Associations between arginine metabolism and gestational diabetes mellitus: an exploratory longitudinal study using widely targeted metabolomics

Objective To characterize longitudinal metabolic alterations associated with gestational diabetes mellitus (GDM) and to identify candidate metabolite signals for earlier risk assessment using a widely targeted metabolomics platform. Methods In this prospective cohort, 35 women who developed GDM and 35 matched healthy controls underwent fasting blood sampling in early pregnancy (6–13 weeks) and mid-pregnancy (24–28 weeks). Widely targeted metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Multivariate analyses, logistic regression, receiver operating characteristic (ROC) analysis, internal cross-validation, and restricted cubic spline modeling were applied within an exploratory framework. Results In early pregnancy, 11 differential metabolites were identified, including 6 amino acid-related metabolites, but no robust signal remained after false discovery rate (FDR) correction. By mid-pregnancy, 35 differential metabolites were identified, including 13 amino acid-related metabolites. Among 19 amino acid-related metabolites examined in focused analyses, L-arginine was the only amino acid-related metabolite that remained significant after FDR correction (FDR = 0.043). Higher mid-pregnancy L-arginine was associated with increased odds of GDM (aOR = 2.840, 95% CI 1.481–5.446), was positively correlated with 1-h ( r  = 0.28) and 2-h ( r  = 0.26) glucose levels during OGTT, and showed modest discrimination (AUC = 0.754; mean cross-validated AUC = 0.754). Quartile analyses showed a more pronounced risk increase in the highest exposure group, and restricted cubic spline analysis suggested an overall positive association with a possible nonlinear trend at higher levels. KEGG analyses highlighted arginine- and amino acid-related pathways, including arginine and proline metabolism and arginine biosynthesis, while network analysis suggested a potential link to mTOR signaling. Conclusion In this exploratory longitudinal analysis, pregnancies complicated by GDM showed progressively increasing amino acid-related metabolic disturbances from early to mid-pregnancy. Mid-pregnancy L-arginine emerged as a candidate metabolic signal associated with GDM risk, post-load glycemia, and greater risk elevation at higher levels. These findings support further investigation of amino acid-focused metabolic profiling as a research-stage approach for earlier GDM risk identification.