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

项目摘要/摘要 1型糖尿病(T1 DM)患者的心血管疾病(CVD)较普通糖尿病患者显著增加 人口。T1 DM的心血管疾病风险在女性中尤其夸大。尽管被认为是一种胰岛素 在缺乏状态的情况下，T1 DM也表现出胰岛素抵抗(IR)，这可能与超生理胰岛素有关 浓度、高血糖、内皮功能障碍和炎症。在健康的人类中，胰岛素导致 骨骼肌和心肌微血管水平的血管扩张以增加内皮表面积 可用于向这些组织输送营养物质、氧气和激素，如胰岛素。使用对比度 增强超声(CEU)和胰岛素钳夹，我们已确认存在血管和代谢IR 在T1 DM受试者中。患有T1 DM的女性可能比患有T1 DM的男性有更高的IR，尽管这 以前没有在血管水平上进行过研究。IR独立预测两种微血管并发症 大血管病变，如T1 DM的CVD。到目前为止，还没有联邦药品管理局批准 针对胰岛素抵抗或T1 DM血管并发症的药物。在大型随机对照临床试验中， 胰升糖素样肽-1(GLP-1)受体激动剂减少2型患者主要不良心血管事件 糖尿病。我们之前已经证明，GLP-1的输注增加了骨骼和心脏的微血管 在健康人中的灌流并恢复胰岛素介导的骨骼和心脏微血管增加 IR啮齿动物的血流灌注。GLP-1在T1 DM血管和全身IR中的作用尚不清楚。这里的内容 拟议的研究解决了以下假设：在患有T1 DM的人中，GLP-1(A)增加了微血管 并改善骨骼肌中胰岛素的微血管反应，从而增强胰岛素- 介导的葡萄糖处置和肌肉氧合，以及(B)增加心脏微血管灌注量和 改善胰岛素在心脏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女性有更大的微血管IR，但对GLP的微血管反应相似- 1.我们将利用CEU直接评估(1)骨骼肌和心肌的微血管反应 男性和女性T1 DM患者的胰岛素，比较性别和(2)注射GLP-1是否有改善 胰岛素介导的骨骼和心脏微血管灌流、大血管顺应性和内皮 1型糖尿病患者的功能障碍。拟议的研究将填补目前关于微血管IR和 T1 DM患者对GLP-1的组织灌注、血管和全身反应及其相关的心血管风险 性别差异。如果我们的假设被证实，这将为缓解IR提供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.