Exploratory Untargeted Serum Lipidomics Identifies Altered Phospholipid and Glycerolipid Features in Established Type 2 Diabetes Mellitus

Background: Type 2 diabetes mellitus (T2DM) is associated with dysregulated lipid metabolism, but the serum lipid species associated with established T2DM may vary across populations and analytical platforms. We conducted an exploratory cross-sectional untargeted lipidomic analysis to characterize serum lipid features differing between adults with established T2DM and control participants. Methods: Serum samples from 36 patients with T2DM and 33 controls were analyzed by ultra-performance liquid chromatography-Orbitrap mass spectrometry. Lipidomic variation was assessed by principal component analysis and hierarchical clustering, followed by univariate analysis of putatively annotated lipid species, covariate-adjusted models, correlation with glycemic and lipid parameters in patients, and internally cross-validated receiver operating characteristic analysis. Results: Several phosphatidylcholine species (PC 38:4, PC 38:5, and PC 40:8) and PE 38:1 were higher in T2DM, whereas PI 36:1, TAG 54:6, and PC 32:2 were lower. These associations persisted after adjustment for age, sex, and body mass index and in participants with comparable reported fasting duration (>8 h but <10 h), but none of the principal species correlated significantly with HbA1c, plasma glucose, triglycerides, non-HDL cholesterol, or the triglyceride-glucose index among patients. A sex-by-disease interaction was supported only for PE 36:1, which was elevated predominantly in female patients. Conclusions: In this exploratory cross-sectional cohort, established T2DM was associated with selective differences in putatively annotated phospholipid and glycerolipid features. These findings do not establish causality, specificity for diabetes relative to broader metabolic dysfunction, or diagnostic utility and require future confirmation in larger longitudinal cohorts with targeted quantification and independent validation.