Plasma Metabolite Associations for Risk and Laboratory Measures of Type 2 Diabetes in a Large-Scale Finnish Prospective Cohort

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Abstract
OBJECTIVE: We aimed to identify plasma metabolites significantly associated with existing type 2 diabetes (T2D), further characterize their associations with T2D-related laboratory measures and lifestyle-related risk factors, and evaluate their potential mediating and predictive roles for incident T2D. RESEARCH DESIGN AND METHODS: We performed metabolomic profiling in 10,163 Finnish men in the Metabolic Syndrome in Men (METSIM) study at baseline. Of these participants, 1,412 had prevalent T2D and 1,234 developed incident T2D during an average follow-up period of 13.6 years. We tested for associations of 979 named metabolites with prevalent T2D. For significant metabolites, we further evaluated their associations with 24 T2D-related laboratory measures of five groups and five T2D lifestyle-related risk factors. We performed an exploratory mediation analysis to examine the mediation effects of metabolites on incident T2D for the five risk factors. We evaluated metabolite associations with incident T2D and built exploratory metabolite predictive models for incident T2D. RESULTS: We identified 193 plasma metabolites significantly associated with prevalent T2D at baseline, including 71 previously unreported. Of these 193 metabolites, 88 were associated with incident T2D. In participants with prevalent T2D, the 193 metabolites showed associations with zero to 24 (mean 10.2) T2D-related laboratory measures. Eighty-one metabolites partially mediated the associations of the five risk factors with T2D onset under standard mediation assumptions. The significant metabolites showed improved predictive ability for future T2D. CONCLUSIONS: This study identifies T2D plasma metabolic biomarkers for further investigation in women and other populations. The findings enhance our understanding of T2D biology.
Funding Information
  • Sigrid Juselius Foundation
  • Jiangsu Professorship
  • Research Council of Finland (no. 321428 (M. L.))
  • American Diabetes Association (Postdoctoral Fellowship 1-19-PDF-061 (X. Y.))
  • Nanjing Medical University (NMUR20230003 (X. Y.))
  • China National Science and Technology Major Project (2025ZD0550702)
  • Clinical Center (R01 DK119380 (X. Q. W.))
  • Clinical Center (R35 GM138121 (X. Q. W.))
  • Clinical Center (U01 DK062370 (M. B.))
  • University of Michigan (Precision Health Scholarship (X. Y.))
  • National Natural Science Foundation of China (X. Y., 82574183)

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