Skip to main content
SpringerLink
Log in

Comparative analysis of glucoinsulinemic markers and proinflammatory cytokines in prepubertal children born large-versus appropriate-for gestational age

  • Original Article
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Children born large for gestational age (LGA) may be at risk for development of obesity and insulin resistance (IR). The reciprocal relationship of adipokines and proinflammatory cytokines is suggested to play a putative role in fine tuning of insulin secretory dynamics. To evaluate serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, insulin-like growth factor-1 (IGF-1), and IGF-binding protein-1 (IGFBP-1) concentrations in idiopathic LGA-born children to appropriate for gestational age (AGA) and idiopathic LGA-born children at prepubertal ages and investigate their associations with IR, evaluated by homeostasis model assessment-IR (HOMA-IR), we conducted a cross-sectional study to compare 40 (19 females) idiopathic LGA-born prepubertal children [mean ± SD age 6.1 ± 2.5 years] and 49 (25 females) (5.4 ± 1.8 years) AGA-born BMI-matched peers with respect to anthropometric and laboratory data. Both groups were further divided into subgroups as being obese/overweight (OW) and non-OW, and the analyses were repeated. LGA-born children were taller and heavier than AGA-born children (p < 0.001). Fasting insulin, HOMA-IR, and leptin were higher in LGA-born children than in AGA-born counterparts (p < 0.001). Serum TNF-α levels were lower and IL-6 levels were significantly higher in LGA- than in AGA-born children (p < 0.001). In the LGA group, TNF-α was correlated with HOMA-IR (r = −0.49, p = 0.002). LGA-born non-OW children had higher serum insulin concentrations and HOMA-IR than AGA-born counterparts. Multivariate regression analysis revealed that HOMA-IR was best explained by (R 2 = 0.517) birth weight SDS (β = +0.418, p = 0.002), leptin (β = +0.620, p = 0.000), and TNF-α (β = −0.374, p = 0.003) in LGA-born children. Idiopathic LGA-born children have significantly lower TNF-α and higher IL-6 levels than AGA-born children. Reduced TNF-α levels are associated with increased IR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. C.N. Hales, D.J. Barker, The thrifty phenotype hypothesis. Br. Med. Bull. 60, 5–20 (2001)

    Article  CAS  PubMed  Google Scholar 

  2. K.K. Ong, C.J. Petry, P.M. Emmett et al., ALSPAC study team. Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels. Diabetologia 47, 1064–1070 (2004)

    CAS  PubMed  Google Scholar 

  3. C.M. Boney, A. Verma, R. Tucker et al., Metabolic syndrome in childhood: association with birth weight, maternal obesity, and gestational diabetes mellitus. Pediatrics 115, 290–296 (2005)

    Article  Google Scholar 

  4. F. Darendeliler, S. Poyrazoglu, O. Sancakli et al., Adiponectin is an indicator of insulin resistance in non-obese prepubertal children born large for gestational age (LGA) and is affected by birth weight. Clin. Endocrinol. (Oxf). 70, 710–716 (2009)

    Article  CAS  PubMed  Google Scholar 

  5. R. Retnakaran, C. Ye, A.J.G. Hanley et al., Effect of maternal weight, adipokines, glucose intolerance and lipids on infant birth weight among women without gestational diabetes mellitus. CMAJ. 184(12), 1353–1360 (2012). doi:10.1503/cmaj.111154

    Article  PubMed Central  PubMed  Google Scholar 

  6. D.A. Fields, E.W. Demerath, Relationship of insulin, glucose, leptin, IL-6 and TNF-a in human breast milk with infant growth and body composition. Pediatr. Obes. 7, 304–312 (2012)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. G. Amarilyo, A. Oren, F.B. Mimouni, Y. Ochshorn, V. Deutsch, D. Mandel, Increased cord serum inflammatory markers in small-for-gestational-age neonates. J. Perinatol. 31, 30–32 (2011)

    Article  CAS  PubMed  Google Scholar 

  8. U. Lindner, E. Tutdibi, S. Binot, D. Monz, A. Hilgendorff, L. Gortner, Levels of cytokines in umbilical cord blood in small for gestational age preterm infants. Klin. Padiatr. 225, 70–74 (2013)

    Article  CAS  PubMed  Google Scholar 

  9. McElrath TF., Allred E.N., Van Marter L., Fichorova R.N., Leviton A., for the ELGAN Study Investigators Perinatal systemic inflammatory responses of growth-restricted preterm newborns, Acta Paediatrica 102:e439–e442 (2013)

    Google Scholar 

  10. J.L. Bartha, R. Romero-Carmona, R. Comino-Delgrado, Inflammatory cytokines in intrauterine growth retardation. Acta Obstet. Gynecol. Scand. 82, 1099–1102 (2003)

    Article  PubMed  Google Scholar 

  11. M.E. Street, M.A. Ziveri, C. Spaggiari et al., Inflammation is a modulator of the IGF-IGFBP system inducing reduced bioactivity of IGFs in cystic fibrosis. Eur. J. Endocrinol. 154, 1–7 (2006)

    Article  Google Scholar 

  12. M.E. Street, C. Volta, M.A. Ziveri et al., Changes and relationships of IGFs and IGFBPs and cytokines in coeliac disease at diagnosis and on gluten-free diet. Clin. Endocrinol. 68, 22–28 (2008)

    Article  CAS  Google Scholar 

  13. M.E. Street, P. Seghini, S. Fieni et al., Changes in interleukin-6 and IGF system and their relationships in placenta and cord blood in newborns with fetal growth restriction compared with controls. Eur. J. Endocrinol. 155, 567–574 (2006)

    Article  CAS  PubMed  Google Scholar 

  14. S. Muller, S. Martin, W. Koenig et al., Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute phase proteins but not TNF-alpha or its receptors. Diabetologia 45, 805–812 (2002)

    Article  CAS  PubMed  Google Scholar 

  15. Y. Miyazaki, R. Pipek, L.J. Mandarino et al., Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int. J. Obes. Relat. Metab. Disord. 27, 88–94 (2003)

    Article  CAS  PubMed  Google Scholar 

  16. R. Retnakaran, Y. Qi, M. Sermer et al., Glucose intolerance in pregnancy and future risk of pre-diabetes or diabetes. Diabetes Care 31, 2026–2031 (2008)

    Article  PubMed Central  PubMed  Google Scholar 

  17. J. Zhang, M. Merialdi, L.D. Platt et al., Defining normal and abnormal fetal growth: promises and challenges. Am. J. Obstet. Gynecol. 202(6), 522–528 (2010)

    Article  PubMed Central  PubMed  Google Scholar 

  18. J.M. Tanner, Recording adolescent physical changes. Tanner System. Del. Med. J. 45, 84–88 (1973)

    Google Scholar 

  19. S. Kurtoğlu, N. Hatipoğlu, M.M. Mazıcıoğlu et al., Body weight, length and head circumference at birth a cohort of Turkish newborns. JCRPE 4, 132–139 (2012)

    Article  PubMed Central  PubMed  Google Scholar 

  20. G. Gökçay, A. Furman, O. Neyzi, Updated growth curves for Turkish children aged 15 days to 60 months. Child Care Health Dev. 34, 454–463 (2008)

    Article  PubMed  Google Scholar 

  21. O. Neyzi, A. Furman, R. Bundak et al., Growth references Turkish children aged 6 to 18 years. Acta. Paediatr. 95, 1635–1641 (2006)

    Article  PubMed  Google Scholar 

  22. R. Bundak, A. Furman, H. Gunoz et al., Body mass index references for Turkish children. Acta Paediatr. 95, 194–198 (2006)

    Article  PubMed  Google Scholar 

  23. N. Hatipoğlu, A. Öztürk, M.M. Mazicioğlu et al., Waist circumference percentiles for 7-to 17-years-old Turkish children and adolescents. Eur. J. Pediatr. 167, 383–389 (2008)

    Article  PubMed  Google Scholar 

  24. N. Hatipoğlu, M.M. Mazicioğlu, S. Poyrazoğlu et al., Waist circumference percentiles among Turkish children under the age of 6 years. Eur. J. Pediatr. (2012). doi:10.1007/s00431-012-1822-5

    PubMed Central  Google Scholar 

  25. R.P. Troiano, K.M. Flegal, R.J. Kuczmarski et al., Overweight prevalence and trends for children and adolescents. The National Health and Nutrition Examination Surveys, 1963 to 1991. Arch. Pediatr. Adolesc. Med. 149, 1085–1091 (1995)

    Article  CAS  PubMed  Google Scholar 

  26. T.J. Cole, M.C. Bellizzi, K.M. Flegal et al., Establishing a standard definition for child overweight and obesity worldwide: international survey. Br. Med. J. 320, 1240–1243 (2000)

    Article  CAS  Google Scholar 

  27. D.R. Matthews, J.P. Hosker, A.S. Rudenski et al., Homeostasis model assessment: insulin resistance and & #x03B2;-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985)

    Article  CAS  PubMed  Google Scholar 

  28. V. Giapros, E. Evagelidou, A. Challa et al., Serum adiponectin and leptin levels and insulin resistance in children born large for gestational age are affected by the degree of overweight. Clin. Endocrinol. 66, 353–359 (2007)

    Article  CAS  Google Scholar 

  29. J.S. Dyer, C.R. Rosenfeld, J. Rice et al., Insulin resistance in Hispanic large-for-gestational-age neonates at birth. J. Clin. Endocrinol. Metab. 92, 3836–3843 (2007)

    Article  CAS  PubMed  Google Scholar 

  30. A.S. Challa, E.N. Evagelidou, V.I. Giapros et al., Growth factors, adiponectin, leptin and body mass index in pre-pubertal children born large for gestational age. J. Endocrinol. Invest. 34, 411–416 (2011)

    Article  CAS  PubMed  Google Scholar 

  31. M.S. Sandhu, A.H. Heald, J.M. Gibson et al., Circulating concentrations of insulin-like growth factor-I and development of glucose intolerance: a prospective observational study. Lancet 359, 1740–1745 (2002)

    Article  CAS  PubMed  Google Scholar 

  32. Y. Miyazaki, R. Pipek, L.J. Mandarino et al., Tumor necrosis factor alpha and insulin resistance in obese type 2 diabetic patients. Int. J. Obes. Relat. Metab. Disord. 27, 88–94 (2003)

    Article  CAS  PubMed  Google Scholar 

  33. H.S. Park, J.Y. Park, R. Yu, Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Res. Clin. Pract. 69(1), 29–35 (2005)

    Article  CAS  PubMed  Google Scholar 

  34. E.H. Choy, D.A. Isenberg, T. Garrood et al., Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis. Rheum. 46, 3143–3150 (2002)

    Article  CAS  PubMed  Google Scholar 

  35. A.M. Petersen, B.K. Pedersen, The anti-inflammatory effect of exercise. J. Appl. Physiol. 98, 1154–1162 (2005)

    Article  CAS  PubMed  Google Scholar 

  36. R. Starkie, S.R. Ostrowski, S. Jauffred et al., Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 17, 884–886 (2003)

    CAS  PubMed  Google Scholar 

  37. C. Jefferies, P. Hofman, J. Keelan et al., Insulin resistance is not due to persistently elevated serum tumour necrosis-α levels in small for gestational age, premature or twin children. Pediatr. Diabetes 5, 20–25 (2004)

    Article  PubMed  Google Scholar 

  38. D.A. Joyce, J.H. Steer, L.J. Abraham, Glucocorticoid modulation of human monocyte/macrophage function: control of TNF-alpha secretion. Inflamm. Res. 46, 447–451 (1997)

    Article  CAS  PubMed  Google Scholar 

  39. S.L. Bakker, R.O.B. Gans, J.C. Ter Maaten et al., The potential role of adenosine in the pathophysiology of the insulin resistance syndrome. Atherosclerosis 155, 283–290 (2001)

    Article  CAS  PubMed  Google Scholar 

  40. M.W. Chong, H.E. Thomas, T.W.H. Kay, Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumour necrosis factor. J. Biol. Chem. 277, 27945–27952 (2002)

    Article  CAS  PubMed  Google Scholar 

  41. L.P. Palaniappan, M.R. Carnethon, S.P. Fortmann, Heterogeneity in the relationship between ethnicity, BMI, and fasting insulin. Diabetes Care 25, 1351–1357 (2002)

    Article  PubMed Central  PubMed  Google Scholar 

  42. D. McCarthy, Body fat measurements in children as predictors for the metabolic syndrome: focus on waist circumference. Proc. Nutr. Soc. 65, 385–392 (2006)

    PubMed  Google Scholar 

  43. C. Levy-Marchal, S. Arslanian, W. Cutfield, et al. and on behalf of ESPE-LWPES-ISPAD-APPES-APEG-SLEP-JSPE, and the Insulin Resistance in Children Consensus Conference Group Insulin. Resistance in Children: consensus, perspective, and future directions. J. Clin. Endocrinol. Metab. 95(12):5189–5198 (2010)

Download references

Acknowledgments

This work was supported by Scientific Research Projects Coordination Unit of Istanbul University. Project Number: 9,584. The authors would like to thank Fatmahan Atalar, Tugba Tarhan, Gökce Akan, and Muammer Cangar for appropriate handling of blood samples and their support in biochemical analyses.

Author information

Authors and Affiliations

  1. Paediatric Endocrinology Unit, Department of Paediatrics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

    Ceren Çetin, Firdevs Baş, Ahmet Uçar, Şükran Poyrazoğlu, Nurçin Saka, Rüveyde Bundak & Feyza Darendeliler

Authors
  1. Ceren Çetin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Firdevs Baş
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ahmet Uçar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Şükran Poyrazoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nurçin Saka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rüveyde Bundak
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Feyza Darendeliler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmet Uçar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Çetin, C., Baş, F., Uçar, A. et al. Comparative analysis of glucoinsulinemic markers and proinflammatory cytokines in prepubertal children born large-versus appropriate-for gestational age. Endocrine 47, 816–824 (2014). https://doi.org/10.1007/s12020-014-0207-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-014-0207-0

Keywords

Search

Navigation