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

Karolina Tuomisto; Joonatan Palmu; Tao Long; Jeramie D Watrous; Kysha Mercader; Kim A Lagerborg; Allen Andres; Marko Salmi; Sirpa Jalkanen; Ramachandran S Vasan; Michael Inouye; Aki S Havulinna; Jaakko Tuomilehto; Pekka Jousilahti; Teemu J Niiranen; Susan Cheng; Mohit Jain; Veikko Salomaa

doi:10.1136/bmjdrc-2021-002519

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

BMJ Open Diabetes Res Care. 2022 Mar;10(2):e002519. doi: 10.1136/bmjdrc-2021-002519.

Authors

Karolina Tuomisto^{1

2}, Joonatan Palmu^{2

3}, Tao Long⁴, Jeramie D Watrous⁴, Kysha Mercader⁴, Kim A Lagerborg⁴, Allen Andres⁴, Marko Salmi⁵, Sirpa Jalkanen⁵, Ramachandran S Vasan^{6

7}, Michael Inouye^{8

9}, Aki S Havulinna^{2

10}, Jaakko Tuomilehto^{11

2}, Pekka Jousilahti², Teemu J Niiranen^{2

3}, Susan Cheng¹², Mohit Jain⁴, Veikko Salomaa²

Affiliations

¹ Department of Public Health, University of Helsinki, Helsinki, Finland karolina.tuomisto@helsinki.fi.
² Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
³ Department of Internal Medicine, University of Turku, Turku, Finland.
⁴ Departments of Medicine and Pharmacology, University of California San Diego, La Jolla, California, USA.
⁵ MediCity, InFLAMES Flagship, and Institute of Biomedicine, University of Turku, Turku, Finland.
⁶ Boston University's and National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.
⁷ Sections of Preventive Medicine and Epidemiology, and Cardiovascular Medicine, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
⁸ Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁹ Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
¹⁰ University of Helsinki Institute for Molecular Medicine Finland, Helsinki, Finland.
¹¹ Department of Public Health, University of Helsinki, Helsinki, Finland.
¹² Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Abstract

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.

Keywords: diabetes mellitus, type 2; eicosanoids; epidemiology; inflammation.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Diabetes Mellitus, Type 2* / complications
Eicosanoids
Female
Humans
Male
Metabolic Syndrome*
Middle Aged
Prospective Studies
Risk Factors

Substances

Eicosanoids

Abstract

Publication types

MeSH terms

Substances

Grants and funding