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，与显著增加的死亡率和高发病率有关 并存的疾病。赖氨酸代谢产物α-氨基己二酸(2-aaa)被认为是一种新的预测因子 弗雷明翰心脏研究(FHS)参与者和验证样本(N~2,000)中糖尿病发展的预测。在……里面 在这些受试者中，健康个体血浆中2-AAA的升高与未来发生糖尿病的风险增加相关。 糖尿病(12年随访)，即使在对已知风险因素进行调整后也能识别高危个体。几个 后来的研究证实了2-AAA和糖尿病之间的联系，但其机制仍然存在 未知。初步数据支持2-AAA在胰岛素分泌和糖尿病病理生理中的作用 提示2-AAA的遗传决定因素与糖尿病及糖尿病并发症有关。然而，它还没有 明确2-AAA本身是糖尿病发生的原因，还是代谢改变的生物标记物 流程。关于行动机制，仍然存在许多问题。在这项建议中，我们将研究 通过研究2-AAA极端水平受试者的赖氨酸-2-AAA代谢，研究2-AAA的决定因素 和饮食干预后(目标1)；确定2-AAA的遗传预测因素(目标2)；并检查 2-AAA与疾病的结构(目标3)。这些目标将推动我们的长期研究目标，以 了解2-AAA的决定因素，并建立2-AAA及其相关通路作为一种新的治疗方法的实用性 糖尿病的靶点。

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.