Purine metabolites and carnitine biosynthesis intermediates are biomarkers for incident type 2 diabetes

Abstract

Context: Metabolomics has the potential to generate biomarkers that can facilitate understanding relevant pathways in the pathophysiology of type 2 diabetes (T2DM). Methods: Nontargeted metabolomics was performed, via liquid chromatography–mass spectrometry, in a discovery case-cohort study from the Malmö Preventive Project (MPP), which consisted of 698 metabolically healthy participants, of whom 202 developed T2DM within a follow-up time of 6.3 years. Metabolites that were significantly associated with T2DM were replicated in the population-based Malmö Diet and Cancer–Cardiovascular Cohort (MDC-CC) (N 5 3423), of whom 402 participants developed T2DM within a follow-up time of 18.2 years. Results: Using nontargeted metabolomics, we observed alterations in nine metabolite classes to be related to incident T2DM, including 11 identified metabolites. N2,N2-dimethylguanosine (DMGU) (OR 5 1.94; P 5 4.9e-10; 95% CI, 1.57 to 2.39) was the metabolite most strongly associated with an increased risk, and beta-carotene (OR 5 0.60; P 5 1.8e-4; 95% CI, 0.45 to 0.78) was the metabolite most strongly associated with a decreased risk. Identified T2DM-associated metabolites were replicated in MDC-CC. Four metabolites were significantly associated with incident T2DM in both the MPP and the replication cohort MDC-CC, after adjustments for traditional diabetes risk factors. These included associations between three metabolites, DMGU, 7-methylguanine (7MG), and 3-hydroxytrimethyllysine (HTML), and incident T2DM. Conclusions: We used nontargeted metabolomics in two Swedish prospective cohorts comprising .4000 study participants and identified independent, replicable associations between three metabolites, DMGU, 7MG, and HTML, and future risk of T2DM. These findings warrant additional studies to investigate a potential functional connection between these metabolites and the onset of T2DM. (J Clin Endocrinol Metab 104: 4921–4930, 2019).