772
  66. Gunther AL, Buyken AE, Kroke A: Protein intake during the period of complementary feeding and early childhood and the association with body mass index and percentage body fat at 7 y of age. Am J Clin Nutr 2007;85:1626-1633
  67. Gunther AL, Buyken AE, Kroke A: The influence of habitual protein intake in early childhood on BMI and age at adiposity rebound: results from the DONALD Study. Int J Obes (Lond) 2006;30:1072-1079
  68. Koletzko B, Brands B, Demmelmair H: The Early Nutrition Programming Project (EARNEST): 5 y of successful multidisciplinary collaborative research. Am J Clin Nutr 2011;94:1749S-1753S
  69. Escribano J, Luque V, Ferre N, et al: Increased protein intake augments kidney volume and function in healthy infants. Kidney Int 2011;79:783-790
  70. Socha P, Grote V, Gruszfeld D, et al: Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr 2011;94:1776S-1784S
  71. Socha P, Grote V, Gruszfeld D, et al: Milk protein intake, the metabolic-endocrine response, and growth in infancy: data from a randomized clinical trial. Am J Clin Nutr 2011;94:(Suppl 6)1776S-1784S
  72. Martin RM, Holly JM, Smith GD, et al: Could associations between breastfeeding and insulin-like growth factors underlie associations of breastfeeding with adult chronic disease? The Avon Longitudinal Study of Parents and Children. Clin Endocrinol (Oxf) 2005;62:728-737
  73. Ben-Shlomo Y, Holly J, McCarthy A, et al: Prenatal and postnatal milk supplementation and adult insulin-like growth factor I: long-term follow-up of a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 2005;14:1336-1339
  74. Elias SG, Keinan-Boker L, Peeters PH, et al: Long term consequences of the 1944-1945 Dutch famine on the insulin-like growth factor axis. Int J Cancer 2004;108:628-630
  75. Larnkjaer A, Ingstrup HK, Schack-Nielsen L, et al: Early programming of the IGF-I axis: negative association between IGF-I in infancy and late adolescence in a 17-year longitudinal follow-up study of healthy subjects. Growth Horm IGF Res 2009;19:82-86
  76. Juul A, Scheike T, Davidsen M, et al: Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 2002;106:939-944
  77. Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008;8:915-928
  78. Koletzko B, Brönstrup A, Cremer M, et al: Säuglingsernährung und Ernährung der stillenden Mutter. Handlungsempfehlungen - Ein Konsensuspapier im Auftrag des bundesweiten Netzwerk Junge Familie. Monatsschr Kinderheilkd 2010;158:679-689

 goto top of outline Article Information

Number of Print Pages : 17

 goto top of outline Publication Details

Book Serie: Nestlé Nutrition Institute Workshop Series, Vol. 71, Year 2013

Editor(s): Gillman, M.W. (Boston, Mass.); Gluckman, P.D. (Auckland); Rosenfeld, R.G. (Los Altos, Calif.)
ISSN: 1664-2147 (Print), eISSN: 1664-2155 (Online)

For additional information:

Book Title: Recent Advances in Growth Research: Nutritional, Molecular and Endocrine Perspectives (71st Nestlé Nutrition Institute Workshop, Vienna, October 2011)

Editor(s): Gillman MW, Gluckman PD, Rosenfeld RG (eds)

For additional information:

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.