2-Aminoadipic acid is a biomarker for diabetes risk

Abstract

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.

Metabolomic profiles as reliable biomarkers of dietary composition

“…We analyzed samples in random order and interspersed replicates of common pooled plasma samples as controls to allow normalization as has been done in prior studies (30)(31)(32).…”

“…These data were obtained through the National Center for Biotechnology Information Genotypes and Phenotypes database with accession number phs000007.v19.p7. Both the study samples and the data collection procedures have been previously described in detail (30)(31)(32). Briefly, the metabolite profiling data consist of measurements for 217 metabolites generated from LC-MS profiling of fasting plasma samples.…”

“…For each diet, we examined the direction of change in the concentrations of the metabolites that have been shown to predict the risk of type 2 diabetes (31,32,(38)(39)(40)(41)(42). We annotated each metabolite by whether the change by diet was in the direction that increased or decreased risk of disease.…”

“…Multiple metabolites that have been linked to risk of type 2 diabetes (31,32,(38)(39)(40)(41)(42) showed strong or moderate associations with diet, including amino acids (isoleucine, leucine, valine, tyrosine, serine and glutamine), lipids (C18:2 lysophosphatidylethanolamine (LPE), C22:6 LPE, C56:9 TAG, C58:10 TAG, and C60:12 TAG), and others (2-aminoadipate, betaine, and C3 carnitine) as depicted in Supplemental Figures 5 and 6. The concordance between the metabolite profile that predicts type 2 diabetes risk and the dietassociated changes varied across classes of metabolites.…”

Chemical Isotope Labeling LC-MS for Monitoring Disease Progression and Treatment in Animal Models: Plasma Metabolomics Study of Osteoarthritis Rat Model

“…Direct analysis of 2-AAA, instead of analyzing oxidized proteins, has been used to determine 2-AAA as a biomarker for autoimmunity and age-associated changes in human collagen46. 2-AAA was reported to a biomarker for diabetes risk and a potential modulator of glucose homeostasis in humans47. In a study of the dietary effect on long-term health including diabetes risk, 2-AAA was measured in human plasma along with several other metabolites and found to be 1.6 times higher after the beef meal than after the baked herring meal48.…”