Effect of GLP-1 on microvascular insulin responses in type 1 diabetes

项目总结/摘要 1型糖尿病（T1 DM）患者的心血管疾病（CVD）发生率显著高于一般糖尿病患者。 人口T1 DM中的CVD风险在女性中尤其突出。虽然被认为是胰岛素 缺乏状态下，T1 DM也表现出胰岛素抵抗（IR），这可能与超生理胰岛素有关 高血糖症、内皮功能障碍和炎症。在健康人中，胰岛素会导致 在骨骼肌和心肌中微血管水平的血管舒张，以增加内皮表面积 可用于将营养物、氧气和激素如胰岛素输送到这些组织。使用造影 增强超声（CEU）和胰岛素钳夹，我们已经证实了血管和代谢IR的存在 在T1 DM受试者中。与T1 DM男性相比，T1 DM女性的IR可能更大，尽管这与T1 DM男性的IR相比， 以前没有在血管水平上研究过。IR独立预测微血管并发症 以及大血管疾病，例如T1 DM中的CVD。到目前为止，还没有联邦药品管理局批准 针对T1 DM中IR或血管并发症的药物。在大型随机对照临床试验中， 胰高血糖素样肽-1（GLP-1）受体激动剂减少2型糖尿病患者的主要不良心血管事件 糖尿病我们先前已经表明GLP-1输注增加骨骼和心脏微血管 灌注在健康人和恢复胰岛素介导的增加骨骼和心脏微血管 IR啮齿类动物中的灌注。GLP-1在T1 DM血管和全身IR中的影响尚不清楚。本文所 拟议的研究解决了以下假设，即在T1 DM患者中，GLP-1（a）增加微血管 灌注和改善骨骼肌中胰岛素的微血管反应，从而提高胰岛素- 介导的葡萄糖处置和肌肉氧合，和（B）增加心脏微血管灌注， 改善胰岛素在心脏中的微血管反应和大血管功能。我们还将测试一个子- 假设T1 DM女性患者的微血管IR更高，但对GLP的微血管反应相似， 1.我们将利用CEU直接评估（1）骨骼肌和心肌中的微血管反应， 男性和女性T1 DM患者中的胰岛素，比较两种性别，以及（2）GLP-1输注是否改善 胰岛素介导的骨骼和心脏微血管灌注、大血管顺应性和内皮 T1 DM的功能障碍。拟议的研究将填补目前关于微血管IR的知识空白， T1 DM患者的组织灌注以及对GLP-1的血管和全身反应和相关CVD风险 性别差异。如果我们的假设得到验证，它将为缓解IR引入一种潜在的治疗途径 以及T1 DM的微血管和大血管并发症。

Project Summary/Abstract Cardiovascular disease (CVD) is significantly increased in type 1 diabetes (T1DM) compared with the general population. The CVD risk in T1DM is particularly exaggerated in women. Although thought of as an insulin deficient state, T1DM also exhibits insulin resistance (IR), which may relate to supraphysiologic insulin concentrations, hyperglycemia, endothelial dysfunction, and inflammation. In healthy humans, insulin causes vasodilation at the microvascular level in skeletal and cardiac muscles to increase endothelial surface area available for the delivery of nutrients, oxygen, and hormones such as insulin to these tissues. Using contrast enhanced ultrasound (CEU) and insulin clamp, we have confirmed the presence of vascular and metabolic IR in T1DM subjects. Women with T1DM may have greater IR compared with men with T1DM although this has not previously been studied at the vascular level. IR independently predicts both microvascular complications and macrovascular ones like CVD in T1DM. Thus far, there are no Federal Drug Administration approved medications which target IR or vascular complications in T1DM. In large, randomized controlled clinical trials, Glucagon-Like Peptide-1 (GLP-1) receptor agonists reduce major adverse cardiovascular events in type 2 diabetes. We have previously shown that GLP-1 infusion increases skeletal and cardiac microvascular perfusion in healthy humans and restores insulin-mediated increase in skeletal and cardiac microvascular perfusion in IR rodents. The impact of GLP-1 in T1DM vascular and systemic IR remains unknown. The herein proposed research addresses the hypotheses that, in humans with T1DM, GLP-1 (a) increases microvascular perfusion and improves insulin's microvascular response in skeletal muscle thereby enhancing insulin- mediated glucose disposal and muscle oxygenation and (b) increases cardiac microvascular perfusion and improves insulin's microvascular response in the heart and large vessel function. We will also test a sub- hypothesis that women with T1DM have greater microvascular IR, but similar microvascular response to GLP- 1. We will utilize CEU to directly assess (1) the microvascular responses in skeletal and cardiac muscles to insulin in men and women with T1DM, comparing the two genders, and (2) whether GLP-1 infusion improves insulin-mediated skeletal and cardiac microvascular perfusion, large vessel compliance, and endothelial dysfunction in T1DM. The proposed studies will fill a current gap in knowledge regarding microvascular IR and tissue perfusion as well as vascular and systemic responses to GLP-1 in T1DM and the associated CVD risk gender disparity. If our hypotheses are validated, it will introduce a potential treatment avenue for mitigating IR and microvascular and macrovascular complications in T1DM.