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）杀死3人中有1人，影响> 2中的3人，被诊断为2型 糖尿病（T2D）。 T2D强调了剩余风险的巨大负担。 T2D患者的死亡率需要有前途的候选候选者的剩余风险 α-氨基丙酸（2-AAA）预测两者和动脉粥样硬化的发展，与其他 已知的风险因素。 特别是在T2D的个体中。 在控制糖尿病的心血管风险的行动中的CVD风险 试验，降低葡萄糖疗法和密集脂质管理都未能衰减CVD风险 T2D的个体，确实显示了风险增加的证据。 剩余风险因素，包括2-AAA。 n = 1,757个协议研究脂质治疗组的参与者，以下目的：1）定义效果 血浆2-AAA上的脂质和降糖疗法的含量，并解决等离子2-AAA是否改变 对脂质靶向治疗或密集性血糖管理的抗议。 2-AAA是尽管经历了最佳疗法的事件的个人的CVD风险机制。 成功完成目标是否受脂质和血糖影响2-AAA水平是否受到影响 在T2D中的管理，并确定了与CVD风险相关的2-AAA协会 关于2-AAA作为风险和PLAU的生物标志物的实用性的重要信息是一种新颖的治疗方法 目标，使我们能够在未来的研究中探讨特定的特定假设。 重要问题并使用现有的NHLBI支持的样本和数据资源来添加大量 科学价值并解决关键知识差距。