Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

1 型糖尿病微血管功能障碍的治疗策略

基本信息

批准号：
10590208
负责人：
Kaitlin M Love
金额：
$ 19.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590208
关键词：
Address Adjuvant Therapy Adult Agonist Antioxidants Arteries Attenuated Award Biometry Blood Vessels Cardiovascular Diseases Cell physiology Cells Cellular biology Cessation of life Chronic Clinical Research Clinical Trials Data Data Analyses Disease Outcome Endothelial Cells Endothelium Ensure Exercise Exercise Tolerance Exhibits Future GLP-I receptor Glucose Goals Harvest Health Heart failure Human Hyperglycemia Impairment Individual Institution Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Interval training Investigation Knowledge Link Measures Mediating Mentors Mentorship Methodology Microvascular Dysfunction Modality Muscle Muscle function NOS3 gene Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Oxidative Stress Oxidative Stress Induction Oxygen Participant Pathway interactions Perfusion Persons Phosphorylation Physical activity Physiological Pilot Projects Placebos Plasma Play Population Production Public Health Randomized Reactive Oxygen Species Research Resources Role Signal Transduction Site Skeletal Muscle Stains Stimulus Techniques Testing Therapeutic Tissues Training United States National Institutes of Health VO2max Vascular Endothelium Vasodilation Work Youth cardiorespiratory fitness cardiovascular disorder risk cardiovascular effects career contrast enhanced data management endothelial dysfunction exercise adherence exercise training fitness glucagon-like peptide 1 glucose uptake improved improved outcome in vivo innovation insight post intervention prevent response ultrasound uptake vascular endothelial dysfunction

项目摘要

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is markedly elevated in type 1 diabetes (T1D), and two prevalent conditions in T1D, insulin resistance and endothelial dysfunction, precede and predict CVD. In health, insulin action at the endothelial cell dilates blood vessels, which promotes glucose and insulin delivery to muscle for glucose uptake. We recently showed, in adults with uncomplicated T1D, insulin commonly fails to enhance muscle microvascular perfusion, indicating microvascular insulin resistance, and even youth with T1D have apparent microvascular endothelial dysfunction. This is significant since the microvasculature is critical for muscle health as the direct supplier and exchange site of substrates. Possibly due to impaired muscle health from microvascular dysfunction, the T1D population has diminished cardiorespiratory fitness, even when matched for activity. Mechanisms of microvascular dysfunction in T1D remain ill-defined, but oxidative stress (OS) contributes to endothelial dysfunction at large arteries and likely the microvasculature as well. OS is clearly amplified in T1D. Adjuvant treatments to improve endothelial function and fitness are critically needed in T1D, and such therapies have potential to prevent CVD in future studies. Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists (GLP-1RA) improve: microvascular function in insulin resistant states, OS outside of glucose effects, cardiorespiratory fitness, and CVD outcomes in type 2 diabetes (T2D). Exercise attenuates large artery endothelial function and OS in T1D, and it improves microvascular endothelial function in T2D. Whether GLP- 1RA or exercise training improve muscle microvascular endothelial function in T1D is unknown. This project will test the hypothesis that, in adults with T1D, GLP-1RA and exercise training each enhance insulin-stimulated muscle microvascular perfusion via attenuating endothelial OS and improving endothelial cell function. Using cutting-edge contrast enhanced ultrasound before and after randomization to 14-wks of: 1) GLP-1RA, 2) exercise training, or 3) placebo, this study will assess whether GLP-1R agonism (Aim 1) or exercise training (Aim 2) improves insulin-mediated microvascular perfusion and muscle function in adults with T1D. Finally, harvesting and analyzing endothelial cells using an innovative technique will assess whether these therapies attenuate endothelial cell OS and improve endothelial function in vivo (Aim 3). Significantly, completion of the proposed studies will increase mechanistic knowledge of microvascular endothelial dysfunction in T1D and ascertain if larger studies examining GLP-1RA and exercise alone/combined are merited and feasible. The proposed research and training will support the candidate’s long-term goal to conduct larger clinical studies in T1D aiming to reverse endothelial dysfunction/prevent CVD. Preparing for that end, goals for this award are training in T1D- focused clinical trial work, human endothelial cell harvesting + cell biology, and biostatistics + data management. A robust mentorship team, with complementary expertise, and abundant institutional resources will ensure successful project completion and facilitate the promising candidate’s future independent research career.

项目摘要/摘要心血管疾病（CVD）在1型糖尿病（T1D）中明显升高，在 T1D，胰岛素抵抗和内皮功能障碍，在CVD之前并进行预测。在健康方面，胰岛素作用在内皮细胞扩张血管，从而促进葡萄糖和胰岛素递送到肌肉以吸收葡萄糖。我们最近表明，在简单T1D的成年人中，胰岛素通常无法增强肌肉微血管灌注，表明微血管胰岛素抵抗，甚至T1D的青年都有明显的微血管内皮功能障碍。这很重要，因为微脉管系统对于直接的肌肉健康至关重要基材的供应商和交换站点。可能是由于微血管的肌肉健康受损功能障碍，即使与活动相匹配，T1D人群的心肺适应性也降低了。 T1D中微血管功能障碍的机制仍然不明确，但氧化应激（OS）有助于大动脉的内皮功能障碍，也可能是微脉管系统。 OS在T1D中明显放大。在T1D中，需要调整治疗以提高内皮功能和适应性，此类疗法需要有可能在以后的研究中预防CVD。胰高血糖素样肽-1（GLP-1）和GLP-1受体激动剂（GLP-1RA）改进：胰岛素抵抗状态的微血管功能，葡萄糖效应之外的OS，心肺适应性和2型糖尿病（T2D）中的CVD结局。运动减弱大动脉内皮功能和T1D中的OS，并改善T2D中的微血管内皮功能。是否GLP- 1RA或运动训练可以改善T1D中肌肉微血管内皮功能。这个项目将检验以下假设，即在患有T1D，GLP-1RA和运动训练的成年人中，每个假设都增强了胰岛素刺激通过减弱内皮OS并改善内皮细胞功能，肌肉微血管灌注。使用在随机化到14周之前和之后的尖端对比度增强了超声波：1）GLP-1RA，2）运动培训或3）安慰剂，本研究将评估GLP-1R激动剂（AIM 1）还是运动训练（AIM 2）改善T1D成年人的胰岛素介导的微血管灌注和肌肉功能。最后，收获并使用创新技术分析内皮细胞将评估这些疗法是否减弱内皮细胞OS并改善体内内皮功能（AIM 3）。值得注意的是，提议的完成研究将增加T1D中微血管内皮功能障碍的机械知识，并确定是否是否检查GLP-1RA和单独运动/组合的大型研究是值得且可行的。提议研究和培训将支持候选人的长期目标，以在T1D目标中进行更大的临床研究逆转内皮功能障碍/预防CVD。为此做准备，该奖项的目标是在T1D- 重点临床试验工作，人体内皮细胞收集 +细胞生物学以及生物统计学 +数据管理。拥有完善专业知识和丰富的机构资源的强大的精通团队将确保成功的项目完成并促进了承诺候选人未来独立研究职业。