A plasma metabolite score of three eicosanoids predicts incident type 2 diabetes – a prospective study in three independent cohorts

Abstract

Aim Peptide markers of inflammation have been associated with the development of type 2 diabetes. The role of upstream, lipid-derived mediators of inflammation such as eicosanoids, remains less clear. The aim was to examine whether eicosanoids are associated with incident type 2 diabetes. Methods In the FINRISK 2002 study, a population-based sample of Finnish men and women aged 25-74 years, we used directed, non-targeted liquid chromatography - mass spectrometry to identify 545 eicosanoids and related oxylipins in the participants' plasma samples (n=8,292). We used multivariable-adjusted Cox regression to examine associations between eicosanoids and incident type 2 diabetes. The findings were replicated in the Framingham Heart Study (FHS, n=2,886) and DILGOM 2007 (n=3,905). Together, these three cohorts had 1070 cases of incident type 2 diabetes. Results 76 eicosanoids were associated individually with incident type 2 diabetes. We identified three eicosanoids independently associated with incident type 2 diabetes using stepwise Cox regression with forward selection and a Bonferroni-corrected inclusion threshold. A three-eicosanoid risk score produced a hazard ratio (HR) of 1.56 (95% confidence interval 1.41-1.72) per one standard deviation (SD) increment for risk of incident diabetes. The HR for comparing the top quartile to the lowest was 2.80 (2.53-3.07). Meta-analysis of the three cohorts yielded a pooled HR per SD of 1.31 (1.05-1.56). Conclusion Plasma eicosanoid profiles predict incident type 2 diabetes and the clearest signals replicate in three independent cohorts. Our findings give new information on the biology underlying type 2 diabetes and suggest opportunities for early identification of people at risk.

Eicosanoid and Eicosanoid-Related Inflammatory Mediators and Exercise Intolerance in Heart Failure with Preserved Ejection Fraction

“…17 Early investigations of eicosanoids and related metabolites leveraging MS-based approaches have demonstrated strong associations between plasma eicosanoids with blood pressure and DM, both clinical precursors to HFpEF. 18,19 In this context, we performed large-scale comprehensive pro ling of >500 pro-and anti-in ammatory eicosanoid and eicosanoid-related metabolites using liquid chromatography-MS (LC-MS) to better understand upstream in ammatory mediators as determinants of HFpEF. We leveraged a hospital-based cohort of individuals who underwent detailed physiologic phenotyping with invasive cardiopulmonary exercise testing to examine eicosanoid pro les of HFpEF and gain a deeper understanding of speci c exercise manifestations of HFpEF across organ systems.…”