Vitamin D Deficiency Associated Dyslipidemia in Type 2 Diabetes and Changes Following Vitamin D₂ Supplementation

Vitamin D deficiency (VDD) is common in type 2 diabetes mellitus (T2DM) and has been linked to dyslipidemia, but the specific lipids associated with low vitamin D status are not well defined. To address this, we sought to characterize lipidomic alterations associated with VDD in T2DM and describe the changes following vitamin D₂ (VD2) supplementation. Specifically, untargeted serum lipidomics with anthropometric and clinical measurements were performed in 219 adults with T2DM, classified as VDD (25(OH)D < 20ng/mL; n = 138) or non-VDD (25(OH)D ≥ 20ng/mL; n = 81). A subset of VDD participants (n = 20) completed a 3-month VD2 supplementation trial. Lipids were profiled by UHPLC-HRMS and analyzed in relation to metabolic and anthropometric measures. Our analysis identified 112 lipid species differentially expressed in VDD, characterized by reduced ether-linked phosphatidylcholines (EtherPCs) and elevated ceramide 16:0. EtherPCs showed negative correlation with HbA1c, BMI, as well as body fat, and positive associations with muscle mass and bone mineral content, whereas ceramides inversely associated with these metabolic indices. Following 3-month VD2 supplementation, increases in circulating 25(OH)D and reductions in HbA1c were observed, accompanied by changes on the targeted lipidome, including elevated EtherPCs and reduced ceramide profiles (Cer 20:0, Cer 22:0, Cer 16:0/24:0). In conclusion, VDD in T2DM is associated with a distinct lipidomic profile marked by EtherPCs depletion and ceramide accumulation. The observed lipidomic changes following VD2 supplementation suggest the presence of a VD2-responsive lipid signature, which may have potential implications for metabolic risk management in T2DM.