Insulin action in human cardiac and skeletal muscle microvasculature

描述（由申请方提供）：2型糖尿病（T2 DM）患者经常发生心血管并发症，这是导致发病率和死亡率显著增加的原因。胰岛素抵抗和内皮功能障碍是2型糖尿病的两个主要特征。微血管胰岛素抵抗是否导致T2 DM患者心血管发病率和死亡率增加仍有待确定。T2 DM与体液和炎症变化相关，这些变化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）的升高和肾素-血管紧张素系统（RAS）的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起关键作用。在本研究中，我们将验证以下假设：1）血浆游离脂肪酸升高通过激活炎症信号和增加内皮素1（ET- 1）的分泌/作用，减弱胰岛素介导的心肌和骨骼肌微血管灌注和葡萄糖摄取; 2）AT 1 R阻断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，并减弱FFA诱导的健康人冠状动脉和骨骼肌微循环功能障碍;和3）糖尿病患者在心脏和骨骼肌微血管系统中具有降低的冠状动脉微血管血流储备和对胰岛素刺激的钝化的血管舒张反应，并且这些异常可以通过抗炎治疗和/或AT 1 R阻断来纠正。我们将量化健康人和糖尿病患者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中胰岛素抵抗的潜在机制，并为未来的机制、诊断和/或治疗研究开辟新的途径。 公共卫生相关性：2型糖尿病患者易患心脏病，如心脏病发作和心力衰竭;两者均导致显著的发病率和死亡率。其潜在机制尚不清楚。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生有关。胰岛素增加血流量，从而增加氧气和营养物质输送到组织，包括心脏和骨骼肌。我们和其他人最近发现，胰岛素抵抗存在于心脏和骨骼肌的小血管中。这是否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相关，这些异常能够引起胰岛素抵抗和外周组织中的异常血管功能。在这项提案中，我们计划研究这些异常是否会损害人体心脏和骨骼肌小血管中的胰岛素作用，以及2型糖尿病患者是否对滋养心脏和骨骼肌的小血管中的胰岛素有异常反应。我们将使用最先进的技术来非侵入性地测量人体心脏和骨骼肌中的小血管灌注。从拟议的研究结果应该阐明我们的2型糖尿病和心血管疾病之间的关系在人类的理解，并开辟了未来的机制，诊断和/或治疗研究的新途径。

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.