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

基本信息

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
项目类别：
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

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

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项目摘要

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）。尽管优化了可用疗法，但CVD仍然是死亡率的主要原因 T2D，突出了剩余风险的大量燃烧。进一步降低了CVD发病率和患有T2D的人的死亡率需要促进承诺候选人的剩余风险的候选人。代谢物 α-氨基丙酸（2-AAA）预测T2D和动脉粥样硬化的发展，与其他无关已知风险因素。这可能代表了开发CVD的新型独立风险机制，特别是在具有T2D的个体中。我们的总体假设是2-AAA是一个独立的调解人 T2D患者的CVD风险。在控制糖尿病的心血管风险的行动中（Accord）试验，降低葡萄糖疗法和密集脂质管理都未能衰减CVD风险具有T2D的人，确实显示出风险增加的证据。我们假设这部分是由于残余危险因素，包括2-AAA。我们提出了对现有血浆样本中2-AAA的分析 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，并解决等离子2-AAA是否变化对脂肪靶向疗法或密集血糖管理的反应。 2）解决了血浆的假设 2-AAA是经历事件目的地最佳治疗的个人的CVD风险机制。成功完成目标将决定2-AAA水平是否受到脂质和血糖的影响在T2D中的管理，并确定是否提高了与CVD风险的2-AAA合伙人。这将提供关于2-AAA作为风险和合理性的生物标志物作为一种新疗法的生物标志物的重要信息目标，使我们能够在未来的研究中探讨特定的假设。这些目标代表小说，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。