, Volume 61, Issue 4, pp 870–880 | Cite as

Telomere length is reduced in 9- to 16-year-old girls exposed to gestational diabetes in utero

  • Line Hjort
  • Regan Vryer
  • Louise G. Grunnet
  • David Burgner
  • Sjurdur F. Olsen
  • Richard Saffery
  • Allan Vaag



Shortened telomere length is a marker of cell damage and is associated with oxidative stress, chronic inflammation and metabolic disease. We hypothesised that the offspring of women with gestational diabetes mellitus (GDM) with increased risk of cardiovascular and metabolic diseases might exhibit shorter telomere length.


We investigated telomere length in 439 GDM and 469 control group offspring, aged between 9 and 16 years, recruited from the Danish National Birth Cohort. Relative telomere length was measured in peripheral blood DNA (n = 908) using a quantitative PCR approach. Multivariate regression analysis was used to investigate the association between mothers’ GDM status and telomere length in the offspring.


Female offspring had longer telomeres than males. Offspring of mothers with GDM had significantly shorter telomere length than control offspring, but this difference was observed only in girls. There was a negative association between telomere length and GDM exposure among the female offspring (14% shorter telomeres, p = 0.003) following adjustment for the age of the offspring. Telomere length in female offspring was negatively associated with fasting insulin levels and HOMA-IR (p = 0.03). Maternal age, smoking, gestational age, birthweight and the offspring’s anthropometric characteristics were not associated with telomere length (p ≥ 0.1).


The 9- to 16-year-old girls of mothers with GDM had shorter telomeres than those from the control population. Further studies are needed to understand the extent to which shortened telomere length predicts and/or contributes to the increased risk of disease later in life among the offspring of women with GDM.


Developmental programming Gestational diabetes Inflammation Offspring Oxidative stress Telomere length Type 2 diabetes 



Body fat percentage


Danish National Birth Cohort


Gestational diabetes mellitus


High-sensitivity C-reactive protein


Maternal BMI



We greatly appreciate all the children and their mothers who participated in the study. Additional GDM study team members include F. Bach Kampmann, M. Egholm, A.-C. Baun Thuesen, C. Møller Madsen, C. Fau Brinkløv and student assistants, who did tremendous work assisting in collecting data (Department of Endocrinology, Copenhagen University Hospital, Denmark). Additionally, we want to acknowledge the great collaboration with Staten’s Serum Institute DNBC study members S. Hansen, M. Strøm, K. Agerskov, C. Granström and A. Ahrendt in the planning and organisation of the GDM study (Centre for Fetal Programming, Statens Serum Institut, Copenhagen, Denmark) and C. Zhang for the collaboration on the Diabetes and Women’s Health (DWH) study (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA). We also kindly thank the clinics across Denmark’s regions for providing housing facilities for the clinical study.

Authors’ contributions

LH, RV and RS designed the telomere study, and LGG, SFO and AV designed the GDM subcohort study. LH and LGG, together with the GDM/DNBC study team, collected the in vivo data. LH processed the blood samples and extracted DNA, and LH and RV performed the telomere length measurements. LH, RV and RS analysed the data, and LH, RV, LGG, DB, RS and AV interpreted the results of the experiments. LH wrote the manuscript, with contributions from RV, LGG, DB and RS. All co-authors revised the manuscript and approved the final version. AV is the guarantor of this work and takes responsibility for the contents and integrity of the data in this article.

Duality of interest

AV is employed by AstraZeneca, Mölndal, Sweden and is shareholder of Novo Nordisk A/S. All other authors declare no potential conflict of interest relevant to this study.

Supplementary material

125_2018_4549_MOESM1_ESM.pdf (128 kb)
ESM (PDF 128 kb)


  1. 1.
    Getahun D, Nath C, Ananth CV, Chavez MR, Smulian JC (2008) Gestational diabetes in the United States: temporal trends 1989 through 2004. Am J Obstet Gynecol 198:525.e1–525.e5CrossRefGoogle Scholar
  2. 2.
    American Diabetes Association (2003) Gestational diabetes mellitus. Diabetes Care 26(Suppl 1):S103–S105Google Scholar
  3. 3.
    Ben-Haroush A, Yogev Y, Hod M (2004) Epidemiology of gestational diabetes mellitus and its association with type 2 diabetes. Diabet Med 21:103–113CrossRefPubMedGoogle Scholar
  4. 4.
    Buchanan TA, Xiang AH (2005) Gestational diabetes mellitus. J Clin Invest 115:485–491CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Clausen TD, Mathiesen ER, Hansen T et al (2008) High prevalence of type 2 diabetes and pre-diabetes in adult offspring of women with gestational diabetes mellitus or type 1 diabetes: the role of intrauterine hyperglycemia. Diabetes Care 31:340–346CrossRefPubMedGoogle Scholar
  6. 6.
    Dabelea D, Hanson RL, Lindsay RS et al (2000) Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49:2208–2211CrossRefPubMedGoogle Scholar
  7. 7.
    Sobngwi E, Boudou P, Mauvais-Jarvis F et al (2003) Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet (London, England) 361:1861–1865CrossRefGoogle Scholar
  8. 8.
    Lawlor DA, Fraser A, Lindsay RS et al (2010) Association of existing diabetes, gestational diabetes and glycosuria in pregnancy with macrosomia and offspring body mass index, waist and fat mass in later childhood: findings from a prospective pregnancy cohort. Diabetologia 53:89–97CrossRefPubMedGoogle Scholar
  9. 9.
    Boerschmann H, Pflüger M, Henneberger L, Ziegler A-G, Hummel S (2010) Prevalence and predictors of overweight and insulin resistance in offspring of mothers with gestational diabetes mellitus. Diabetes Care 33:1845–1849CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Patel S, Fraser A, Davey Smith G et al (2012) Associations of gestational diabetes, existing diabetes, and glycosuria with offspring obesity and cardiometabolic outcomes. Diabetes Care 35:63–71CrossRefPubMedGoogle Scholar
  11. 11.
    Blackburn EH (1991) Structure and function of telomeres. Nature 350:569–573CrossRefPubMedGoogle Scholar
  12. 12.
    Blackburn EH (2000) Telomere states and cell fates. Nature 408:53–56CrossRefPubMedGoogle Scholar
  13. 13.
    Shore D, Bianchi A (2009) Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase. EMBO J 28:2309–2322CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Frenck RW, Blackburn EH, Shannon KM (1998) The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci U S A 95:5607–5610CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Willeit P, Raschenberger J, Heydon EE et al (2014) Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis. PLoS One 9:e112483CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Brouilette SW, Moore JS, McMahon AD et al (2007) Telomere length, risk of coronary heart disease, and statin treatment in the west of Scotland primary prevention study: a nested case-control study. Lancet (London, England) 369:107–114CrossRefGoogle Scholar
  17. 17.
    Haycock PC, Heydon EE, Kaptoge S, Butterworth AS, Thompson A, Willeit P (2014) Leucocyte telomere length and risk of cardiovascular disease: systematic review and meta-analysis. BMJ 349:g4227CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Chen S, Lin J, Matsuguchi T et al (2014) Short leukocyte telomere length predicts incidence and progression of carotid atherosclerosis in American Indians: the strong heart family study. Aging (Albany NY) 6:414–427CrossRefGoogle Scholar
  19. 19.
    Tzanetakou IP, Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN (2012) “Is obesity linked to aging?”: adipose tissue and the role of telomeres. Ageing Res Rev 11:220–229CrossRefPubMedGoogle Scholar
  20. 20.
    Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361:393–395CrossRefPubMedGoogle Scholar
  21. 21.
    Diotti R, Loayza D. Shelterin complex and associated factors at human telomeres. Nucleus. 2:119–135Google Scholar
  22. 22.
    Okuda K, Bardeguez A, Gardner JP et al (2002) Telomere length in the newborn. Pediatr Res 52:377–381CrossRefPubMedGoogle Scholar
  23. 23.
    Elbers CC, Garcia ME, Kimura M et al (2014) Comparison between southern blots and qPCR analysis of leukocyte telomere length in the health ABC study. J Gerontol A Biol Sci Med Sci 69:527–531CrossRefPubMedGoogle Scholar
  24. 24.
    Biron-Shental T, Sukenik-Halevy R, Sharon Y, Laish I, Fejgin MD, Amiel A (2014) Telomere shortening in intra uterine growth restriction placentas. Early Hum Dev 90:465–469CrossRefPubMedGoogle Scholar
  25. 25.
    Salihu HM, Pradhan A, King L et al (2015) Impact of intrauterine tobacco exposure on fetal telomere length. Am J Obstet Gynecol 212:205.e1–205.e8CrossRefGoogle Scholar
  26. 26.
    Entringer S, Epel ES, Lin J et al (2013) Maternal psychosocial stress during pregnancy is associated with newborn leukocyte telomere length. Am J Obstet Gynecol 208:134.e1–134.e7CrossRefGoogle Scholar
  27. 27.
    Wojcicki JM, Olveda R, Heyman MB et al (2016) Cord blood telomere length in Latino infants: relation with maternal education and infant sex. J Perinatol 36:235–241CrossRefPubMedGoogle Scholar
  28. 28.
    Xu J, Ye J, Wu Y et al (2014) Reduced fetal telomere length in gestational diabetes. PLoS One 9:e86161CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Biron-Shental T, Sukenik-Halevy R, Naboani H, Liberman M, Kats R, Amiel A (2015) Telomeres are shorter in placentas from pregnancies with uncontrolled diabetes. Placenta 36:199–203CrossRefPubMedGoogle Scholar
  30. 30.
    Cross JA, Temple RC, Hughes JC et al (2010) Cord blood telomere length, telomerase activity and inflammatory markers in pregnancies in women with diabetes or gestational diabetes. Diabet Med 27:1264–1270CrossRefPubMedGoogle Scholar
  31. 31.
    Harville EW, Williams MA, Qiu C-F, Mejia J, Risques RA (2010) Telomere length, pre-eclampsia, and gestational diabetes. BMC Res Notes 3:113CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Cross JA, Brennan C, Gray T et al (2009) Absence of telomere shortening and oxidative DNA damage in the young adult offspring of women with pre-gestational type 1 diabetes. Diabetologia 52:226–234CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang C, Hu FB, Olsen SF et al (2014) Rationale, design, and method of the Diabetes & Women’s health study--a study of long-term health implications of glucose intolerance in pregnancy and their determinants. Acta Obstet Gynecol Scand 93:1123–1130CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Olsen SF, Houshmand-Oeregaard A, Granström C et al (2017) Diagnosing gestational diabetes mellitus in the Danish National Birth Cohort. Acta Obstet Gynecol Scand 96:563–569CrossRefPubMedGoogle Scholar
  35. 35.
    Grunnet LG, Hansen S, Hjort L et al (2017) Adiposity, Dysmetabolic traits and earlier onset of female puberty in adolescent offspring of women with gestational diabetes mellitus: a clinical study within the Danish National Birth Cohort. Diabetes Care 40:1746–1755CrossRefPubMedGoogle Scholar
  36. 36.
    Tanner JM (1963) The regulation of human growth. Child Dev 34:817–847PubMedGoogle Scholar
  37. 37.
    Cawthon RM (2009) Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res 37:e21CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gilfillan C, Naidu P, Gunawan F, Hassan F, Tian P, Elwood N (2016) Leukocyte telomere length in the neonatal offspring of mothers with gestational and pre-gestational diabetes. Saretzki G, editor. PLoS One 11:e0163824CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Asghar M, Bensch S, Tarka M, Hansson B, Hasselquist D (2015) Maternal and genetic factors determine early life telomere length. Proc Biol Sci 282:20142263CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Holmes DK, Bellantuono I, Walkinshaw SA et al (2009) Telomere length dynamics differ in foetal and early post-natal human leukocytes in a longitudinal study. Biogerontology 10:279–284CrossRefPubMedGoogle Scholar
  41. 41.
    Martens DS, Plusquin M, Gyselaers W, De Vivo I, Nawrot TS (2016) Maternal pre-pregnancy body mass index and newborn telomere length. BMC Med 14:148CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    García-Calzón S, Moleres A, Marcos A et al (2014) Telomere length as a biomarker for adiposity changes after a multidisciplinary intervention in overweight/obese adolescents: the EVASYON study. PLoS One 9:e89828CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Lappas M, Hiden U, Desoye G, Froehlich J, Hauguel-de Mouzon S, Jawerbaum A (2011) The role of oxidative stress in the pathophysiology of gestational diabetes mellitus. Antioxid Redox Signal 15:3061–3100CrossRefPubMedGoogle Scholar
  44. 44.
    Myatt L (2006) Placental adaptive responses and fetal programming. J Physiol 572:25–30CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Nergadze SG, Farnung BO, Wischnewski H et al (2009) CpG-island promoters drive transcription of human telomeres. RNA 15:2186–2194CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Li H, Simpson ER, Liu J-P (2010) Oestrogen, telomerase, ovarian ageing and cancer. Clin Exp Pharmacol Physiol 37:78–82CrossRefPubMedGoogle Scholar
  47. 47.
    O’Tierney-Ginn P, Presley L, Minium J, Hauguel de Mouzon S, Catalano PM (2014) Sex-specific effects of maternal anthropometrics on body composition at birth. Am J Obstet Gynecol 211:292.e1–292.e9CrossRefGoogle Scholar
  48. 48.
    Regnault N, Botton J, Heude B et al (2011) Higher cord C-peptide concentrations are associated with slower growth rate in the 1st year of life in girls but not in boys. Diabetes 60:2152–2159CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Kubo A, Ferrara A, Windham GC et al (2014) Maternal hyperglycemia during pregnancy predicts adiposity of the offspring. Diabetes Care 37:2996–3002CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Landon MB, Rice MM, Varner MW et al (2015) Mild gestational diabetes mellitus and long-term child health. Diabetes Care 38:445–452CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Endocrinology (Diabetes and Metabolism), Section 7652, RigshospitaletCopenhagen University HospitalCopenhagenDenmark
  2. 2.Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
  3. 3.The Danish Diabetes AcademyOdenseDenmark
  4. 4.Murdoch Children’s Research InstituteMelbourneAustralia
  5. 5.Department of PaediatricsMelbourne UniversityMelbourneAustralia
  6. 6.Department of PaediatricsMonash UniversityClaytonAustralia
  7. 7.Centre for Fetal ProgrammingStatens Serum InstitutCopenhagenDenmark
  8. 8.Department of NutritionHarvard TH Chan School of Public HealthBostonUSA
  9. 9.AstraZeneca, Innovative MedicinesEarly Clinical DevelopmentGothenburgSweden

Personalised recommendations