How does exposure to overnutrition in utero lead to childhood adiposity? Testing the insulin hypersecretion hypothesis in the EPOCH cohort

Abstract

Aims/hypothesis

Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children.

Methods

We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up.

Results

>All participants were normal weight at baseline (BMIZ −0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm2), VAT (2.0 [95% CI 0.1, 3.8] mm2), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD).

Conclusions/interpretation

Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia.

Graphical abstract

This is a preview of subscription content, access via your institution.

Data availability

Data are available upon request from the authors.

Abbreviations

EPOCH:

Exploring Perinatal Outcomes among Children

GDM:

Gestational diabetes mellitus

HAPO:

Hyperglycemia and Adverse Pregnancy Outcomes

KPCO:

Kaiser Permanente of Colorado

MET:

Metabolic equivalent

SAT:

Subcutaneous adipose tissue

VAT:

Visceral adipose tissue

References

  1. 1.

    Mayer-Davis EJ, Lawrence JM, Dabelea D et al (2017) Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med 376(15):1419–1429. https://doi.org/10.1056/NEJMoa1610187

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    D’Adamo E, Caprio S (2011) Type 2 diabetes in youth: epidemiology and pathophysiology. Diabetes Care 34(Supplement 2):S161–S165. https://doi.org/10.2337/dc11-s212

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bianco ME, Kuang A, Josefson JL et al (2021) Hyperglycemia and adverse pregnancy outcome follow-up study: newborn anthropometrics and childhood glucose metabolism. Diabetologia 64(3):561–570. https://doi.org/10.1007/s00125-020-05331-0

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC (1994) Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 17(9):961–969. https://doi.org/10.2337/diacare.17.9.961

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Carey VJ, Walters EE, Colditz GA et al (1997) Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women. The Nurses’ Health Study. Am J Epidemiol 145(7):614–619. https://doi.org/10.1093/oxfordjournals.aje.a009158

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Oken E, Gillman MW (2003) Fetal origins of obesity. Obes Res 11(4):496–506. https://doi.org/10.1038/oby.2003.69

    Article  PubMed  Google Scholar 

  7. 7.

    Dabelea D, Harrod CS (2013) Role of developmental overnutrition in pediatric obesity and type 2 diabetes. Nutr Rev 71(Suppl 1):S62–S67. https://doi.org/10.1111/nure.12061

    Article  PubMed  Google Scholar 

  8. 8.

    Dabelea D, Crume T (2011) Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 60(7):1849–1855. https://doi.org/10.2337/db11-0400

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Scholtens DM, Kuang A, Lowe LP et al (2019) Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): maternal glycemia and childhood glucose metabolism. Diabetes Care 42(3):381–392. https://doi.org/10.2337/dc18-2021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Ahlqvist E, Storm P, Käräjämäki A et al (2018) Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 6(5):361–369. https://doi.org/10.1016/s2213-8587(18)30051-2

    Article  PubMed  Google Scholar 

  11. 11.

    Esser N, Utzschneider KM, Kahn SE (2020) Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia. Diabetologia 63(10):2007–2021. https://doi.org/10.1007/s00125-020-05245-x

    Article  PubMed  Google Scholar 

  12. 12.

    Erion K, Corkey BE (2018) β-Cell failure or β-cell abuse? Front Endocrinol (Lausanne) 9:532–532. https://doi.org/10.3389/fendo.2018.00532

    Article  Google Scholar 

  13. 13.

    Corkey BE (2012) Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 61(1):4–13. https://doi.org/10.2337/db11-1483

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Nolan CJ, Prentki M (2019) Insulin resistance and insulin hypersecretion in the metabolic syndrome and type 2 diabetes: time for a conceptual framework shift. Diab Vasc Dis Res 16(2):118–127. https://doi.org/10.1177/1479164119827611

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    RISE Consortium (2018) Metabolic contrasts between youth and adults with impaired glucose tolerance or recently diagnosed type 2 diabetes: I. observations using the hyperglycemic clamp. Diabetes Care 41(8):1696. https://doi.org/10.2337/dc18-0244

  16. 16.

    Rowley KG, Best JD, McDermott R, Green EA, Piers LS, O'Dea K (1997) Insulin resistance syndrome in Australian aboriginal people. Clin Exp Pharmacol Physiol 24(9–10):776–781. https://doi.org/10.1111/j.1440-1681.1997.tb02131.x

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Pontiroli AE, Alberetto M, Capra F, Pozza G (1990) The glucose clamp technique for the study of patients with hypoglycemia: insulin resistance as a feature of insulinoma. J Endocrinol Investig 13(3):241–245. https://doi.org/10.1007/bf03349549

    CAS  Article  Google Scholar 

  18. 18.

    Del Prato S, Riccio A, Vigili de Kreutzenberg S et al (1993) Mechanisms of fasting hypoglycemia and concomitant insulin resistance in insulinoma patients. Metabolism 42(1):24–29. https://doi.org/10.1016/0026-0495(93)90167-m

    Article  PubMed  Google Scholar 

  19. 19.

    Battezzati A, Terruzzi I, Perseghin G et al (1995) Defective insulin action on protein and glucose metabolism during chronic hyperinsulinemia in subjects with benign insulinoma. Diabetes 44(7):837–844. https://doi.org/10.2337/diab.44.7.837

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M, DeFronzo RA (1994) Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man. Diabetologia 37(10):1025–1035. https://doi.org/10.1007/bf00400466

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Crume TL, Ogden L, West NA et al (2011) Association of exposure to diabetes in utero with adiposity and fat distribution in a multiethnic population of youth: the Exploring Perinatal Outcomes among Children (EPOCH) Study. Diabetologia 54(1):87–92. https://doi.org/10.1007/s00125-010-1925-3

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Freedman DS, Sherry B (2009) The validity of BMI as an indicator of body fatness and risk among children. Pediatrics 124(Suppl 1):S23–S34. https://doi.org/10.1542/peds.2008-3586E

    Article  PubMed  Google Scholar 

  23. 23.

    Perng WOE, Dabelea D (2019) Developmental overnutrition and obesity and type 2 diabetes in offspring. Diabetologia 62(10):1779–2788. https://doi.org/10.1007/s00125-019-4914-1

  24. 24.

    National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28(12):1039–1057. https://doi.org/10.2337/diab.28.12.1039

    Article  Google Scholar 

  25. 25.

    Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419. https://doi.org/10.1007/bf00280883

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Centers for Disease Control and Prevention (2007) National Health and Nutrition Examination Survey (NHANES): Anthropometry Procedures Manual. Available from https://www.cdc.gov/nchs/data/nhanes/nhanes_07_08/manual_an.pdf

  27. 27.

    Perng W, Hockett CW, Sauder KA, Dabelea D (2020) In utero exposure to gestational diabetes mellitus and cardiovascular risk factors in youth: a longitudinal analysis in the EPOCH cohort. Pediatr Obes 15(5):e12611. https://doi.org/10.1111/ijpo.12611

    Article  PubMed  Google Scholar 

  28. 28.

    Marshall WA, Tanner JM (1968) Growth and physiological development during adolescence. Annu Rev Med 19:283–300. https://doi.org/10.1146/annurev.me.19.020168.001435

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Chavarro JE, Watkins DJ, Afeiche MC et al (2017) Validity of self-assessed sexual maturation against physician assessments and hormone levels. J Pediatr 186:172–178.e173. https://doi.org/10.1016/j.jpeds.2017.03.050

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Weston AT, Petosa R, Pate RR (1997) Validation of an instrument for measurement of physical activity in youth. Med Sci Sports Exerc 29(1):138–143. https://doi.org/10.1097/00005768-199701000-00020

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Cullen KW, Watson K, Zakeri I (2008) Relative reliability and validity of the Block Kids Questionnaire among youth aged 10 to 17 years. J Am Diet Assoc 108(5):862–866. https://doi.org/10.1016/j.jada.2008.02.015

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Kaess BM, Pedley A, Massaro JM, Murabito J, Hoffmann U, Fox CS (2012) The ratio of visceral to subcutaneous fat, a metric of body fat distribution, is a unique correlate of cardiometabolic risk. Diabetologia 55(10):2622–2630. https://doi.org/10.1007/s00125-012-2639-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Tu YK, West R, Ellison GT, Gilthorpe MS (2005) Why evidence for the fetal origins of adult disease might be a statistical artifact: the “reversal paradox” for the relation between birth weight and blood pressure in later life. Am J Epidemiol 161(1):27–32. https://doi.org/10.1093/aje/kwi002

    Article  PubMed  Google Scholar 

  34. 34.

    Tam WH, Ma RCW, Ozaki R et al (2017) In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring. Diabetes Care 40(5):679–686. https://doi.org/10.2337/dc16-2397

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Sauder KA, Hockett CW, Ringham BM, Glueck DH, Dabelea D (2017) Fetal overnutrition and offspring insulin resistance and β-cell function: the Exploring Perinatal Outcomes among Children (EPOCH) study. Diabet Med 34(10):1392–1399. https://doi.org/10.1111/dme.13417

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Chen YY, Wang JP, Jiang YY et al (2015) Fasting plasma insulin at 5 years of age predicted subsequent weight increase in early childhood over a 5-year period—the Da Qing children cohort study. PLoS One 10(6):e0127389. https://doi.org/10.1371/journal.pone.0127389

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Schooling CM (2015) Life course epidemiology: recognising the importance of puberty. J Epidemiol Community Health 69(8):820. https://doi.org/10.1136/jech-2015-205607

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center staff and EPOCH participants.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

The EPOCH study is supported by the National Institutes of Health (NIH), National Institute of Diabetes, Digestive, and Kidney Diseases (R01 DK068001). WP is supported by the Center for Clinical and Translational Sciences Institute KL2-TR002534. The study sponsor/funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

Author information

Affiliations

Authors

Contributions

WP made substantial contributions to design of the study, interpretation of the data, drafted the first draft of the article and revised it critically for important intellectual content. MMK and KAS made substantial contributions to analysis and interpretation of the data, and provided critical and important intellectual feedback on the article. DD made substantial contributions to the conception and design of the study, analysis and interpretation of the data, and provided critical feedback on the paper. All authors gave final approval of the version to be published. WP is the guarantor of this work.

Corresponding author

Correspondence to Wei Perng.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM

(PDF 103 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Perng, W., Kelsey, M.M., Sauder, K.A. et al. How does exposure to overnutrition in utero lead to childhood adiposity? Testing the insulin hypersecretion hypothesis in the EPOCH cohort. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05515-2

Download citation

Keywords

  • Beta cell dysfunction
  • Beta cell hypersecretion
  • Fasting insulin
  • Longitudinal cohort
  • Type 2 diabetes
  • Youth