Integrated proteomic characterization of maternal blood, umbilical cord blood and placental tissue in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is associated with adverse maternal and neonatal outcomes, but molecular alterations across the maternal-placental-fetal interface remain incompletely defined. We applied data-independent acquisition mass spectrometry to matched maternal blood (MB), umbilical cord blood (UCB) and placental tissue collected at delivery from 28 women with GDM and 21 controls. Differential protein abundance analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, gene set enrichment analysis, weighted co-expression network analysis and pathway-level corroboration using two independent public placental transcriptomic cohorts were performed. Proteomic changes were compartment specific. Placental tissue showed the greatest number of differentially abundant proteins, whereas maternal blood and umbilical cord blood showed more limited alterations. Exploratory pathway-level analyses in MB suggested metabolic stress- and extracellular matrix-related patterns, whereas UCB suggested immune- and coagulation-related patterns. Placental tissue showed more prominent alterations involving extracellular matrix remodeling and ribosome-related pathways. A GDM-associated placental co-expression module contained both extracellular matrix proteins and ribosomal proteins. Independent transcriptomic datasets provided additional pathway-level support for ribosome-related and inflammatory processes. These findings suggest that GDM is associated with distinct proteomic changes in maternal blood, umbilical cord blood and placental tissue at delivery, with the most prominent alterations involving placental extracellular matrix remodeling and ribosome-related processes. SIGNIFICANCE: This matched multi-compartment proteomic study provides a placenta-centered view of GDM-associated molecular alterations at delivery. By integrating DIA proteomics, co-expression network analysis and pathway-level corroboration using independent transcriptomic datasets, the study identifies placental extracellular matrix remodeling and ribosome-related processes, while exploratory analyses of UCB suggest immune- and coagulation-related pathway patterns. These findings provide a basis for future hypothesis-driven studies of GDM-related placental dysfunction.