Metabolomic Profiling of Gestational Diabetes Mellitus and Its Subtypes Among Chinese Pregnant Women

Background: This study aimed to explore first-trimester metabolic profiles associated with gestational diabetes mellitus (GDM) and its glycemic subtypes. Methods: This nested case–control study included 90 women with GDM, comprising 30 with isolated fasting hyperglycemia (IFH), 30 with isolated post-load hyperglycemia (IPH), and 30 with combined hyperglycemia (CH), together with 30 women with normal glucose tolerance (NGT). Untargeted UHPLC-MS metabolomic profiling was performed on fasting plasma samples collected during the first trimester. Exploratory metabolic features were compared between GDM or its subtypes and NGT, and Spearman correlation analyses were performed to examine associations between candidate metabolic features and maternal fasting blood glucose (FBG), BMI, thyroid-related parameters, parity, education, and gestational weight gain. Exploratory pathway analyses were conducted to characterize potentially related metabolic processes. Results: At the exploratory threshold of VIP > 1 and nominal p < 0.05, 107 candidate metabolic features were observed in the GDM vs. NGT comparison, with 89, 76, and 123 candidate features observed in the IFH vs. NGT, IPH vs. NGT, and CH vs. NGT comparisons, respectively. These candidate features were mainly annotated as organoheterocyclic compounds and lipids and lipid-like molecules, with differences in chemical-class distributions across subtype comparisons. Organosulfur-related annotations were observed among the IFH candidate features, whereas alkaloid-related annotations were observed among the CH candidate features. No individual feature remained statistically significant after multiple-testing correction. Correlation analyses identified FDR-adjusted associations between selected candidate metabolic features and maternal FBG, BMI, and thyroid-related parameters. Exploratory pathway mapping highlighted processes related to lipid, amino acid, carbohydrate, and nucleotide metabolism. Conclusions: This exploratory study suggests that first-trimester plasma metabolic patterns may differ among women who subsequently develop different glycemic subtypes of GDM. The observed candidate features, clinical correlations, and pathway-level patterns provide hypotheses regarding metabolic heterogeneity in GDM but should not be considered validated biomarkers or subtype-specific metabolic signatures. Further studies using targeted metabolomics and larger independent cohorts are needed to confirm these observations.