Insulin action in human cardiac and skeletal muscle microvasculature

胰岛素在人体心脏和骨骼肌微血管中的作用

基本信息

批准号：
8223319
负责人：
ZHENQI LIU
金额：
$ 38.12万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223319
关键词：
Address Angiopoietin-2 Angiotensin II Anti-Inflammatory Agents Anti-inflammatory Attenuated BDKRB2 gene Biochemical Biopsy Blood Vessels Blood flow Bradykinin Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Contrast Media Contrast echocardiography procedure Coronary Coronary Arteriosclerosis Development Diabetes Mellitus Diagnostic Endothelial Cells Endothelin-1 Functional disorder Future Hand Heart Heart Diseases Heart failure Hormones Human Inflammatory Insulin Insulin Resistance Light MAP Kinase Gene MEKs Measures Mediating Microcirculation Morbidity - disease rate Muscle Myocardial Myocardial Infarction Myocardium Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Obesity Oxidative Stress Oxygen Patients Perfusion Peripheral Persons Pharmaceutical Preparations Plasma Play Positron-Emission Tomography Receptor, Angiotensin, Type 1 Renin-Angiotensin System Resistance Role Sampling Signal Transduction Signaling Molecule Skeletal Muscle Techniques Testing Therapeutic Studies Tissues Ultrasonography Up-Regulation design diabetic diabetic patient effective therapy feeding glucose uptake improved insulin signaling interest mortality public health relevance receptor response salicylsalicylic acid vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Patients with type 2 diabetes mellitus (T2DM) frequently develop cardiovascular complications which contribute significantly to morbidity and mortality. Insulin resistance and endothelial dysfunction are two cardinal features of T2DM. Whether microvascular insulin resistance contributes to the increased cardiovascular morbidity and mortality in patients with T2DM remains to be defined. T2DM is associated with humoral and inflammatory changes that can cause insulin resistance and endothelial dysfunction. Among them, elevation of plasma free fatty acids (FFAs) and over-activation of the renin-angiotensin system (RAS) are thought to play pivotal roles in vascular insulin resistance and endothelial dysfunction, and in the increased cardiovascular morbidity and mortality of diabetes. In the proposed studies, we will test the hypotheses that: 1) elevation of plasma FFAs blunts insulin-mediated cardiac and skeletal muscle microvascular perfusion and glucose uptake by activating inflammatory signaling and increasing endothelin 1 (ET- 1) secretion/action; 2) AT1R blockade increases cardiac and skeletal muscle microvascular perfusion, augments insulin-mediated glucose uptake, and attenuates FFA-induced dysfunction in the coronary and skeletal muscle microcirculation in healthy humans; and 3) patients with diabetes have decreased coronary microvascular flow reserve and blunted vasodilatory response upon insulin stimulation in the cardiac and skeletal muscle microvasculature, and that these abnormalities are corrected with anti-inflammatory therapy and/or AT1R blockade. We will quantify cardiac and skeletal muscle microvascular perfusion in healthy and diabetic humans and examine the potential mechanisms underlying microvascular insulin resistance. Results from the proposed studies should help to define the mechanisms underlying insulin resistance in cardiac and skeletal muscle microvasculature in diabetic humans and open a new avenue for future mechanistic, diagnostic and/or therapeutic studies. PUBLIC HEALTH RELEVANCE: Patients with type 2 diabetes are prone to suffer heart diseases such as heart attack and heart failure; both cause significant morbidity and mortality. The underlying mechanisms remain unclear. Patients with type 2 diabetes have decreased responses to insulin, a condition called insulin resistance. Insulin resistance has been implicated in the development of cardiovascular diseases in diabetic patients. Insulin increases blood flow, hence oxygen and nutrient delivery, to tissues, including heart and skeletal muscle. We and others have recently shown that insulin resistance is present in the small blood vessels in heart and skeletal muscle. Whether this contributes to the increased cardiovascular morbidity and mortality in persons with diabetes is not known. Diabetes is associated with many biochemical abnormalities which are capable of causing insulin resistance and abnormal vascular function in peripheral tissues. In this proposal, we plan to examine whether these abnormalities impair insulin action in the small vessels in human heart and skeletal muscle and whether patients with type 2 diabetes have an abnormal response to insulin in small blood vessels that nourish the heart and skeletal muscle. We will use state-of-the-art techniques to non- invasively measure small blood vessel perfusion in the human heart and skeletal muscle. Results from the proposed studies should shed light to our understanding of the relationship between type 2 diabetes and cardiovascular diseases in humans and open a new avenue for future mechanistic, diagnostic and/or therapeutic studies.

描述（由申请人提供）：2 型糖尿病 (T2DM) 患者经常出现心血管并发症，这对发病率和死亡率有显着影响。胰岛素抵抗和内皮功能障碍是 T2DM 的两个主要特征。微血管胰岛素抵抗是否导致 T2DM 患者心血管发病率和死亡率增加仍有待确定。 T2DM 与体液和炎症变化有关，可导致胰岛素抵抗和内皮功能障碍。其中，血浆游离脂肪酸（FFA）升高和肾素-血管紧张素系统（RAS）过度激活被认为在血管胰岛素抵抗和内皮功能障碍以及糖尿病心血管发病率和死亡率增加中发挥关键作用。在拟议的研究中，我们将测试以下假设：1）血浆 FFA 升高通过激活炎症信号和增加内皮素 1 (ET-1) 分泌/作用来减弱胰岛素介导的心脏和骨骼肌微血管灌注和葡萄糖摄取； 2) AT1R阻断可增加心脏和骨骼肌微血管灌注，增强胰岛素介导的葡萄糖摄取，并减轻FFA引起的健康人冠状动脉和骨骼肌微循环功能障碍； 3) 糖尿病患者在心脏和骨骼肌微血管系统中胰岛素刺激后，冠状动脉微血管血流储备减少，血管舒张反应减弱，这些异常可以通过抗炎治疗和/或 AT1R 阻断来纠正。我们将量化健康人和糖尿病人的心脏和骨骼肌微血管灌注，并研究微血管胰岛素抵抗的潜在机制。拟议研究的结果应有助于确定糖尿病患者心脏和骨骼肌微血管系统胰岛素抵抗的潜在机制，并为未来的机制、诊断和/或治疗研究开辟新途径。公共卫生相关性：2型糖尿病患者容易罹患心脏病和心力衰竭等心脏病；两者都会导致显着的发病率和死亡率。根本机制仍不清楚。 2 型糖尿病患者对胰岛素的反应降低，这种情况称为胰岛素抵抗。胰岛素抵抗与糖尿病患者心血管疾病的发展有关。胰岛素增加血流量，从而增加氧气和营养物质向组织（包括心脏和骨骼肌）的输送。我们和其他人最近表明，胰岛素抵抗存在于心脏和骨骼肌的小血管中。这是否会导致糖尿病患者心血管发病率和死亡率增加尚不清楚。糖尿病与许多生化异常有关，这些异常能够导致胰岛素抵抗和外周组织血管功能异常。在这项提案中，我们计划检查这些异常是否会损害人类心脏和骨骼肌小血管中的胰岛素作用，以及2型糖尿病患者在滋养心脏和骨骼肌的小血管中是否对胰岛素有异常反应。我们将使用最先进的技术来非侵入性地测量人类心脏和骨骼肌中的小血管灌注。拟议研究的结果应该有助于我们理解人类 2 型糖尿病和心血管疾病之间的关系，并为未来的机制、诊断和/或治疗研究开辟新途径。