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

靶向内皮糖萼以增强 2 型糖尿病的血管功能和运动诱发的血管适应

• 批准号: 10363914
• 负责人: Camila Margarita Manrique Acevedo
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363914
• 关键词: Adjuvant; Adult; Arteries; Biochemical; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Caring; Cause of Death; Characteristics; Charge; Chronic; Clinical Trials; Diabetes Mellitus; Diagnosis; Dietary Supplementation; Double-Blind Method; Endothelium; Epidemic; Exercise; Exhibits; Exposure to; Glucosamine Sulfate; Glycocalyx; Glycoproteins; Hyaluronan; Impairment; Individual; Inflammation; Left; Life Style Modification; Mediating; Methodology; Molecular Weight; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Patients; Phase; Physical activity; Placebos; Population; Prevalence; Proteoglycan; Randomized; Research; Role; Side; Signal Transduction; Stimulus; Structure; Superoxide Dismutase; Supplementation; Testing; Therapeutic; Thick; Veterans; db/db mouse; design; diabetic; exercise training; fucoidan; hemodynamics; improved; lifestyle intervention; mechanical force; mechanotransduction; military veteran; mortality; mouse model; novel; prevent; prospective; randomized placebo controlled trial; restoration; shear stress

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.

项目摘要/摘要 心血管疾病（CVD）是2型糖尿病（T2D）退伍军人的主要原因。 建议对生活方式的改变，包括增加体育锻炼，作为一线治疗 T2D的管理。不幸的是，这些生活方式干预措施防止CVD发病的功效 T2D患者的死亡率尚不确定。我们小组和其他人的可用证据 表明在患有T2D的受试者中，对运动训练的血管适应受损。我们提出了这一点 血管适应减少解释了为什么增加体育锻炼不会导致强大的减少 T2D中的CVD发病率和死亡率。但是，导致这种血管缺陷的机制 在T2D中进行运动的适应仍然未知。这是识别新佐剂的主要限制 糖尿病人群中运动的心血管益处最大化。锻炼 通过重复暴露血液动力学刺激或剪切应力对脉管系统的直接影响。这 每次锻炼每次出现的血液流量和腔剪应力的增加是主要机制 促进血管适应。机械敏感的内皮腔检测到剪切应力 结构，例如糖蛋白，将机械力通过 机械转导。因此，我们建议需要完整的内皮糖卵形 剪切应力增加的机械转导和随后的慢性血管适应 进行运动。值得注意的是，糖脂降解是T2D的经典特征。因此，我们的 总体假设是内皮糖脂降解是排除剪切应力的关键因素 T2D中的机械转导和随之而来的运动引起的血管适应。推论的 假设是通过补充糖脂前体的饮食补充内皮糖脂的恢复 （DSGP）将改善在T2D中运动的血管适应。具体而言，在AIM 1中（概念证明临床证明 试验阶段），我们将记录DSGP可以增强T2D患者的内皮糖脂完整性。 尽管我们提供了初步证据表明DSGP可以增加糖蛋白的厚度和内皮 在T2D的小鼠模型中的功能，这将是第一个在T2D受试者中证明这些影响的研究。这 DSGP将使用双盲随机安慰剂对照试验研究DSGP八周的影响。 随后，在AIM 2（消耗临床试验阶段）中，我们将证明 T2D患者运动诱导的运动诱导的血管适应的内皮糖脂。显示了这一点 在T2D受试者中，通过DSGP恢复内皮糖脂蛋白是可行的，我们现在将研究是否研究 这种补充将增强运动训练引起的内皮功能的改善。这会 可以在阶乘平衡设计中完成，其中T2D受试者将被随机分为DSGP或安慰剂 有和没有并进行的运动训练八周。我们的团队准备移动心血管和 糖尿病研究通过一个转化项目，该项目将在 在概念，方法论和治疗上都是新颖的调查水平。的确， 靶向糖脂具有非凡的诺言，可以实现最佳运动引起的血管 具有T2D的退伍军人的适应性，从而最大程度地提高了运动的心血管益处。