The role of alpha-aminoadipic acid (2-AAA) in residual CVD risk in T2D

α-氨基己二酸 (2-AAA) 在 T2D 残余 CVD 风险中的作用

• 批准号: 10713291
• 负责人: Jane F Ferguson
• 金额: $ 13.13万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713291
• 关键词: Acids; Address; Affect; Aftercare; Animal Model; Atherosclerosis; Attenuated; Biological Markers; Blood; Blood Glucose; Cardiovascular Diseases; Cell model; Cholesterol; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Outcome; Disease Progression; Event; Fenofibrate; Functional disorder; Future; Glucose; Heart Diseases; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Hyperinsulinism; Hypertriglyceridemia; Hypoglycemia; Individual; Insulin; Kidney Diseases; Knowledge; Learning; Lipids; Measures; Mediator; Modeling; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Participant; Persons; Pharmaceutical Preparations; Plasma; Population; Residual state; Retinal Diseases; Risk; Risk Factors; Role; Sampling; Simvastatin; Stroke; Triglycerides; cardiovascular disorder risk; cardiovascular risk factor; data resource; disorder risk; effective therapy; experience; follow-up; high risk; improved; insulin secretion; mitochondrial metabolism; mortality; new therapeutic target; novel; optimal treatments; response; secondary outcome; targeted treatment; treatment arm

PROJECT SUMMARY / ABSTRACT Cardiovascular disease (CVD) kills 1 in 3 individuals and affects >2 in 3 individuals diagnosed with type 2 diabetes (T2D). Despite optimization of available therapies, CVD remains the leading cause of mortality in T2D, highlighting the considerable burden of residual risk. Achieving further reduction in CVD morbidity and mortality in people with T2D requires advancing promising candidate mediators of residual risk. The metabolite α-aminoadipic acid (2-AAA) predicts the development of both T2D and atherosclerosis, independent of other known risk factors. This may represent a novel independent risk mechanism for the development of CVD, particularly among individuals with T2D. Our overarching hypothesis is that 2-AAA is an independent mediator of CVD risk among individuals with T2D. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, both intensive glucose-lowering therapy, and intensive lipid management failed to attenuate CVD risk in individuals with T2D, and indeed showed evidence of increased risk. We hypothesize this was, in part, due to residual risk factors, including 2-AAA. We propose an analysis of 2-AAA in existing plasma samples from N=1,757 participants of the ACCORD study lipid treatment arms, with the following aims: 1) Define the effects of lipid- and glucose-lowering therapies on plasma 2-AAA, and address whether plasma 2-AAA changes in response to lipid-targeted therapy or intensive glycemic management. 2) Address the hypothesis that plasma 2-AAA is a CVD risk mechanism among individuals who experienced events despite optimal therapy. Successful completion of the aims will determine whether 2-AAA levels are impacted by lipid and glycemic management in T2D and establish whether elevated 2-AAA associates with CVD risk. This will provide important information on the utility of 2-AAA as a biomarker of risk and plausibility as a novel therapeutic target, allowing us to refine specific hypotheses to be probed in future studies. These aims represent novel and important questions and use existing NHLBI-supported sample and data resources to add considerable scientific value and address a key knowledge gap.

项目摘要/摘要 心血管疾病(CVD)导致三分之一的人死亡，并影响3名确诊为2型的人中的2人。 糖尿病(T2D)。尽管优化了现有的治疗方法，但心血管疾病仍然是#年死亡的主要原因。 T2D，突显了剩余风险的相当大负担。实现进一步降低心血管疾病发病率和 T2D患者的死亡率需要提出有前途的残余风险的候选介体。代谢物 α-氨基己二酸(2-AAA)可独立于其他疾病预测T2D和动脉粥样硬化的发展 已知的风险因素。这可能代表了一种新的独立的心血管疾病发展风险机制， 尤其是在患有T2D的个体中。我们的主要假设是2-AAA是一种独立的调节剂。 在患有T2D的个体中心血管疾病的风险。控制糖尿病心血管风险的行动(ACCORD) 试验中，强化降糖治疗和强化血脂管理都未能降低心血管疾病的风险 患有T2D的个体，确实显示出风险增加的证据。我们假设这在一定程度上是由于 残余危险因素，包括2-AAA。我们建议对现有血浆样品中的2-AAA进行分析， N=1,757名ACCORD研究脂质治疗武器的参与者，目的如下：1)确定影响 降脂降糖治疗对血浆2-AAA的影响，并探讨血浆2-AAA是否在 对脂类靶向治疗或强化血糖治疗的反应。2)解决了血浆 2-AAA是一种心血管疾病的风险机制，在经历过事件的个人中，尽管有最佳的治疗方案。 AIMS的成功完成将决定2-AAA水平是否受到血脂和血糖的影响 T2D的管理，并确定2-AAA升高是否与心血管疾病风险相关。这将提供 关于2-AAA作为一种新的治疗方法的风险和似是而非的生物标志物的用途的重要信息 目标，使我们能够完善具体的假设，以便在未来的研究中进行探索。这些目标代表了新奇和 重要问题并使用现有NHLBI支持的样本和数据资源来添加大量 科学价值和解决一个关键的知识鸿沟。