Serum metabolomic profile of incident diabetes

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

Research output: Contribution to journalArticle


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.

Original languageEnglish (US)
Pages (from-to)1046-1054
Number of pages9
Issue number5
StatePublished - May 1 2018



  • Amino acids
  • Branched chain amino acids
  • Diabetes
  • Metabolic pathways
  • Metabolomics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rebholz, C., Yu, B., Zheng, Z., Chang, P., Tin, A., Köttgen, A., Wagenknecht, L. E., Coresh, J., Boerwinkle, E., & Selvin, E. (2018). Serum metabolomic profile of incident diabetes. Diabetologia, 61(5), 1046-1054.