Obesity/Insulin Resistance, Vitamin C and Endothelin-1

描述(申请人提供)：有证据表明，内皮病是肥胖/胰岛素抵抗的内在原因，进而导致2型糖尿病。在肥胖/胰岛素抵抗的糖尿病前期阶段，血管运动功能的改变，特别是血管扩张和血管收缩之间的失衡，被认为是2型糖尿病动脉粥样硬化性血管疾病加速发生的原因之一。内皮素-1(ET-1)是一种由血管内皮细胞产生的强效血管收缩因子。除了对血管紧张性的影响，ET-1还与动脉粥样硬化的发生和发展有关。重要的是，氧化应激与肥胖/胰岛素抵抗、内皮依赖性血管扩张受损以及ET-1的产生和活性增加有关。本建议的具体目的将是确定：1)肥胖/胰岛素抵抗成年人内源性ET-1的血管收缩活性是否增加；2)口服维生素C是否能降低肥胖/胰岛素抵抗成年人的内源性ET-1血管收缩活性，与常规有氧运动一样或更多；以及3)口服维生素C对肥胖/胰岛素抵抗成年人的内皮依赖性血管扩张的改善是否与常规有氧运动一样多或更多；以及确定内皮血管扩张的改善是否至少部分归因于ET-1血管收缩活性的降低。为了达到这些目标，将对252名肥胖/胰岛素抵抗和瘦/胰岛素敏感的中老年成年人进行研究。内源性ET-1血管收缩活性将通过动脉内注射选择性和非选择性ET-1受体拮抗剂以及外源性ET-1后前臂血流(体积描记)的变化来评估。此外，血管扩张剂对乙酰胆碱和硝普钠的反应将在没有和存在ET-1受体阻断的情况下进行测定。在对肥胖/胰岛素抵抗的成年人进行为期12周的口服维生素C补充剂(500 mg/d)或有氧运动训练的干预前后，还将评估内源性ET-1血管收缩活性。这项拟议的研究结果将为肥胖/胰岛素抵抗患者ET-1系统的活性，以及补充维生素C在减少ET-L介导的血管收缩，进而改善肥胖/胰岛素抵抗成年人的内皮血管运动调节方面的有效性提供重要的临床信息。

DESCRIPTION (provided by applicant): There is evidence that endotheliopathy is intrinsic to obesity/insulin resistance and, in turn, type 2 diabetes. Alterations in vasomotor function, specifically an imbalance between vasodilation and vasoconstriction, occurring in the obese/insulin resistant prediabetic stage is thought to contribute to the accelerated rates of atherosclerotic vascular disease in type 2 diabetes. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the vascular endothelium. In addition to its effects on vascular tone, ET-1 has been linked to the initiation and development of atherosclerosis. Importantly, oxidative stress is associated with obesity/insulin resistance, impaired endothelium-dependent vasodilation and increased ET-1 production and activity. The specific aims of the present proposal will be to determine: 1) whether the vasoconstrictor activity of endogenous ET-1 is increased in obese/insulin resistant adult humans; 2) if oral vitamin C supplementation reduces endogenous ET-1 vasoconstrictor activity in obese/insulin resistant adults as much or more than regular aerobic exercise; and 3) if oral vitamin C supplementation improves endotheliumdependent vasodilation in obese/insulin resistant adult humans as much or more than regular aerobic exercise; and to determine whether improvements in endothelial vasodilation is due, at least in part, to reduced ET-1 vasoconstrictor activity. To address these aims, 252 middle-aged and older obese/insulin resistant and lean/insulin sensitive adult humans will be studied. Endogenous ET-1 vasoconstrictor activity will be assessed by changes in forearm blood flow (plethysmography) in response to intra-arterial infusion of selective and nonselective ET-1 receptor antagonists as well as exogenous ET-1. In addition, the vasodilator response to both acetylcholine and sodium nitroprusside will be determined in the absence and presence of ET-1 receptor blockade. Endogenous ET-1 vasoconstrictor activity will also be assessed before and after a 12-week intervention of either oral vitamin C supplementation (500 mg/d) or aerobic exercise training in obese/insulin resistant adults. The results of the proposed study should provide clinically important information regarding the activity of the ET-1 system with obesity/insulin resistance; and the efficacy of vitamin C supplementation in reducing ET-l-mediated vasoconstriction and, in turn, improving endothelial vasomotor regulation in obese/insulin resistant adults.