Targeting the Endothelial Glycocalyx to Enhance Vascular Function and Exercise-Induced Vascular Adaptations in Type 2 Diabetes

项目摘要/摘要 心血管疾病(CVD)是2型糖尿病(T2D)退伍军人死亡的主要原因。 建议改变生活方式，包括增加体力活动，作为治疗高血压的一线疗法。 T2D的管理。不幸的是，这些生活方式干预对预防心血管疾病发病率的有效性 而T2D患者的死亡率还没有确定下来。我们小组和其他人提供的证据 提示T2D受试者对运动训练的血管适应性受损。我们建议 血管适应能力的减弱解释了为什么增加体力活动并不会导致 T2D患者心血管疾病的发病率和死亡率。然而，导致这种血管缺陷的机制 对T2D运动的适应尚不清楚。这是鉴定新佐剂的一个主要限制。 最大限度地提高糖尿病患者运动对心血管的益处。锻炼使人精疲力竭 通过反复暴露于血流动力学刺激或剪应力而对血管系统产生的直接影响。这个 伴随着每一轮运动的血流和管腔切应力的增加是主要机制 有助于血管适应。用机械敏感的内皮管腔检测切应力 一种能将机械力转化为生物化学信号的结构，如糖萼 机械转导。因此，我们认为一个完整的内皮糖基化是必需的 剪应力增加的机械转导与随后相关的慢性血管适应 随着锻炼的进行。值得注意的是，糖萼降解是T2D的一个典型特征。因此，我们的 最重要的假设是内皮细胞的糖基化降解是消除切应力的关键因素。 T2D中的机械转导和随后的运动诱导的血管适应。由此得出的推论是 假说是通过饮食补充糖催化前体来恢复内皮细胞糖催化 (Dsgp)将改善血管对T2D运动的适应。具体地说，在目标1(临床概念验证 试验阶段)，我们将证明DSGP增强了T2D患者的内皮糖萼完整性。 虽然我们提供的初步证据表明，丹参总皂甙可以增加糖萼厚度和内皮细胞。 在T2D小鼠模型中的作用，这将是第一次在T2D受试者中展示这些影响的研究。这个 将使用双盲随机安慰剂对照试验来研究dsgp治疗8周的效果。 随后，在目标2(扩大临床试验阶段)中，我们将展示 T2D患者运动诱导的血管适应中内皮细胞的糖基化反应。证明了这一点 在T2D受试者中，通过DSGP恢复内皮细胞糖基化是可行的，我们现在将调查是否 这样的补充将加强运动训练引起的内皮功能的改善。这将是 在因子平衡设计中完成，在该设计中，T2D受试者将被随机分为DSGP组或安慰剂组 同时进行和不进行为期八周的运动训练。我们的团队准备将心血管和 通过一个翻译项目推进糖尿病研究，该项目将在整个 在概念上、方法上和治疗上都是新颖的调查水平的数量。的确， 靶向糖萼对实现最佳运动诱导血管具有非凡的前景 退伍军人对T2D的适应，从而最大限度地发挥运动对心血管的好处。

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in Veterans with type 2 diabetes (T2D). Lifestyle modifications, including increased physical activity, are recommended as first-line therapy for the management of T2D. Unfortunately, the efficacy of these lifestyle interventions for preventing CVD morbidity and mortality in patients with T2D is not well-established. Available evidence from our group and others indicates that vascular adaptations to exercise training are impaired in subjects with T2D. We propose that diminished vascular adaptations explain why increased physical activity does not lead to a robust reduction in CVD morbidity and mortality in T2D. However, the mechanisms responsible for this deficit in vascular adaptations to exercise in T2D remain unknown. This is a major limitation for identifying new adjuvant therapeutics to maximize the cardiovascular benefits of exercise in the diabetic population. Exercise exerts direct effects on the vasculature via repetitive exposure to hemodynamic stimuli or shear stress. The increased blood flow and luminal shear stress attendant to each bout of exercise are primary mechanisms contributing to vascular adaptations. Shear stress is detected by mechanosensitive endothelial luminal structures, such as the glycocalyx, that convert mechanical forces into biochemical signals via mechanotransduction. As such, we propose that an intact endothelial glycocalyx is required for the mechanotransduction of increased shear stress and the subsequent chronic vascular adaptations associated with exercise to occur. Notably, glycocalyx degradation is a classic feature of T2D. Accordingly, our overarching hypothesis is that endothelial glycocalyx degradation is a key factor precluding shear stress mechanotransduction and consequent exercise-induced vascular adaptations in T2D. The corollary to this hypothesis is that restoration of the endothelial glycocalyx by dietary supplementation of glycocalyx precursors (DSGP) will improve vascular adaptations to exercise in T2D. Specifically, in Aim 1 (Proof of Concept Clinical Trial Phase), we will document that DSGP enhances endothelial glycocalyx integrity in patients with T2D. Although we provide preliminary evidence that DSGP can increase glycocalyx thickness and endothelial function in a mouse model of T2D, this will be the first study to demonstrate these effects in T2D subjects. The effects of DSGP for eight weeks will be studied using a double-blinded randomized placebo control trial. Subsequently, in Aim 2 (Expended Clinical Trial Phase), we will demonstrate the permissive role of the endothelial glycocalyx in exercise-induced vascular adaptations in patients with T2D. Having shown that restoration of the endothelial glycocalyx via DSGP is feasible in T2D subjects, we will now investigate whether such supplementation will potentiate exercise training-induced improvements in endothelial function. This will be accomplished in a factorial balanced design in which T2D subjects will be randomized to DSGP or placebo with and without concurrent exercise training for eight weeks. Our team is poised to move cardiovascular and diabetes research forward with a translational project that will exert a sustained, powerful impact across a number of levels of inquiry that are novel conceptually, methodologically, and therapeutically. Indeed, targeting the glycocalyx holds extraordinary promise for achieving optimal exercise-induced vascular adaptations in Veterans with T2D, thus maximizing the cardiovascular benefits of exercise.