Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39–1.95], P = 8.46 × 10⁻⁹) and was moderately heritable (h² = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 × 10⁻⁶) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 × 10⁻³). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.Currently, stratification of individuals at risk for type 2 diabetes (T2D) within the general population is based on well-established factors such as age, BMI, and fasting glucose (1). Although these factors contribute considerably to disease risk, they may not identify at-risk individuals before the disease process is well under way.Recently, a number of studies have found several metabolites to be correlated with insulin resistance and T2D (2–6), and T2D-associated metabolic profiles have been identified 10–15 years before the diagnosis/onset of the disease (7–9). To help preventive strategies, and maximize the potential for existing effective interventions, it is important to characterize the molecular changes that take place in the development of T2D.We aim to understand other biochemical changes, in addition to hyperglycemia, that take place at the onset of T2D using the largest metabolomic screening approach to date. We assessed >400 metabolites to determine which metabolomic profiles are correlated with T2D and impaired fasting glucose (IFG) in a large cohort of females from TwinsUK with independent replication.