Determinants of alpha-aminoadipic acid (2-AAA) and relationship to diabetes

糖尿病是一个主要的全球健康问题，与死亡率显著增加和高发病率相关 合并症赖氨酸衍生的代谢产物α-氨基己二酸（2-AAA）被确定为一种新的预测因子 FHS参与者和验证样本（N~ 2，000）中糖尿病发展的风险。在 在这些受试者中，健康个体血浆2-AAA水平升高与未来糖尿病风险增加相关。 糖尿病（12年随访），即使在调整已知的风险因素后，也能识别出风险个体。几 随后的研究证实了2-AAA和糖尿病之间的联系，但机制仍然存在 未知初步数据支持2-AAA在胰岛素分泌和糖尿病病理生理学中的作用， 提示2-AAA遗传决定因素与糖尿病和糖尿病并发症有关。然而， 明确2-AAA本身是否是糖尿病发展的原因，或者是代谢改变的生物标志物 流程.在作用机制方面仍有许多问题。在本建议中，我们将研究 决定因素2-AAA，通过研究赖氨酸-2-AAA代谢的受试者与极端水平的2-AAA之前， 和饮食干预后（目标1）;确定2-AAA的遗传预测因子（目标2）;并检查遗传 2-AAA的结构和疾病（目的3）。这些目标将推进我们的长期研究目标， 了解2-AAA的决定因素，并建立2-AAA和相关途径作为一种新的治疗方法的效用 糖尿病的目标。

Diabetes is a major global health concern, associated with significantly increased mortality and high incidence of co-morbidities. The lysine-derived metabolite α-aminoadipic acid (2-AAA) was identified as a novel predictor of diabetes development in Framingham Heart Study (FHS) participants and validation samples (N~2,000). In these subjects, increased plasma 2-AAA in healthy individuals was associated with increased future risk of diabetes (12-year follow-up), identifying at-risk individuals even after adjustment for known risk factors. Several subsequent studies have confirmed the association between 2-AAA and diabetes, but the mechanisms remain unknown. Preliminary data support a role for 2-AAA in insulin secretion and diabetes pathophysiology, and suggest genetic determinants of 2-AAA relate to diabetes and diabetic complications. However it is not yet clear whether 2-AAA is itself causal in diabetes development, or is a biomarker for altered metabolic processes. Many questions remain as to mechanisms of action. In this proposal, we will examine the determinants of 2-AAA, by studying lysine-2-AAA metabolism in subjects with extreme levels of 2-AAA before and after dietary intervention (Aim 1); identify the genetic predictors of 2-AAA (Aim 2); and examine the genetic architecture of 2-AAA and disease (Aim 3). These aims will advance our long-term research objective, to understand determinants of 2-AAA, and establish utility of 2-AAA and related pathways as a novel therapeutic target in diabetes.