Reversing vascular dysfunction in type 1 diabetes

逆转 1 型糖尿病的血管功能障碍

基本信息

批准号：
8818217
负责人：
EUGENE Joseph BARRETT
金额：
$ 60.83万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-10 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818217
关键词：
Adolescent Adult Affect Age Arteries Atherosclerosis Biological Markers Blood Vessels Blood Volume Cardiovascular Diseases Cerebrum Clinical Trials Coronary Discrimination Disease Disease Outcome Employee Strikes Exercise Figs - dietary Functional disorder Gender General Population General Practices Health Hypertension Hypoglycemia Inflammation Insulin Insulin-Dependent Diabetes Mellitus Intervention Laboratories Life Style Lipids Measurement Measures Mediating Methods Mineralocorticoid Receptor Morbidity - disease rate Multicenter Trials Muscle function Myocardial Myocardium Nitric Oxide Patients Perfusion Peripheral Peripheral arterial disease Persons Physiologic pulse Population Positioning Attribute Prevalence Property Relaxation Reporting Resistance Risk Factors Skeletal Muscle Structure Testing Training Trees Ultrasonography Vascular Diseases Vasodilation Weight Weight Gain Woman Work arterial stiffness basal insulin base blood glucose regulation brachial artery cardiovascular disorder risk diabetic patient diet and exercise drug candidate efficacy testing endothelial dysfunction eplerenone fitness glycemic control high risk improved indexing insulin sensitivity men middle age mortality novel strategies prevent programs prospective public health relevance type I diabetic vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Large and small cerebral, coronary and peripheral arterial disease is the major cause of morbidity/mortality in type 1 diabetes (DM1). This begins early as indicated by evidence for arterial dysfunction in DM1 adolescents. Multicenter trials testing efficacy of vascular interventions to improve CVD outcomes in DM1 are lacking. Our general hypothesis is that DM1 impairs vascular function at multiple levels of the arterial vasculature and arterial vessels are resistant to insulin-induced vascular relaxation. We further hypothesize that mineralocorticoid receptor (MCR) blockade and/or enhanced fitness will improve DM1 arterial dysfunction. We will use non-invasive methods to assess arterial stiffness, (i.e. Pulse Wave Velocity and Augmentation Index) in conduit vessels, We will measure Flow-Mediated Dilation and Post-Ischemic Flow Velocity to assess endothelial function in conduit and resistance vessels and contrast-enhanced ultrasound to assess microvascular function. In Aim 1 we will measure pan-arterial vascular function in 18-50 y.o. DM1 and healthy age/gender matched controls in both the basal and insulin-stimulated state. Aim 1 will define whether the entire arterial tree is adversely affected by DM1 and whether vascular insulin sensitivity is impaired. It may also indicate which specific tests provide greatest discrimination between DM1 and controls. Duration of DM1, glycemic control, lipid profile, hypertension and evidence of inflammation will be co-variates in this analysis, In Aim 2 we will test whether basal or insulin-responsive pan-arterial function in 18-50 y.o. DM1 responds to a 12 week lifestyle (fitness training) or pharmacologic (eplerenone) intervention or combined fitness plus eplerenone. Fitness and eplerenone have beneficial vascular effects in other populations. If these hypotheses prove correct, they will indicate: A) whether in the basal or insulin treated state ther is pan-arterial vascular dysfunction or is it restricted to one or another vascular level; B) whethr insulin's vascular action (or resistance) contributes to the linkage between DM 1 and CVD; C) a compelling rationale for further emphasizing diet/exercise interventions or early pharmacologic interventions to avoid CVD. In addition, the approach used here may suggest that early assessment pan-arterial function can afford a platform to improve selection of drug candidates for later hard endpoint clinical trials in DM1.

描述（由适用提供）：大脑，冠状动脉和周围伪像是1型糖尿病（DM1）发病/死亡率的主要原因。这是从DM1青少年中动脉功能障碍的证据来开始的。缺乏血管干预措施的多中心试验，以改善DM1中CVD结果的效率。我们的一般假设是，DM1在多个级别上会损害血管功能，我们将使用非侵入性方法评估导管血管中的动脉刚度（即脉冲波速度和增强指数），我们将测量流动介导的膨胀膨胀和缺血后的流动速度以评估辅导功能和对比度的内皮功能。在AIM 1中，我们将在18-50 Y.O.中测量泛动脉血管功能。 DM1和健康的年龄/性别匹配基本和胰岛素刺激状态的对照。 AIM 1将定义整个动脉树是否受到DM1的不利影响，以及是否损害了血管胰岛素敏感性。它还可能表明哪些特定测试在DM1和对照组之间提供了最大的歧视。 DM1的持续时间，血糖控制，脂质谱，高血压和炎症的证据将在此分析中共同变化，在AIM 2中，我们将测试18-50 Y.O.的基本或胰岛素反应性的泛动物功能。 DM1对12周的生活方式（健身培训）或药物（eplerenone）干预或健身和eplerenone的响应。健身和eplenone在其他人群中具有有益的血管作用。如果这些假设被证明是正确的，它们将指出：a）在基本或胰岛素治疗的状态中，其泛动血管功能障碍，还是仅限于一个或另一个血管水平； b）胰岛素的血管作用（或抗性）是否有助于DM 1和CVD之间的联系； c）令人信服的理由，以进一步强调饮食/运动干预措施或早期药理干预措施，以避免CVD。此外，此处使用的方法可能表明，早期评估泛动功能可以负担得起一个平台，以改善候选药物的选择，以供DM1中的后期硬端点临床试验。