Endothelial Abnormalities in Obesity/Insulin Resistance

描述（由申请人提供）：发生在胰岛素抵抗的糖尿病前期状态的血管内皮功能损伤，特别是内皮依赖性血管舒张，被认为是2型糖尿病患者动脉粥样硬化性血管疾病发病率加快的原因之一。内皮血管舒张功能障碍在血管疾病的发病早期就出现，并有助于动脉粥样硬化病变、血管痉挛、斑块破裂、内膜生长，进而导致冠状动脉和脑血管事件的发生。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剂功能丧失的机制可能会导致治疗干预的新靶点。因此，本提案的具体目的将是确定：1)肥胖/胰岛素抵抗观察到的前臂内皮血管扩张剂对乙酰胆碱的钝化反应是否反映了一种特定的激动剂相关缺陷或更普遍的内皮血管扩张剂异常；2)肥胖/胰岛素抵抗中观察到的前臂内皮血管扩张剂对乙酰胆碱的钝化反应是否与：(a)对乙酰胆碱的反应性降低；(b)增加胆碱酯酶活性；(c)受刺激一氧化氮释放的选择性损伤；(d)毒蕈碱受体功能和/或数量减少；3)定期耐力运动是否能改善血管内皮舒张剂功能，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名中老年肥胖/胰岛素抵抗和非肥胖/胰岛素敏感的成年人进行研究。通过臂内输注乙酰胆碱、P物质、缓激肽、异丙肾上腺素和甲胆碱后前臂血流量（FBF：容积描记图）的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对某些激动剂的反应也将在NG存在的情况下确定。单甲基精氨酸（一氧化氮合酶抑制剂）或阿托品（毒蕈碱受体阻滞剂）解决特定目标2c和2d。在一个肥胖/胰岛素抵抗的成人亚组中，内皮血管扩张功能也将在3个月的有氧运动计划后进行评估。该研究的结果将为肥胖/胰岛素抵抗成人前臂内皮血管扩张剂功能障碍是否与特定受体缺陷或更普遍的内皮异常有关提供机制见解。

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.