Diabetologia

, Volume 61, Issue 5, pp 1046–1054 | Cite as

Serum metabolomic profile of incident diabetes

  • Casey M. Rebholz
  • Bing Yu
  • Zihe Zheng
  • Patrick Chang
  • Adrienne Tin
  • Anna Köttgen
  • Lynne E. Wagenknecht
  • Josef Coresh
  • Eric Boerwinkle
  • Elizabeth Selvin
Article

Abstract

Aims/hypothesis

Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction.

Methods

We prospectively analysed known metabolites using an untargeted approach in serum specimens from baseline (1987–1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes.

Results

Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35, p = 3.18 × 10−8; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25, p = 1.87 × 10−5), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85, p = 4.19 × 10−8). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735, p = 0.001 for the difference in C statistics).

Conclusions/interpretation

Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes.

Keywords

Amino acids Branched chain amino acids Diabetes Metabolic pathways Metabolomics 

Abbreviations

ARIC

Atherosclerosis Risk in Communities

TCA

Tricarboxylic acid

Notes

Acknowledgements

The authors thank the staff and participants of the ARIC study for their important contributions.

Contribution statement

CMR proposed the study, planned the statistical analysis and wrote the manuscript. EB obtained the metabolomics data. BY, ZZ, PC and AT contributed to the statistical analysis. AK, LEW, JC, EB and ES provided methodological and content-related expertise. All authors provided substantial contributions to the conception and design, acquisition of data, or analysis and interpretation of data; drafted the article or revised it critically for important intellectual content; and provided final approval of the version to be published. CMR is responsible for the integrity of the work as a whole.

Data availability

Selected data elements of the ARIC study are available upon request through the National Health, Lung, and Blood Institute (NHLBI) Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4573_MOESM1_ESM.pdf (113 kb)
ESM Tables (PDF 113 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Casey M. Rebholz
    • 1
    • 2
  • Bing Yu
    • 3
  • Zihe Zheng
    • 1
    • 2
  • Patrick Chang
    • 3
  • Adrienne Tin
    • 1
    • 2
  • Anna Köttgen
    • 1
    • 4
  • Lynne E. Wagenknecht
    • 5
  • Josef Coresh
    • 1
    • 2
  • Eric Boerwinkle
    • 3
  • Elizabeth Selvin
    • 1
    • 2
  1. 1.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  2. 2.Welch Center for Prevention, Epidemiology and Clinical ResearchJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Department of Epidemiology, Human Genetics & Environmental SciencesUniversity of Texas Health Sciences Center at Houston School of Public HealthHoustonUSA
  4. 4.Institute of Genetic Epidemiology, Medical Center and Faculty of MedicineUniversity of FreiburgFreiburgGermany
  5. 5.Division of Public Health SciencesWake Forest School of MedicineWinston-SalemUSA

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