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Metabolite profiles and the risk of developing diabetes

Abstract

Emerging technologies allow the high-throughput profiling of metabolic status from a blood specimen (metabolomics). We investigated whether metabolite profiles could predict the development of diabetes. Among 2,422 normoglycemic individuals followed for 12 years, 201 developed diabetes. Amino acids, amines and other polar metabolites were profiled in baseline specimens by liquid chromatography–tandem mass spectrometry (LC-MS). Cases and controls were matched for age, body mass index and fasting glucose. Five branched-chain and aromatic amino acids had highly significant associations with future diabetes: isoleucine, leucine, valine, tyrosine and phenylalanine. A combination of three amino acids predicted future diabetes (with a more than fivefold higher risk for individuals in top quartile). The results were replicated in an independent, prospective cohort. These findings underscore the potential key role of amino acid metabolism early in the pathogenesis of diabetes and suggest that amino acid profiles could aid in diabetes risk assessment.

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Figure 1: Correlation matrix for plasma metabolite levels.

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Acknowledgements

This work was supported by US National Institutes of Health contract NO1-HC-25195, R01-DK-HL081572, the Donald W. Reynolds Foundation, the Leducq Foundation and the American Heart Association. S.C. is also supported by an award from the Ellison Foundation. J.C.F. is also supported by the Massachusetts General Hospital and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation.

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Contributions

T.J.W. conceived of the study, designed the experiments, analyzed and interpreted the data and wrote the manuscript. A.S. and E.P.R., under the direction of C.B.C., developed the metabolic profiling platform, performed mass spectrometry experiments and analyzed the data. S.A.C. and V.K.M. helped in the establishment of the metabolite profiling platform and manuscript revision. G.D.L. contributed to data analysis and manuscript generation. M.G.L., R.S.V., S.C. and E.M. helped in experimental design, performed statistical analyses and assisted in manuscript generation. C.J.O. and C.S.F. helped in experimental design and manuscript revision. P.F.J. directed the dietary analyses in the Framingham Heart Study and contributed to manuscript revision. J.C.F. assisted in the interpretation of the data and contributed to manuscript revision. O.M. and C.F. performed the replication analyses in the Malmö Diet and Cancer cohort and contributed to manuscript revision. R.E.G. conceived of the study, designed the experiments, analyzed and interpreted the data and wrote the manuscript.

Corresponding authors

Correspondence to Thomas J Wang or Robert E Gerszten.

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Competing interests

T.J.W., R.S.V., M.G.L., V.K.M. and R.E.G. are named as co-inventors on a patent application to the US Patent Office pertaining to metabolite predictors of diabetes. J.C.F. has received consulting honoraria from Publicis Healthcare, Merck, bioStrategies, XOMA and Daiichi-Sankyo and has been a paid invited speaker at internal scientific seminars hosted by Pfizer and Alnylam Pharmaceuticals.

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Supplementary Figure 1, Supplementary Tables 1–4 and Supplementary Methods (PDF 121 kb)

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Wang, T., Larson, M., Vasan, R. et al. Metabolite profiles and the risk of developing diabetes. Nat Med 17, 448–453 (2011). https://doi.org/10.1038/nm.2307

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