Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.
Thomas J. Wang, Debby Ngo, Nikolaos Psychogios, Andre Dejam, Martin G. Larson, Ramachandran S. Vasan, Anahita Ghorbani, John O’Sullivan, Susan Cheng, Eugene P. Rhee, Sumita Sinha, Elizabeth McCabe, Caroline S. Fox, Christopher J. O’Donnell, Jennifer E. Ho, Jose C. Florez, Martin Magnusson, Kerry A. Pierce, Amanda L. Souza, Yi Yu, Christian Carter, Peter E. Light, Olle Melander, Clary B. Clish, Robert E. Gerszten
Fasting plasma glucose levels were measured weekly in mice fed either SCD (left) or HFD (right) beginning at 6 weeks of age, with simultaneous 2-AAA treatment via drinking water (500/mg/kg/d) or water alone for the subsequent 5 weeks (