Metabolomic signatures of low birthweight: Pathways to insulin resistance and oxidative stress.

Sarah Jane Metrustry,Ville Karhunen,Ana M Valdes,Cyrus Cooper,Mark H Edwards,Tim Spector,Anja Huber,Thomas Geisendorfer,Cristina Menni,Christian Reichel,Marjo-Riitta Jarvelin,Elaine M Dennison

doi:10.1371/journal.pone.0194316

Sarah Jane Metrustry, Ville Karhunen + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0194316

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Abstract

Several studies suggest that low birthweight resulting from restricted intrauterine growth can leave a metabolic footprint which may persist into adulthood. To investigate this, we performed metabolomic profiling on 5036 female twins, aged 18–80, with weight at birth information available from the TwinsUK cohort and performed independent replication in two additional cohorts. Out of 422 compounds tested, 25 metabolites associated with birthweight in these twins, replicated in 1951 men and women from the Hertfordshire Cohort Study (HCS, aged 66) and in 2391 men and women from the North Finland Birth 1986 cohort (NFBC, aged 16). We found distinct heterogeneity between sexes and, after adjusting for multiple tests and heterogeneity, two metabolites were reproducible overall (propionylcarnitine and 3-4-hydroxyphenyllactate). Testing women only, we found other metabolites associated with lower birthweight from the meta-analysis of the three cohorts (2-hydroxy-butyric acid and γ-glutamylleucine). Higher levels of all these metabolites can be linked to insulin resistance, oxidative stress or a dysfunction of energy metabolism, suggesting that low birthweight in both twins and singletons are having an impact on these pathways in adulthood.

Highlights

HCS: The Hertfordshire Cohort Study has governance and access arrangements that comply with Medical Research Council (MRC) data sharing policy
The analyses suggest that increased urinary inositol may constitute a marker of altered glucose metabolism during fetal development in intrauterine growth restriction (IUGR) and large size for gestational age (LGA) newborns [19]
We explored the hypothesis that birthweight differences are reflected in the metabolic profile and persist into adulthood and to do so we have used cohorts with very different age ranges, TwinsUK for discovery and two birth cohorts- one sampled at age 66 years and the other at 16 years for replication

Summary

Introduction

Twenty five metabolites from the Metabolon and Biocrates platforms were identified as correlated with birthweight in the TwinsUK cohort (Table 2). Assays were developed to test these metabolites in serum from the two singleton replication cohorts from the UK and Finland comprising both men and women (Table 1).

Results

Conclusion