Metabolites in Early‐Mid Pregnancy Mediate the Association Between Prepregnancy Body Mass Index and Risk of Gestational Diabetes Mellitus

Aims: The study is aimed at identifying the shared metabolites in early-mid pregnancy associated with prepregnancy body mass index (pBMI) and subsequent gestational diabetes mellitus (GDM) risk and at exploring the mediating role of metabolites. Methods: One hundred pregnant women with GDM and 100 matched controls were enrolled in the study. Serum samples were collected in 10-20 weeks' gestation and used for targeted metabolomic assay measurement. The associations among pBMI, metabolites, and GDM were investigated using linear regression and logistic regression models. Mediation analysis was conducted to evaluate the mediating effect of individual metabolite and clustered latent variable (LV) on the association of pBMI with GDM. Results: We identified eight metabolites significantly associated with both pBMI and GDM, which contained three organic acids, three acylcarnitines, and two fatty acids. Mediation analysis found five individual metabolites and two clustered LVs exhibited significant mediation effects in the association between pBMI and GDM risk. LV1 showed mediated proportions of 24.0%, which represented as organic acids and enriched in branched-chain amino acid biosynthesis. LV2 showed mediated proportions of 19.1%, which represented as acylcarnitines and enriched in linoleic acid metabolism. Furthermore, we validated the mediating role of branched-chain amino acids during the OGTT period. Conclusion: The association between pBMI and GDM risk was attributed to serum metabolites in early-mid pregnancy, especially metabolites related to branched-chain amino acid biosynthesis.