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。我们进一步假设这种改变是蛋白质代谢特异性的，而与葡萄糖耐量状态无关。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变化，这可能会损害氨基酸对餐后肌肉蛋白质增加的积极作用。本提案的目标是确定胰岛素刺激肌肉蛋白质合成代谢的年龄相关变化，以便能够开发特定的干预措施来减少或逆转随着年龄增长而失去的肌肉质量。我们将检验在健康老年志愿者和年轻健康对照中肌肉肌纤维和混合蛋白合成和分解对胰岛素的反应性降低的假设。胰岛素将在股动脉局部输注，以便使肌肉组织暴露于特定的胰岛素浓度，并尽可能避免高胰岛素血症（即低胺酸血症和低血糖症）的全身影响。由于老年人肌肉蛋白合成代谢的缺陷可能是任何胰岛素浓度的普遍缺陷，也可能是剂量依赖性的，即特异性地局限于某一胰岛素水平（如膳食），因此我们将在逐步胰岛素输注速率下测量肌肉蛋白动力学，这将使股静脉胰岛素浓度增加到约30 muU/ml（低剂量），约80 muU/ml（膳食剂量），约200 muU/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改变是独立的还是糖耐量的问题，我们将在健康的青年和老年志愿者以及青年和老年2型糖尿病患者中同时测量肌肉和全身葡萄糖动力学和蛋白质动力学。纳入这两组额外的2型糖尿病患者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.