Lipid Subclasses Differentiate Insulin Resistance by Triglyceride-Glucose Index

Abstract

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.

Keywords: glycerophospholipids; metabolomics; plasmalogens; sphingomyelins.

Figure 1

The OPLS-DA score (A) and loading plots (B) between the insulin-resistant (IS) and insulin-sensitive (TyG-low) groups across all participants (n = 1255). R2Y = 76.2%; Q2 = 72.1%. The metabolites in color are the key discriminators, while the less influential metabolites are shown in gray to reduce visual noise.

Figure 2

The metabolites significantly associated with insulin sensitivity (FDR < 0.001) from the enriched pathways. The dots and bars represent the means and the 95% confidence intervals of the normalized metabolite values.

Figure 3

A correlation heatmap showing Spearman’s correlation between the significant metabolites associated with insulin sensitivity and clinical parameters. The size of the circles within each cell corresponds to the magnitude of Spearman’s correlation coefficient. The color intensity in each cell represents the strength and direction of the correlation between a specific metabolite and a clinical trait. (*/**/*** denote a p-value <0.05/<0.01/<0.001).