Endothelial Abnormalities in Obesity/Insulin Resistance

描述（由申请人提供）：胰岛素抵抗前驱糖尿病状态中发生的血管内皮功能受损，特别是内皮依赖性血管舒张，被认为是2型糖尿病中动脉粥样硬化血管疾病发生率加快的原因。 内皮血管舒张功能障碍在血管疾病的发病机制中早期出现，并有助于动脉粥样硬化病变、血管痉挛、斑块破裂、内膜生长的表现，进而导致冠状动脉和脑血管事件。 此外，前臂内皮血管舒张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舒张功能丧失的机制可能会导致治疗干预的新靶点。 因此，本发明的具体目的是确定：1）在肥胖/胰岛素抵抗的情况下观察到的前臂内皮血管扩张剂对乙酰胆碱的反应迟钝是否反映了特定的激动剂相关缺陷或更一般的内皮血管扩张剂异常; 2）在肥胖/胰岛素抵抗的情况下观察到的前臂内皮血管扩张剂对乙酰胆碱的反应迟钝是否与以下有关：（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的选择性损害;（d）毒蕈碱受体功能和/或数量减少;和3）定期耐力运动计划是否改善内皮血管舒张功能，以及该改善是否与胰岛素敏感性增加相关。 为了实现这些目标，将对180名中老年肥胖/胰岛素抵抗和非肥胖/胰岛素敏感成人进行研究。 将通过前臂血流（FBF：体积描记法）对臂内输注乙酰胆碱、P物质、缓激肽、异丙肾上腺素和乙酰甲胆碱的反应变化来评估内皮依赖性血管舒张。 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NO释放。 FBF对一些激动剂的反应也将在NG.单甲基精氨酸（一氧化氮合酶抑制剂）或阿托品（毒蕈碱受体阻断剂）存在下测定，以解决具体目标2c和2d。 在一个肥胖/胰岛素抵抗成人亚组中，也将在3个月的有氧运动计划后评估内皮血管舒张功能。 拟议的研究结果应提供机制洞察前臂内皮血管舒张功能障碍的肥胖/胰岛素抵抗的成年人是否与一个特定的受体缺陷或更普遍的内皮异常。

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.