Discovery Metabolomics across a Population Scale Study Identifies a Community of Glycerolipids Associated with Incident Type 2 Diabetes

It is well appreciated that changes in metabolic pathways precede the development of overt type 2 diabetes (T2D), but a systematic and unbiased evaluation of such metabolic changes is lacking. Here, we applied a novel high-throughput untargeted liquid chromatography-mass spectrometry (LC-MS) method to the FINRISK 2002 cohort (n=8014) to identify plasma metabolite predictors of incident T2D. We analyzed LC-MS data consisting of 14,615 metabolite features from individuals without prevalent T2D to discover 171 that predicted T2D incidence at a threshold of P<10-6 (Cox regression). To identify discrete molecular pathways, we performed Gaussian graphical modeling to create a network of all detected metabolite features finding that the T2D predictor metabolites were enriched in 11 distinct metabolite communities containing between 6 and 48 interconnected metabolites. Here we highlight one community consisting of 26 plasma diacylglycerols (DAGs) and closely related metabolites. One member of this community, a DAG with carbon:unsaturated bond sum composition of 36:4, predicted T2D incidence (HR = 1.22, p = 7.6×10-10) independently of insulin, glucose and HbA1c, but not 2-hour glucose as measured by OGTT. Thus, this metabolite is a novel predictor of incident T2D that can capture the metabolic dysregulation identifiable by OGTT. In summary, we have identified multiple communities of T2D metabolite biomarkers, representative of distinct pathways that are dysregulated preceding T2D, with potentially clinical useful properties. Disclosure A. Begzati: None. K. P. Godinez Macias: None. J. Watrous: None. T. Long: None. E. Kantz: None. J. Tuomilehto: Stock/Shareholder; Orion pharma. A. S. Havulinna: None. T. Niiranen: Speaker's Bureau; AstraZeneca, Servier Laboratories. P. Jousilahti: None. V. Salomaa: Research Support; Bayer Inc. T. Ideker: None. M. Jain: Employee; Sapient Bioanalytics. A. R. Majithia: None. Funding National Institutes of Health (5R01DK129840-02)