Reversing vascular dysfunction in type 1 diabetes

 描述(申请人提供)：大大小小的脑部、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。DM1青少年动脉功能障碍的证据表明，这种情况很早就开始了。目前尚缺乏多中心试验来测试血管干预改善DM1患者心血管疾病预后的有效性。我们的一般假设是，DM1在动脉血管系统的多个水平上损害血管功能，动脉血管对胰岛素诱导的血管松弛具有抵抗力。我们进一步假设，阻断盐皮质激素受体(MCR)和/或增强适应性将改善DM1动脉功能障碍。我们将使用无创性方法来评估管道血管的动脉硬度(即脉搏波速度和增强指数)，我们将测量血流介导的扩张和缺血后血流速度来评估管道和阻力血管的内皮功能，并使用超声造影来评估微血管功能。在目标1中，我们将测量18-50岁的泛动脉血管功能。在基础状态和胰岛素刺激状态下，DM1和健康的年龄/性别都与对照组匹配。目标1将确定整个动脉树是否受到DM1的不利影响，以及血管胰岛素敏感性是否受损。它还可以指出哪些特定测试在DM1和对照之间提供了最大的区分度。在这项分析中，DM1持续时间、血糖控制、血脂谱、高血压和炎症证据将是协变量，在目标2中，我们将测试18-50岁的基础或胰岛素反应性泛动脉功能。DM1对12周的生活方式(健身训练)或药物干预(依普利酮)或综合健身加依普利酮有效。健身和依普利酮在其他人群中也有有益的血管作用。如果这些假设被证明是正确的，它们将表明：A)在基础状态或胰岛素治疗状态下，存在泛动脉血管功能障碍，还是仅限于一个或另一个血管水平；B)胰岛素的血管作用(或抵抗)是否有助于DM 1和CVD之间的联系；C)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，早期评估泛动脉功能可以提供一个平台，为DM1稍后的硬终点临床试验改进候选药物的选择。

 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.