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

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.

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).

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.