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 spectrum of metabolites related to T2D in a large population-based cohort. We conducted a metabolomic analysis of 4,281 male participants 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 β-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 ( < 3.5 × 10 ). The strongest signals associated with T2D were of carbohydrates origin, including glucose, 1,5-anhydroglucitol (1,5-AG), and mannose (β = 0.34, -0.91, and 0.41, respectively; all < 10 ). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates ( = 1.3 × 10 ), amino acids ( = 2.7 × 10 ), energy ( = 1.5 × 10 ), and xenobiotics ( = 1.2 × 10 ). 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 < 10 ). 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. These metabolomic patterns may provide new additional evidence and potential insights relevant to the molecular basis of insulin resistance and the etiology of T2D.