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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
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
Subcutaneous adipose tissue
Visceral adipose tissue
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
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
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
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
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
Oken E, Gillman MW (2003) Fetal origins of obesity. Obes Res 11(4):496–506. https://doi.org/10.1038/oby.2003.69
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
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
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
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
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
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
Corkey BE (2012) Banting lecture 2011: hyperinsulinemia: cause or consequence? Diabetes 61(1):4–13. https://doi.org/10.2337/db11-1483
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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
- Beta cell dysfunction
- Beta cell hypersecretion
- Fasting insulin
- Longitudinal cohort
- Type 2 diabetes