HDL structural and compositional alterations in type 2 diabetes mellitus patients: identifying potential biomarkers for subclinical atherosclerosis detection and disease progression

Abstract Background Diabetes mellitus (DM) significantly elevates the risk of cardiovascular disease beyond traditional risk factors. High-density lipoprotein (HDL) generally supports atheroprotective roles through its lipid and protein constituents. However, emerging evidence suggests that diabetes may alter HDL’s composition and function. It remains unclear whether qualitative changes in HDL, even when HDL-cholesterol (HDL-C) levels are normal, contribute to subclinical atherosclerosis. Purpose This study aims to investigate the relationship between structural and compositional abnormalities in HDL particles and the presence of subclinical atherosclerosis and disease progression in individuals with type 2 diabetes mellitus (T2DM) who maintain normal HDL-C levels. Methods We conducted a cross-sectional study in T2DM patients (n=75) assessing subclinical atherosclerosis by computed tomography. A control group (n=29) without subclinical atherosclerosis was included. HDL particles were isolated from fasting plasma, and comprehensive lipidomic and proteomic profiles were obtained through high-resolution LC–MS/MS. HDL characterization, including particle size, composition, and subclasses, was performed using 1H-NMR spectroscopy. Results T2DM patients exhibiting subclinical atherosclerosis showed marked alterations in HDL proteome and lipidome. Specifically, ApoE and PON3 levels were lower, and PCSK9 content was higher in T2DM patients vs controls (p