INSULIN AND SARCOPENIA IN THE ELDERLY

我们的一般假设是，肌肉蛋白质合成代谢对胰岛素的反应减弱在随着年龄增长而发生的肌肉质量损失中起着重要作用。我们进一步假设，无论糖耐量状态如何，这种改变都是蛋白质代谢所特有的。我们的初步结果表明，老年人肌肉合成代谢对胰岛素的反应发生了改变，这可能抵消了氨基酸对餐后肌肉蛋白质增加的积极作用。这项建议的目的是确定胰岛素刺激的肌肉蛋白质合成代谢与年龄相关的变化，以便能够开发特定的干预措施来减少或逆转随年龄增长而造成的肌肉质量损失。我们将检验这一假设，即在健康的老年志愿者和年轻的健康对照组中，肌肉、肌原纤维和混合蛋白的合成和分解对胰岛素的反应性降低。胰岛素将被局部注入股动脉，以使肌肉组织暴露在特定浓度的胰岛素下，并尽可能避免高胰岛素血症(即低氨基酸血症和低血糖)的全身影响。由于老年人肌肉蛋白质合成代谢的缺陷可以概括为任何胰岛素浓度，也可以是剂量依赖性的，即特定于某一胰岛素水平(例如膳食)，我们将在分级胰岛素输注速率下测量肌肉蛋白质动力学，这将使股静脉中的胰岛素浓度增加到约30Muu/ml(低剂量)，约80Muu/ml(膳食剂量)，约200Muu/ml(高剂量)。为了解决肌肉蛋白质代谢对胰岛素反应的年龄相关性改变是否是独立的或葡萄糖耐量的问题，我们不仅在健康的年轻人和老年人志愿者中，而且在年轻人和老年2型糖尿病患者中，同时测量肌肉和全身的葡萄糖动力学和蛋白质动力学。将这两组额外的2型糖尿病患者包括在内，将使我们能够测试胰岛素抵抗(2型糖尿病)和年龄对肌肉蛋白质和葡萄糖代谢的影响是否独立。

Our general hypothesis is that a reduced response of muscle protein anabolism to insulin plays an important role in the loss of muscle mass that takes place with aging. We further hypothesize that this alteration is specific for protein metabolism regardless of glucose tolerance status. Our preliminary results suggest that there is an alteration in the response of muscle anabolism to insulin in the elderly, which can compromise the positive effect of amino acids on postprandial muscle protein gain. The goal of this proposal is to define the age-related changes in insulin stimulated muscle protein anabolism, in order to be able to develop specific interventions to reduce or reverse the loss of muscle mass with aging. We will test the hypothesis that the responsiveness of muscle myofibrillar and mixed protein synthesis and breakdown to insulin is reduced in healthy elderly volunteers and in young healthy controls. Insulin will be infused locally in the femoral artery in order to expose the muscle tissue to specific insulin concentrations and avoids as much as possible the systemic effects of hyperinsulinemia (i.e. hypoaminoacidemia and hypoglycemia). Since the defect of muscle protein anabolism in the elderly might be either generalized for any insulin concentration, or dose-dependent, i.e. specifically localized to a certain insulin level (e.g. prandial), we will measure muscle protein kinetics at graded insulin infusion rates that will increase insulin concentration in the femoral vein to approximatley 30 muU/ml (low dose), approximately 80 muU/ml (prandial dose), approximately 200 muU/ml (high dose). To address the issue as to whether the age-related alteration in the response of muscle protein metabolism to insulin is independent or glucose tolerance, we will measure muscle and whole body glucose kinetics simultaneously with protein kinetics not only in the healthy young and elderly volunteers, but also in young and elderly type 2 diabetes patients. The inclusion of these two additional groups of type 2 diabetic patients will allow us to test if the effects of insulin resistance (type 2 diabetes) and age on muscle protein and glucose metabolism are indpendent.