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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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.

Author information


  1. Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Thomas J Wang
    • , Eugene P Rhee
    • , Gregory D Lewis
    •  & Robert E Gerszten
  2. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Thomas J Wang
    • , Susan Cheng
    • , Elizabeth McCabe
    • , Gregory D Lewis
    • , Christopher J O'Donnell
    •  & Robert E Gerszten
  3. Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University School of Medicine, Framingham, Massachusetts, USA.

    • Thomas J Wang
    • , Martin G Larson
    • , Ramachandran S Vasan
    • , Susan Cheng
    • , Elizabeth McCabe
    • , Caroline S Fox
    •  & Christopher J O'Donnell
  4. Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.

    • Martin G Larson
  5. Cardiology Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Ramachandran S Vasan
  6. Division of Cardiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Susan Cheng
  7. Renal Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Eugene P Rhee
  8. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Eugene P Rhee
    • , Gregory D Lewis
    • , Christopher J O'Donnell
    • , Stephen A Carr
    • , Vamsi K Mootha
    • , Jose C Florez
    • , Amanda Souza
    • , Clary B Clish
    •  & Robert E Gerszten
  9. Division of Endocrinology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Caroline S Fox
  10. National Heart, Lung, and Blood Institute, Division of Intramural Research, Bethesda, Maryland, USA.

    • Caroline S Fox
  11. Jean Mayer US Department of Agriculture Human Nutrition Research Center, Tufts University, Boston, Massachusetts, USA.

    • Paul F Jacques
  12. Department of Experimental Medical Science, Lund University, Malmö, Sweden.

    • Céline Fernandez
  13. Diabetes Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Vamsi K Mootha
    •  & Jose C Florez
  14. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Vamsi K Mootha
  15. Department of Clinical Sciences, Lund University, Malmö, Sweden.

    • Olle Melander


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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.

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.

Corresponding authors

Correspondence to Thomas J Wang or Robert E Gerszten.

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