A prospective study of associations between in utero exposure to gestational diabetes mellitus and metabolomic profiles during late childhood and adolescence
This study aimed to: (1) identify metabolite patterns during late childhood that differ with respect to exposure to maternal gestational diabetes mellitus (GDM); (2) examine the persistence of GDM/metabolite associations 5 years later, during adolescence; and (3) investigate the associations of metabolite patterns with adiposity and metabolic biomarkers from childhood through adolescence.
This study included 592 mother–child pairs with information on GDM exposure (n = 92 exposed), untargeted metabolomics data at age 6–14 years (T1) and at 12–19 years (T2), and information on adiposity and metabolic risk biomarkers at T1 and T2. We first consolidated 767 metabolites at T1 into factors (metabolite patterns) via principal component analysis (PCA) and used multivariable regression to identify factors that differed by GDM exposure, at α = 0.05. We then examined associations of GDM with individual metabolites within factors of interest at T1 and T2, and investigated associations of GDM-related factors at T1 with adiposity and metabolic risk throughout T1 and T2 using mixed-effects linear regression models.
Of the six factors retained from PCA, GDM exposure was associated with greater odds of being in quartile (Q)4 (vs Q1–3) of ‘Factor 4’ at T1 after accounting for age, sex, race/ethnicity, maternal smoking habits during pregnancy, Tanner stage, physical activity and total energy intake, at α = 0.05 (OR 1.78 [95% CI 1.04, 3.04]; p = 0.04). This metabolite pattern comprised phosphatidylcholines, diacylglycerols and phosphatidylethanolamines. GDM was consistently associated with elevations in a subset of individual compounds within this pattern at T1 and T2. While this metabolite pattern was not related to the health outcomes in boys, it corresponded with greater adiposity and a worse metabolic profile among girls throughout the follow-up period. Each 1-unit increment in Factor 4 corresponded with 0.17 (0.08, 0.25) units higher BMI z score, 8.83 (5.07, 12.59) pmol/l higher fasting insulin, 0.28 (0.13, 0.43) units higher HOMA-IR, and 4.73 (2.15, 7.31) nmol/l higher leptin.
Exposure to maternal GDM was nominally associated with a metabolite pattern characterised by elevated serum phospholipids in late childhood and adolescence at α = 0.05. This metabolite pattern was associated with greater adiposity and metabolic risk among female offspring throughout the late childhood-to-adolescence transition. Future studies are warranted to confirm our findings.
KeywordsAdiponectin Adolescence Gestational diabetes mellitus Insulin resistance Leptin Prospective cohort study Untargeted metabolomics
3-Day Physical Activity Recall
Exploring Perinatal Outcomes among Children
Gestational diabetes mellitus
Kaiser Permanente of Colorado
Principal component analysis
Subcutaneous adipose tissue
Stearoyl- CoA desaturase
2006–2009 study period
2012–2015 study period (follow-up)
Visceral adipose tissue
We thank the EPOCH participants, as well as past and present research assistants.
WP and DD conceived the research question. WP is the guarantor of this work. WP conducted the analysis, wrote the initial draft of the paper and incorporated co-author comments. BMR, KMK and HAS curated the data and provided feedback on the analysis. GM oversaw the laboratory analysis for the metabolomics assays and participated in the writing of the manuscript. BMR, HAS, KMK and DD revised the article critically for important intellectual content. All co-authors approved the final version of the paper.
This study was supported by the National Institutes of Health (NIH), National Institute of Diabetes, Digestive, and Kidney Diseases (R01 DK068001). The funders had no role in the design, conduct or reporting of this work.
Duality of interest
GM is an employee at Metabolon, Inc. All other authors declare that there is no duality of interest associated with this manuscript.
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