Untargeted metabolomic profiling identifies serum metabolites associated with type 2 diabetes in a cross-sectional study of the Alpha-Tocopherol, Beta- Carotene Cancer Prevention (ATBC) Study

Type 2 diabetes (T2D) is a complex chronic disease with substantial phenotypic heterogeneity affecting millions of individuals. Yet, its relevant metabolites and etiological pathways are not fully understood. The aim of this study is to assess a broad spec-trum of metabolites related to T2D in a large population-based cohort. We conducted a metabolomic analysis of 4,281 male par-ticipants within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The serum metabolomic analysis was performed using an LC-MS/GC-MS platform. Associations between 1,413 metabolites and T2D were examined using linear regression, controlling for important baseline risk factors. Standardized b-coefficients and standard errors (SEs) were computed to estimate the difference in metabolite concentrations. We identified 74 metabolites that were significantly associated with T2D based on the Bonferroni-corrected threshold (P < 3.5 x 10-5). The strongest signals associated with T2D were of carbohydrates origin, including glucose, 1,5-anhydroglucitol (1,5-AG), and mannose (b = 0.34, -0.91, and 0.41, respectively; all P < 10-75). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates (P = 1.3 x 10-11), amino acids (P = 2.7 x 10-6), energy (P = 1.5 x 10-4), and xenobiotics (P = 1.2 x 10-3). The strongest subpathway associations were seen for fructose-mannose-galactose metabolism, glycolysis-gluconeogenesis-pyruvate metabolism, fatty acid metabolism (acyl choline), and leucine-isoleucine-valine metabolism (all P < 10-8). Our findings identified various metabolites and candidate chemical class pathways that can be characterized by glycolysis and gluconeogenesis metabolism, fructose-mannose-galactose metabolism, branched-chain amino acids, diacylglycerol, acyl cholines, fatty acid oxidation, and mitochondrial dysfunction. NEW & NOTEWORTHY These metabolomic patterns may provide new additional evidence and potential insights relevant to the molecular basis of insulin resistance and the etiology of T2D.