2-Aminoadipic acid is a biomarker for diabetes risk
2-Aminoadipic acid is a biomarker for diabetes risk
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DOI：
10.1172/jci64801
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发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Gerszten, Robert E.
中科院分区：
文献类型：
--
作者：
Wang, Thomas J.;Ngo, Debby;Gerszten, Robert E.
代谢物分析技术的改进增加了人类代谢组的覆盖范围，并可能突出糖尿病等常见疾病的生物标志物和途径。我们使用分析中间有机酸、嘌呤、嘧啶和其他化合物的代谢组学平台，对 188 名患有糖尿病的个体和来自 2,422 名血糖正常参与者的 188 名倾向匹配对照进行了一项巢式病例对照研究，在弗雷明汉心脏研究中进行了 12 年的跟踪。代谢物 2-氨基己二酸 (2-AAA) 与患糖尿病的风险密切相关。 2-AAA 浓度位于前四分之一的个体患糖尿病的风险是其四倍以上。 2-AAA 的水平与糖尿病的其他代谢生物标志物（例如支链氨基酸和芳香族氨基酸）没有很好的相关性，这表明它们报告了独特的病理生理学途径。在实验研究中，给予标准食物和高脂肪饮食的小鼠服用 2-AAA 可以降低空腹血糖水平。此外，2-AAA 治疗增强了胰腺 β 细胞系以及小鼠和人类胰岛的胰岛素分泌。这些数据强调了一种以前与糖尿病风险无关的代谢物，该代谢物在明显疾病发作前 12 年就会增加。我们的研究结果表明，2-AAA 是糖尿病风险的标志物，也是人类葡萄糖稳态的潜在调节剂。
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 beta 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.