Obesity/Insulin Resistance, Vitamin C and Endothelin-1

肥胖/胰岛素抵抗、维生素 C 和内皮素-1

• 批准号: 6760537
• 负责人: CHRISTOPHER A DESOUZA
• 金额: $ 31.27万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760537
• 关键词: acetylcholine; aerobic exercise; ascorbate; clinical research; dietary supplements; endothelin; hormone receptor; human subject; insulin sensitivity /resistance; nitroferricyanide; obesity; patient oriented research; plethysmography; vasoconstriction; vasodilation

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.

描述（由申请人提供）：有证据表明内皮病是肥胖/胰岛素抵抗以及 2 型糖尿病所固有的。 肥胖/胰岛素抵抗糖尿病前期阶段发生的血管舒缩功能的改变，特别是血管舒张和血管收缩之间的不平衡，被认为会加速 2 型糖尿病中动脉粥样硬化性血管疾病的发生。 内皮素-1 (ET-1) 是一种由血管内皮产生的有效血管收缩剂。 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以及 ET-1 产生和活性增加有关。 本提案的具体目标是确定：1​​）内源性 ET-1 的血管收缩活性在肥胖/胰岛素抵抗的成年人中是否增加； 2) 口服维生素 C 补充剂对肥胖/胰岛素抵抗成人的内源性 ET-1 血管收缩活性的降低程度是否与常规有氧运动相同或更多； 3) 口服维生素 C 补充剂对肥胖/胰岛素抵抗成年人的内皮依赖性血管舒张的改善效果是否与常规有氧运动一样多或更多；并确定内皮血管舒张的改善是否至少部分归因于 ET-1 血管收缩活性的降低。 为了实现这些目标，将对 252 名中老年肥胖/胰岛素抵抗和瘦/胰岛素敏感的成年人进行研究。 通过动脉内输注选择性和非选择性 ET-1 受体拮抗剂以及外源性 ET-1 引起的前臂血流变化（体积描记法）来评估内源性 ET-1 血管收缩活性。 此外，将在存在或不存在 ET-1 受体阻断的情况下测定对乙酰胆碱和硝普钠的血管舒张反应。 在肥胖/胰岛素抵抗成人中口服维生素 C 补充剂（500 毫克/天）或有氧运动训练的 12 周干预前后，还将评估内源性 ET-1 血管收缩活性。 拟议研究的结果应提供有关 ET-1 系统活性与肥胖/胰岛素抵抗的临床重要信息；以及维生素 C 补充剂在减少 ET-1 介导的血管收缩方面的功效，进而改善肥胖/胰岛素抵抗成人的内皮血管舒缩调节。