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



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


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.


>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).


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.

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Data availability

Data are available upon request from the authors.



Exploring Perinatal Outcomes among Children


Gestational diabetes mellitus


Hyperglycemia and Adverse Pregnancy Outcomes


Kaiser Permanente of Colorado


Metabolic equivalent


Subcutaneous adipose tissue


Visceral adipose tissue


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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.


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.

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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.

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Correspondence to Wei Perng.

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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).

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