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

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Long, Tao 
Watrous, Jeramie D 
Mercader, Kysha 


INTRODUCTION: 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 of this study was to examine whether eicosanoids are associated with incident type 2 diabetes. RESEARCH DESIGN & METHODS: In the FINRISK (Finnish Cardiovascular Risk Study) 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=8292). We used multivariable-adjusted Cox regression to examine associations between eicosanoids and incident type 2 diabetes. The significant independent findings were replicated in the Framingham Heart Study (FHS, n=2886) and DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) 2007 (n=3905). Together, these three cohorts had 1070 cases of incident type 2 diabetes. RESULTS: In the FINRISK 2002 cohort, 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 an HR of 1.56 (95% CI 1.41 to 1.72) per 1 SD increment for risk of incident diabetes. The HR for comparing the top quartile with the lowest was 2.80 (95% CI 2.53 to 3.07). In the replication analyses, the three-eicosanoid risk score was significant in FHS (HR 1.24 (95% CI 1.10 to 1.39, p<0.001)) and directionally consistent in DILGOM (HR 1.12 (95% CI 0.99 to 1.27, p=0.07)). Meta-analysis of the three cohorts yielded a pooled HR of 1.31 (95% CI 1.05 to 1.56). CONCLUSIONS: 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.



Genetics/Genomes/Proteomics/Metabolomics, 1506, 1879, eicosanoids, inflammation, diabetes mellitus, type 2, epidemiology

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BMJ Open Diabetes Res Care

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Paavo Nurmi Foundation (N/A)
Emil Aaltonen Foundation (N/A)
Eli Lilly Finland (N/A)
The Future Forum, Astra Zeneca (N/A)
Academy of Finland (141136, 321351, 321356, 46558)
National Institutes of Health (K01DK116917, R01ES027595, S10OD020025)
Social Insurance Institution of Finland (N/A)
Framingham Heart Study (75N92019D00031, HHSN268201500001I, N01-HC-25195)
Aarne Koskelo Foundation (N/A)
Department of Medicine, Boston University School of Medicine (Evans Scholar award and Jay and Louis Coffman Foun)
Finnish Foundation for Cardiovascular Research (N/A)
Finnish Medical Foundation (N/A)