Lipid Subclasses Differentiate Insulin Resistance by Triglyceride–Glucose Index

Background: Insulin resistance is a key driver of metabolic syndrome and related disorders, yet its underlying metabolic alterations remain incompletely understood. The Triglyceride–Glucose (TyG) index is an emerging, accessible marker for insulin resistance, with growing evidence supporting its clinical utility. This study aimed to characterize the metabolic profiles associated with insulin resistance using the TyG index in a large, population-based cohort, and to identify metabolic pathways potentially implicated in insulin resistance. Methods: Here, we conducted a cross-sectional study using data from the Qatar Biobank, including 1255 participants without diabetes classified as insulin-sensitive or insulin-resistant based on TyG index tertiles. Untargeted serum metabolomics profiling was performed using high-resolution mass spectrometry. Our statistical analyses included orthogonal partial least squares discriminate analysis and linear models. Results: Distinct metabolic signatures differentiated insulin-resistant from insulin-sensitive participants. Phosphatidylethanolamines, phosphatidylinositols, and phosphatidylcholines, were strongly associated with insulin resistance, while plasmalogens and sphingomyelins were consistently linked to insulin sensitivity. Conclusions: Lipid-centric pathways emerge as potential biomarkers and therapeutic targets for the early detection and personalized management of insulin resistance and related metabolic disorders. Longitudinal studies are warranted to validate causal relationships.