1509-P: Global Metabolomic Profiling and the Pathobiology of Prediabetes and Type 2 Diabetes

Introduction: Metabolomics has provided valuable insights into metabolic alterations associated with diabetes. However, prior studies profiled only a small subset of metabolites that was possible with the contemporaneous technology. We aimed to reassess and extend the current knowledge by implementing comprehensive LC-MS/MS metabolomic analyses. Methods: Untargeted metabolomic analysis was performed using serum samples from people with normal glucose tolerance, prediabetes, and type 2 diabetes (n=30, balanced ORIGINS cohort subset, NCT02226640), at baseline and 2 hours (2h) after an oral glucose tolerance test (OGTT). Differential expression (MetaboAnalyst) and coexpression network (WGCNA) analyses were implemented. Random Forest classification was used to further assess variable importance. Results: A total of 697 known metabolites were detected in more than 80% of the samples. This represents a significant increase in the number of detected circulating metabolites compared to previous studies in diabetes. WGCNA identified modules of correlated metabolites that associated with glucose tolerance at baseline and 2h. The top module for each timepoint was enriched in metabolites that significantly changed in response to the glucose challenge and highlighted an underappreciated role of glyoxylate and dicarboxylate metabolism in early stages of diabetes evolution. Elevation of hexoses and bile acids, and downregulation of amino acids, lipids, and free fatty acids were demonstrated after the glucose challenge. Random forest classification further unveiled the biomarker potential of baseline levels of aminoadipic and methyluric acids. Conclusions: Comprehensive profiling of serum metabolites in humans underscored the role of carbohydrate metabolism, the citric acid and urea cycles, suppression of lipolysis, ketogenesis, and proteolysis in response to a glucose challenge. Potential biomarkers of early diabetes development and progression were identified. Disclosure D.Dubey: None. T.Dutta: None. Y.O.Nunez lopez: None. S.J.Gardell: None. R.E.Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp & Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. Funding AdventHealth Translational Research Institute