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：
9127220
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/9127220
关键词：
Adolescent Adult Affect Age 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 VO2max Vascular Diseases Vasodilation Weight Gain Woman Work arterial stiffness basal insulin base blood glucose regulation brachial artery cardiovascular disorder risk contrast enhanced diabetic patient diet and exercise drug candidate efficacy testing endothelial dysfunction eplerenone exercise intervention exercise program exercise training fitness glycemic control healthy weight high risk improved indexing insulin sensitivity men middle age mortality novel strategies prevent prospective 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（由申请人提供）：大、小脑动脉、冠状动脉和外周动脉疾病是 1 型糖尿病 (DM1) 发病/死亡的主要原因，多中心试验表明，这一点很早就开始了。缺乏血管干预措施来改善 DM1 的 CVD 结局的有效性，我们的一般假设是 DM1 损害动脉脉管系统的多个水平的血管功能，并且动脉血管的功能受到损害。我们进一步阻碍盐皮质激素受体（MCR）阻断和/或增强健康将改善 DM1 动脉功能障碍，我们将使用非侵入性方法来评估动脉僵硬度（即脉搏波速度和增强指数）。在导管血管中，我们将测量血流介导的扩张和缺血后流速，以评估导管和阻力血管中的内皮功能，在目标 1 中，我们将测量 18-50 岁 DM1 和健康年龄/性别匹配的对照组在基础状态和胰岛素刺激状态下的全动脉血管功能。动脉树是否受到 DM1 的不利影响以及血管胰岛素敏感性是否受损，这也可能表明哪些特定测试可以最大程度地区分 DM1 和对照的持续时间。控制、血脂状况、高血压和炎症证据将成为本分析中的协变量，在目标 2 中，我们将测试 18-50 岁 DM1 的基础或胰岛素反应性全动脉功能是否对 12 周的生活方式（健身训练）有反应。）或药物（依普利酮）干预或联合健身加依普利酮对其他人群具有有益的血管作用如果这些假设被证明是正确的，它们将表明： A) 在基础或胰岛素治疗状态下是否存在全动脉血管功能障碍，或者是否仅限于一个或另一个血管水平；B) 胰岛素的血管作用（或阻力）是否有助于 DM 1 和 CVD 之间的联系；进一步强调饮食/运动干预或早期药物干预以避免CVD的令人信服的理由此外，这里使用的方法可能表明早期评估全动脉功能可以提供一个改进药物选择的平台。后续 DM1 硬终点临床试验的候选者。