Metabolite Triplet in Serum Improves the Diagnostic Accuracy of Prediabetes and Diabetes Screening

Large-scale population screenings are not feasible by applying laborious oral glucose tolerance tests, but using fasting blood glucose (FPG) and glycated hemoglobin (HbA1c), a considerable number of diagnoses are missed. A novel marker is urgently needed to improve the diagnostic accuracy of broad-scale diabetes screening in easy-to-collect blood samples. In this study, by applying a novel knowledge-based, multistage discovery and validation strategy, we scaled down from 108 diabetes-associated metabolites to a diagnostic metabolite triplet (Met-T), namely hexose, 2-hydroxybutyric/2-hydroxyisobutyric acid, and phenylalanine. Met-T showed in two independent cohorts, each comprising healthy controls, prediabetic, and diabetic individuals, distinctly higher diagnostic sensitivities for diabetes screening than FPG alone (>79.6 vs 32% using fasting plasma glucose down to