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.