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

基本信息

批准号：
9758935
负责人：
Kaitlin M Love
金额：
$ 7.22万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-30 至 2021-06-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9758935
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

项目摘要

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.

项目概要/摘要与一般人群相比，1 型糖尿病 (T1DM) 的心血管疾病 (CVD) 显着增加人口。女性 T1DM 的 CVD 风险尤其高。虽然被认为是胰岛素在缺乏状态下，T1DM还表现出胰岛素抵抗（IR），这可能与超生理性胰岛素有关浓度、高血糖、内皮功能障碍和炎症。在健康人类中，胰岛素会导致骨骼肌和心肌微血管水平的血管舒张以增加内皮表面积可用于向这些组织输送营养物质、氧气和胰岛素等激素。使用对比增强超声（CEU）和胰岛素钳夹，我们确认了血管和代谢IR的存在在 T1DM 受试者中。与患有 T1DM 的男性相比，患有 T1DM 的女性可能具有更高的 IR，尽管这已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以及 T1DM 中的 CVD 等大血管疾病。迄今为止，美国联邦药物管理局尚未批准任何药物针对 IR 或 T1DM 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) 受体激动剂可减少 2 型患者的主要不良心血管事件糖尿病。我们之前已经表明，GLP-1 输注可增加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 啮齿动物的灌注。 GLP-1 对 T1DM 血管和全身 IR 的影响仍不清楚。本文中的拟议的研究提出了这样的假设：在患有 T1DM 的人类中，GLP-1 (a) 会增加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- 介导的葡萄糖处理和肌肉氧合，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患有 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) 骨骼肌和心肌的微血管反应男性和女性 T1DM 患者的胰岛素，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细胞 T1DM 功能障碍。拟议的研究将填补目前有关微血管 IR 和 T1DM 中的组织灌注以及血管和全身对 GLP-1 的反应以及相关的 CVD 风险性别差异。如果我们的假设得到验证，它将为减轻 IR 带来潜在的治疗途径以及 T1DM 的微血管和大血管并发症。