Abstract MP31: Association of Eicosanoid Metabolites with Insulin Resistance

Introduction: Eicosanoids are bioactive lipids that govern upstream initiation of inflammation. Their role in the development of cardiometabolic disease including insulin resistance remains unclear. Objective: We sought to investigate the association of specific pro- and anti-inflammatory eicosanoid metabolites with insulin resistance in the community. Methods: We ascertained eicosanoid metabolites among Framingham Heart Study (FHS) offspring cohort participants using a directed, non-targeted mass spectrometry-based platform, and examined associations with insulin resistance (HOMA-IR) using multivariable linear regression after excluding individuals with diabetes. Statistical significance was determined at a false discovery rate (FDR) q-value <0.01. Results: We studied 2055 individuals (65 ± 9 years; 58% women, HOMA-IR 3.3 ± 1.9 mg*μU/dL*mL). Of 650 eicosanoids analyzed, 76 showed significant associations with HOMA-IR (Figure for putative metabolite identities). Top hits associated with higher HOMA-IR included prostaglandins (15-epi-PGA1, β = 0.18, SE = 0.02), arachidonic acid derivatives (5S-HpETE, β = 0.14, SE = 0.02), and epoxides (12,13 EpOME, β = 0.12, SE = 0.02) with known pro-inflammatory actions. By contrast, top hits associated with lower HOMA-IR included docosahexaenoic derivatives (resolvins) and oxylipins (10,11-DiHDPA, β = -0.11, SE = 0.02), known to have anti-inflammatory actions. Conclusions: We identified 76 eicosanoid metabolites associated with HOMA-IR. Of these, 51 were linked with higher HOMA-IR including epoxides and arachidonic acid derivatives known to be pro-inflammatory, while 25 eicosanoids were associated with lower HOMA-IR including resolvins and oxylipids with known anti-inflammatory properties. These findings highlight bioactive lipids that may underlie adverse cardiometabolic consequences of insulin resistance.