Abstract
BackgroundThe 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-adjusted p-values ranging 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.
Highlights
Dyslipidemia, one of the major determinants of cardiovascular disease (CVD) [1], is defined by elevated circulating triglycerides and decreased high-density lipoprotein (HDL) cholesterol [2]
In combination with small dense low-density lipoprotein (LDL) particles, these lipid abnormalities contribute to the insulinresistant metabolic syndrome [2, 3], a major risk factor for type 2 diabetes (T2D)
The level of fasting glucose, fasting insulin and homeostatic model assessment-insulin resistance (IR) (HOMA-IR) increased by lipoprotein insulin resistance (LPIR) quintile category
Summary
Dyslipidemia, one of the major determinants of cardiovascular disease (CVD) [1], is defined by elevated circulating triglycerides and decreased high-density lipoprotein (HDL) cholesterol [2]. The LPIR score is a novel composite metabolomic index, developed to capture the effect of IR on six lipoprotein quantities in a single algorithm [7, 8] This score, derived from nuclear magnetic resonance (NMR) measurements, captures the accumulation of triglyceriderich, very low-density lipoprotein particles (VLDL-P), and the consequent increase in small LDL particles (LDL-P) and reduction in large HDL particles (HDL-P) [10]. It reflects insulin-resistant dyslipoproteinemia with more precision compared to traditional lipid measures and provides stronger evidence for its association with IR than each of its individual components alone [8]. The molecular basis underlying the LPIR utility for classification remains unclear
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