Obesity/Insulin Resistance, Vitamin C and Endothelin-1

描述（由申请人提供）：有证据表明，内皮病变是肥胖/胰岛素抵抗和2型糖尿病的内在原因。 在肥胖/胰岛素抵抗的糖尿病前期阶段发生的血管舒张功能的改变，特别是血管舒张和血管收缩之间的不平衡，被认为有助于2型糖尿病中动脉粥样硬化性血管疾病的加速发生。 内皮素-1（ET-1）是由血管内皮细胞产生的一种强有力的血管收缩剂。 除了对血管张力的影响外，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、内皮依赖性血管舒张受损和ET-1产生和活性增加相关。 本发明的具体目的是确定：1）内源性ET-1的血管收缩活性是否在肥胖/胰岛素抵抗的成年人中增加; 2）口服维生素C补充剂是否与常规有氧运动一样多或更多地降低肥胖/胰岛素抵抗的成年人中的内源性ET-1血管收缩活性;和3）口服维生素C补充剂是否与常规有氧运动一样或更多地改善肥胖/胰岛素抵抗成年人的内皮依赖性血管舒张;并确定内皮血管舒张的改善是否至少部分是由于ET-1血管收缩剂活性的降低。 为了实现这些目标，将对252名中年和老年肥胖/胰岛素抵抗和瘦/胰岛素敏感的成年人进行研究。 内源性ET-1血管收缩活性将通过前臂血流（体积描记法）对选择性和非选择性ET-1受体拮抗剂以及外源性ET-1动脉内输注的反应变化进行评估。 此外，将在不存在和存在ET-1受体阻断剂的情况下测定对乙酰胆碱和硝普钠的血管舒张反应。 内源性ET-1血管收缩活性也将在肥胖/胰岛素抵抗成人口服维生素C补充剂（500 mg/d）或有氧运动训练12周干预前后进行评估。 所提出的研究的结果应该提供关于肥胖/胰岛素抵抗的ET-1系统的活性的临床重要信息;以及维生素C补充在减少ET-1介导的血管收缩中的功效，并且进而改善肥胖/胰岛素抵抗成人中的内皮血管收缩调节。

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.