Untargeted Metabolomic Profiling Identifies Serum Metabolites Associated with Type 2 Diabetes in a Cross-Sectional Study of the 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 (SE) 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 × 10-5). 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 P <10-75). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates (P=1.3 × 10-11), amino acids (P=2.7 × 10-6), energy (P=1.5 × 10-4) and xenobiotics (P=1.2 × 10-3). The strongest sub-pathway 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.