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.

项目概要/摘要心血管疾病 (CVD) 在 1 型糖尿病 (T1D) 中显着升高，并且两种常见病症 T1D、胰岛素抵抗和内皮功能障碍先于并预测 CVD。内皮细胞扩张血管，促进葡萄糖和胰岛素输送到肌肉以吸收葡萄糖。我们最近表明，在患有无并发症的 T1D 的成人中，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，甚至患有 T1D 的青少年也有明显的微血管这很重要，因为微血管系统作为直接的肌肉健康至关重要。可能是由于微血管损害肌肉健康所致。由于功能障碍，T1D 人群的心肺健康水平下降，即使在活动匹配的情况下也是如此。 T1D 微血管功能障碍的机制仍不明确，但氧化应激 (OS) 有助于 T1D 中大动脉的内皮功能障碍以及微血管系统的功能障碍明显加剧。 T1D 迫切需要改善内皮功能和健康的辅助治疗，此类疗法在未来的研究中，胰高血糖素样肽-1 (GLP-1) 和 GLP-1 受体激动剂具有预防 CVD 的潜力。 (GLP-1RA) 改善：胰岛素抵抗状态下的微血管功能、葡萄糖影响之外的 OS、运动会减弱 2 型糖尿病 (T2D) 的心肺健康和 CVD 结局。 GLP- 是否能改善 T1D 中的内皮功能和 OS，并改善 T2D 中的微血管内皮功能。 1RA 或运动训练能否改善 T1D 的肌肉微血管内皮功能尚不清楚。检验以下假设：在患有 T1D 的成人中，GLP-1RA 和运动训练各自增强胰岛素刺激通过减弱内皮 OS 和改善内皮细胞功能来调节肌肉微血管灌注。随机化至 14 周之前和之后的尖端超声造影：1) GLP-1RA，2) 运动训练，或 3) 安慰剂，本研究将评估 GLP-1R 激动作用（目标 1）还是运动训练（目标 2）改善 1 型糖尿病成人患者胰岛素介导的微血管灌注和肌肉功能。使用创新技术分析内皮细胞将评估这些疗法是否会减弱显着改善内皮细胞 OS 并改善体内内皮功能（目标 3）。研究将增加对 T1D 微血管内皮功能障碍的机制了解，并确定是否更大规模的检查研究 GLP-1RA 和单独/联合运动是值得且可行的。研究和培训将支持候选人的长期目标，即针对 T1D 进行更大规模的临床研究为了扭转内皮功能障碍/预防 CVD，该奖项的目标是 T1D 培训。专注于临床试验工作、人类内皮细胞采集+细胞生物学、生物统计学+数据管理。强大的导师团队、互补的专业知识和丰富的机构资源将确保成功完成项目并促进有前途的候选人未来的独立研究生涯。