Endothelial Abnormalities in Obesity/Insulin Resistance

描述(由申请人提供)：在胰岛素抵抗的糖尿病前期状态中发生的血管内皮功能受损，特别是内皮依赖性血管扩张，被认为是导致2型糖尿病动脉粥样硬化性血管疾病加速发生的原因。内皮血管扩张功能障碍在血管疾病的发病机制中早期存在，并导致动脉粥样硬化病变、血管痉挛、斑块破裂、内膜生长，进而导致冠状动脉和脑血管事件。此外，前臂内皮血管扩张剂功能障碍已被证明是未来心血管事件的标志。因此，更好地了解与胰岛素抵抗相关的内皮血管扩张功能丧失的机制可能会为治疗干预带来新的靶点。因此，本提案的具体目的将是确定：1)肥胖/胰岛素抵抗时观察到的对乙酰胆碱的钝性前臂内皮血管扩张反应是否反映了特定的激动剂相关缺陷，或者更确切地说，反映了更一般的内皮血管扩张异常；2)肥胖/胰岛素抵抗时观察到的对乙酰胆碱的迟钝的前臂内皮血管扩张反应是否与：(A)对乙酰胆碱的反应性降低；(B)胆碱酯酶活性增加；(C)刺激的一氧化氮释放选择性受损；(D)M受体功能和/或数量减少；3)定期耐力运动是否能改善内皮血管扩张剂功能，以及这种改善是否与胰岛素敏感性增加有关。为了实现这些目标，将对180名肥胖/胰岛素抵抗和非肥胖/胰岛素敏感的中年和老年成年人进行研究。内皮依赖性血管扩张将通过臂内注射乙酰胆碱、P物质、缓激肽、异丙肾上腺素和乙酰甲胆碱后前臂血流(FBF：体积描记)的变化来评估。这些内皮激动剂通过不同的细胞表面受体和细胞内G蛋白介导的信号转导途径刺激内皮细胞释放NO。FBF对某些激动剂的反应也将在NG.一甲基精氨酸(一氧化氮合酶抑制剂)或阿托品(毒鼠碱受体阻滞剂)存在的情况下进行测定，以解决特定的目标2c和2d。在一组肥胖/胰岛素抵抗的成年人进行为期3个月的有氧运动后，还将对内皮血管扩张功能进行评估。这项拟议的研究结果应该为肥胖/胰岛素抵抗成年人的前臂内皮血管扩张功能障碍提供机制上的洞察，是与特定的受体缺陷有关，还是与更普遍的内皮异常有关。

DESCRIPTION (provided by applicant): Impairments in vascular endothelial function, particularly endothelium-dependent vasodilation, occurring in insulin resistant prediabetic states are thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelial vasodilatory dysfunction presents early in the pathogenesis of vascular disease, and contributes to the manifestation of atherogenic lesions, vasospasm, plaque rupture, intimal growth, and, in turn, coronary and cerebrovascular events. Moreover, forearm endothelial vasodilator dysfunction has been shown to be a marker of future cardiovascular events. Thus, a better understanding of the mechanisms responsible for the loss in endothelial vasodilator function associated with insulin resistance may lead to new targets for therapeutic intervention. Accordingly, the specific aims of the present proposal will be to determine: 1) if the blunted forearm endothelial vasodilator response to acetylcholine observed with obesity/insulin resistance reflects a specific agonist-related defect or rather a more general endothelial vasodilator abnormality; 2) whether the blunted forearm endothelial vasodilator response to acetylcholine observed with obesity/insulin resistance is related to: (a) decreased responsiveness to acetylcholine; (b) increase cholinesterase activity; (c) a selective impairment in stimulated nitric oxide release; (d) reduced muscarinic receptor function and/or number; and 3) if a program of regular endurance exercise improves endothelial vasodilator function, and whether the improvement is associated with increased insulin sensitivity. To address these aims, 180 middle-aged and older obese/insulin resistant and non-obese/insulin sensitive adults will be studied. Endothelium-dependent vasodilation will be assessed by changes in forearm blood flow (FBF: plethysmography) in response to intrabrachial infusions of acetylcholine, substance P, bradykinin, isoproterenol and methacholine. These endothelial agonists stimulate endothelial NO release via different cell surface receptors and intracellular G-protein-mediated signal transduction pathways. FBF responses to some agonists will also be determined in the presence of either NG.monomethyl arginine (nitric oxide synthase inhibitor) or atropine (muscarinic receptor blocker) to address specific aim 2c and 2d. Endothelial vasodilator function will also be assesed after a 3-month aerobic exercise program in a subgroup of obese/insulin resistant adults. The results of the proposed study should provide mechanistic insight into whether forearm endothelial vasodilator dysfunction in obese/insulin resistant adults is related to a specific receptor defect or a more general endothelial abnormality.