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

GLP-1对1型糖尿病微血管胰岛素反应的影响

• 批准号: 9980177
• 负责人: Kaitlin M Love
• 金额: $ 2.07万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980177
• 关键词: Address; Adjuvant; Agonist; Area; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinical Trials; Closure by clamp; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Development; Diabetic Angiopathies; Disease Outcome; Endothelium; Event; Exhibits; GLP-I receptor; Gender; General Population; Heart; Hormones; Human; Hyperglycemia; Individual; Inflammation; Infusion procedures; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Kidney Diseases; Knowledge; Mediating; Metabolic; Microvascular Dysfunction; Muscle; Myocardium; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Oxygen; Patients; Perfusion; Peripheral arterial disease; Pharmaceutical Preparations; Physiologic pulse; Randomized Controlled Clinical Trials; Research; Resistance; Retinal Diseases; Risk; Rodent; Skeletal Muscle; Surface; Testing; Therapeutic; Tissues; Ultrasonography; Vasodilation; Woman; arteriole; cardiovascular disorder risk; contrast enhanced; endothelial dysfunction; gender disparity; glucagon-like peptide 1; glucose disposal; glucose uptake; human subject; improved; indexing; insulin secretion; liraglutide; macrovascular disease; men; prevent; response; secondary outcome; skeletal

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.

项目摘要/摘要 1型糖尿病（T1DM）的心血管疾病（CVD）显着增加 人口。 T1DM中的CVD风险在女性中特别夸张。虽然被认为是一种胰岛素 缺陷状态，T1DM还表现出胰岛素抵抗（IR），这可能与造影症胰岛素有关 浓度，高血糖，内皮功能障碍和炎症。在健康的人类中，胰岛素原因 骨骼肌和心脏肌肉的微血管水平的血管舒张以增加内皮表面积 可用于将营养素，氧气和激素（例如胰岛素）递送到这些组织中。使用对比 增强的超声（CEU）和胰岛素夹，我们已经确认存在血管和代谢红外 在T1DM受试者中。与患有T1DM的男性相比，患有T1DM的女性可能具有更大的IR 以前没有在血管水平上进行研究。 IR独立预测两个微血管并发症 和大血管含量，例如T1DM中的CVD。到目前为止，尚未批准联邦药物管理局 针对T1DM中IR或血管并发症的药物。在大的，随机对照的临床试验中， 胰高血糖素样肽-1（GLP-1）受体激动剂减少了2型的主要不良心血管事件 糖尿病。我们以前已经表明，GLP-1输注增加了骨骼和心脏微血管 健康人的灌注并恢复胰岛素介导的骨骼和心脏微血管的增加 IR啮齿动物中的灌注。 GLP-1在T1DM血管和系统性IR中的影响仍然未知。这里 拟议的研究解决了以下假设，即在具有T1DM的人类中，GLP-1（a）增加了微血管 灌注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和 改善胰岛素在心脏和大血管功能中的微血管反应。我们还将测试一个子 假设T1DM的女性具有更大的微血管IR，但对GLP的微血管反应相似 1。我们将利用CEU直接评估（1）骨骼和心脏肌肉中的微血管反应 具有T1DM的男性和女性的胰岛素，比较了两个性别，（2）GLP-1输注是否有所改善 胰岛素介导的骨骼和心脏微血管灌注，大容器依从性和内皮 T1DM中的功能障碍。拟议的研究将填补有关微血管IR和 组织灌注以及T1DM中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了验证，它将引入一个潜在的治疗途径来减轻IR T1DM中的微血管和大血管并发症。