Effects of Insulin on Post-Burn Hypermetabolism

描述(由申请人提供)： 对损伤的高代谢反应通过增加相对于蛋白质合成的蛋白质分解而导致肌肉萎缩。这种肌肉萎缩会延长愈合时间和延迟完全功能恢复的时间，从而增加发病率和死亡率。我们小组最近所做的研究表明，在严重烧伤患者短期使用胰岛素等合成代谢剂会降低蛋白质分解代谢。然而，住院期间持续应用合成代谢药物治疗对体成分和功能恢复的临床参数的影响还没有系统的研究。我们研究的目的是证明用胰岛素可以减轻因损伤而导致的肌肉萎缩，从而改善临床结果。在这项建议中，我们将研究以下目标：1.确定整个住院过程中正常血糖高胰岛素血症对肌肉蛋白质净合成的影响，并将持续的肌肉合成代谢与改善严重烧伤患者的瘦体重和改善功能恢复联系起来。2.探讨严重烧伤患者胰岛素对骨骼肌生理和分子效应的关系。我们将测试以下假设：a)胰岛素对净蛋白质合成的急性影响在整个住院过程中持续存在，以及b)在整个住院过程中持续刺激肌肉净蛋白质合成并伴随正常血糖高胰岛素血症将与可识别的分子变化相关。随着这项提议的完成，我们将首次证明，长期使用合成代谢剂胰岛素治疗不仅可以改善生理测量，还可以改善瘦体重、肌肉功能和临床结果。我们还将演示这些变化发生的机制，为严重损伤相关的分解代谢过程中的合成代谢药物治疗提供进一步的基础。

DESCRIPTION (provided by applicant): The hypermetabolic response to injury causes muscle wasting through increased protein breakdown relative to protein synthesis. This muscle wasting increases morbidity and mortality by prolonging healing and delaying time to full functional recovery. Recent studies done by our group indicate that anabolic agents such as insulin decrease protein catabolism when used over short terms in the severely burned. However, continuous anabolic agent treatment throughout hospitalization on clinical parameters of body composition and functional recovery have not been systematically studied. The goal of our studies is to show that muscle wasting with injury can be attenuated with insulin to improve clinical outcomes. In this proposal, we will investigate these aims: 1. To determine the effect of euglycemic hyperinsulinemia throughout the hospital course on net muscle protein synthesis, and to relate continued muscle anabolism to improved lean body mass and improved functional recovery in severely burned patients. 2. To assess the relationship of insulin's physiologic and molecular effects on skeletal muscle in severely burned patients. We will test the hypotheses that: a) the acute effects of insulin on net protein synthesis are sustained throughout the hospital course, and b) continued stimulation of net muscle protein synthesis with euglycemic hyperinsulinemia throughout the hospital course will be associated with identifiable molecular changes. With completion of this proposal, we will demonstrate, for the first time, that prolonged treatment with the anabolic agent, insulin, will not only result in improved physiologic measurements, but will also improve lean body mass, muscular function, and clinical outcomes. We will also demonstrate mechanisms by which these changes take place, to provide further basis for anabolic agent therapy during catabolism associated with severe injury.