INSULIN RESISTANCE AND PROTEIN METABOLISM

胰岛素抵抗和蛋白质代谢

• 批准号: 6790873
• 负责人: WIlliam J Evans
• 金额: $ 26.81万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6790873
• 关键词: dietary control; glucose tolerance; glucose tolerance test; human old age (65+); human subject; insulin sensitivity /resistance; metformin; muscle metabolism; muscle proteins; patient oriented research; protein biosynthesis; restricted physical activity

Aging is associated with decreased skeletal muscle mass and increased total body and visceral fat. Elderly people are the most likely segment of the population to remain in bed for extended periods of time for a variety of reasons. Considerable literature exists on the effects of prolonged bedrest in healthy young people---accelerated loss of muscle and the development of insulin resistance--but very little is known about the physiological, metabolic, and functional consequences of bedrest in older people. Therefore, the effects of 10 days of bedrest will be examined in two groups of elderly men and women: normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). The overall goal is to examine the effects of reduced insulin action on skeletal muscle protein metabolism. Five hypotheses will be tested. (1) Insulin resistance exerts an important effect on muscle protein metabolism. (2) Hepatic insulin resistance plays a role in the bedrest-induced peripheral insulin resistance with IGT, Increased hepatic glucose production, even during conditions of elevated insulin levels will result in hyperglycemia and reduced muscle fat oxidation. It is clear that bedrest increases tissue sensitivity to cortisol, potentially exacerbating the hepatic insulin resistance and accelerating loss of muscle protein. (3) Reduced insulin-stimulated glucose disposal results in a decreased rate of muscle protein synthesis and an accelerated loss of muscle during bedrest. Specifically, individuals with NGT will demonstrate reduced loss of muscle compared with those individuals with IGT. (4) Insulin resistance and bedrest will result in an alteration in the skeletal muscle insulin signaling cascade ultimately affecting the rate of muscle protein synthesis. (5) Metformin, a powerful hypoglycemic agent, will prevent many of the bedrest induced adaptations in subjects with IGT. Dietary intake during bedrest will be carefully controlled (eucaloric with 0.8 g protein ? kg-1 ? d-1) so that nitrogen balance may be measured during the entire 10-day period. This project and the interaction with the other projects in this PPG will, for the first time, examine the effect of bedrest in elderly people and provide critical information for the clinical management of bedrest-induced metabolic abnormalities in this vulnerable population.

衰老与骨骼肌质量减少以及全身和内脏脂肪增加有关。 由于各种原因，老年人是最有可能长时间卧床的人群。有大量文献探讨长期卧床对健康年轻人的影响——加速肌肉流失和胰岛素抵抗的发展——但对老年人卧床休息的生理、代谢和功能后果知之甚少。因此，将在两组老年男性和女性中检查卧床休息 10 天的影响：正常糖耐量 (NGT) 和糖耐量受损 (IGT)。总体目标是检查胰岛素作用减少对骨骼肌蛋白质代谢的影响。将测试五个假设。 (1)胰岛素抵抗对肌肉蛋白质代谢有重要影响。 (2)肝脏胰岛素抵抗发挥作用 在卧床诱导的外周胰岛素抵抗伴 IGT 中，即使在胰岛素水平升高的情况下，肝葡萄糖生成也会增加，从而导致高血糖并减少肌肉脂肪氧化。很明显，卧床休息会增加组织对皮质醇的敏感性，可能会加剧肝脏胰岛素抵抗并加速肌肉蛋白的损失。 (3) 胰岛素刺激的葡萄糖处理减少导致肌肉蛋白质合成速率降低，卧床期间肌肉损失加速。具体来说，与 IGT 患者相比，NGT 患者的肌肉损失减少。 (4) 胰岛素抵抗和卧床会导致骨骼肌胰岛素信号级联的改变，最终影响肌肉蛋白质合成的速率。 (5) 二甲双胍是一种强效降血糖药，可防止 IGT 患者卧床休息引起的许多适应。卧床休息期间的膳食摄入量将得到仔细控制（0.8克蛋白质的等热量×kg-1×d-1），以便可以在整个10天期间测量氮平衡。这个项目和 与该 PPG 中其他项目的互动将首次检查卧床休息对老年人的影响，并为这一弱势群体卧床休息引起的代谢异常的临床管理提供关键信息。