AbstractBackgroundThe lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear.ObjectiveTo identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980).MethodsLinear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48,p < 0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590).ResultsIn GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjustedp-valuesranging from 4.59 × 10^{− 161}to 49.50 × 10^{− 3}). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (β = 0.025,p = 4.52 × 10^{− 71}and β = 0.021,p = 5.84 × 10^{− 41}, respectively) and factor 2 (phospholipids/non-storage lipids) was inversely (β = − 0.013,p = 2.28 × 10^{− 18}) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (β = 0.10,p = 1.21 × 10^{− 02}for storage, β = − 0.13,p = 3.14 × 10^{− 04}for non-storage, and β = 0.19,p = 8.40 × 10^{− 07}for mixed lipids).ConclusionsNon-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.