Therapeutic Strategies for Microvascular Dysfunction in Type 1 Diabetes

项目摘要/摘要 心血管疾病(CVD)在1型糖尿病(T1D)中显著增加，在 T1D、胰岛素抵抗和内皮功能障碍是心血管疾病的先兆和预测指标。在健康方面，胰岛素在 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。 我们最近发现，在患有简单T1D的成年人中，胰岛素通常不能增强肌肉微血管。 血流灌注，提示微血管胰岛素抵抗，甚至年轻人的T1D也有明显的微血管 内皮功能障碍。这一点意义重大，因为微血管系统对于肌肉健康至关重要，因为 基材供应商和交换地点。可能是由于微血管损害了肌肉健康 由于功能障碍，T1D人群的心肺健康状况有所减弱，即使在活动方面与之相匹配。 T1D微血管功能障碍的机制仍不明确，但氧化应激(OS)参与了 大动脉内皮细胞功能障碍，可能还有微血管。OS在T1D中明显扩增。 在T1D中，迫切需要辅助治疗来改善内皮功能和适合性，而这种治疗 在未来的研究中具有预防心血管疾病的潜力。胰高血糖素样肽-1及其受体激动剂 (GLP-1RA)改善：胰岛素抵抗状态下的微血管功能，糖以外的OS效应， 心肺适合度和2型糖尿病(T2D)的心血管结局。运动使大动脉变细 改善T1D的微血管内皮功能。普洛斯是否- 1RA或运动训练对T1D肌肉微血管内皮功能的改善作用尚不清楚。这个项目将 验证这样一种假设：在患有T1D的成年人中，GLP-1RA和运动训练都能增强胰岛素刺激 通过减少内皮细胞OS和改善内皮细胞功能的肌肉微血管灌流。vbl.使用 随机分为14周：1)GLP-1RA，2)锻炼前后的尖端超声造影 训练，或3)安慰剂，这项研究将评估GLP-1R激动症(目标1)或运动训练(目标2) 改善成年T1D患者胰岛素介导的微血管灌流和肌肉功能。最后，收获 使用一种创新技术分析内皮细胞将评估这些疗法是否会减弱 体内内皮细胞OS和改善内皮功能(目标3)。值得注意的是，拟议的 研究将增加T1D微血管内皮细胞功能障碍的机制知识，并确定 检查GLP-1RA和单独/联合锻炼的更大规模的研究是值得和可行的。建议数 研究和培训将支持候选人的长期目标，即在T1D目标中进行更大规模的临床研究 逆转内皮功能障碍/预防心血管疾病。为此做准备，该奖项的目标是T1D培训- 重点临床试验工作，人内皮细胞采集+细胞生物学，生物统计+数据管理。 一个强大的指导团队，拥有互补的专业知识和充足的机构资源，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。

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.