Discussion
Through these analyses, we developed a novel integrated biomarker signature composed of LPC 22:6, PC(16:0/20:4), PE(22:6/16:0), Cer(d18:1/24:0)/SM(d18:1/19:0), Cer(d18:1/24:0)/SM(d18:0/16:0), TG(18:1/18:2/18:2), TG(16:0/16:0/20:3), and TG(18:0/16:0/18:2). The area under the curve (AUC) values for this integrated biomarker signature for prediabetes and T2DM patients were 0.841 (cutoff: 0.565) and 0.894 (cutoff: 0.633), respectively. Furthermore, theresults of western blot analysis of frozen adipose tissue from 3 week (prediabetes) and 12 week (T2DM) Goto-Kakizaki (GK) rats also confirmed that acid sphingomyelinase is responsible for significant disruptions in ceramide and sphingomyelin homeostasis. Network analyses of the biomarkers associated with this biosignature suggested that the most profoundly affected lipid metabolism pathways in the context of diabetes include de novo ceramide synthesis, sphingomyelin metabolism, and additional pathways associated with phosphatidylcholine synthesis. Together, these results offer new biological insights regarding the role of serum lipids in the context of insidious T2DM development, and may offer new avenues for future diagnostic and/or therapeutic research.
Methods
Untargeted and targeted lipidomics approaches were used to analyze serum samples from newly diagnosed 93 Chinese participants in discovery cohort and 440 in validation cohort via UHPLC-MS and UHPLC-MS/MS first. The acid sphingomyelinase protein expression was analyzed by Western blot.