INSULIN AND SARCOPENIA IN THE ELDERLY

我们的一般假设是，肌肉蛋白质对胰岛素的反应降低在随着年龄的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，这种改变是特定的蛋白质代谢，无论葡萄糖耐量状态。 我们的初步研究结果表明，有一个改变，在老年人的肌肉胰岛素的反应，这可以妥协的积极作用，氨基酸餐后肌肉蛋白质的增益。该提案的目标是定义胰岛素刺激的肌肉蛋白质的年龄相关变化，以便能够开发特定的干预措施，以减少或逆转肌肉质量随年龄增长而减少。 我们将测试这一假设，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质合成和分解对胰岛素的反应性降低。 将在股动脉局部输注胰岛素，以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的全身效应（即低氨基酸血症和低血糖症）。 由于老年人肌肉蛋白合成代谢的缺陷可能对于任何胰岛素浓度都是普遍存在的，或者是剂量依赖性的，即特异性地局限于一定的胰岛素水平（例如，餐时），我们将在分级的胰岛素输注速率下测量肌肉蛋白动力学，所述胰岛素输注速率将使股静脉中的胰岛素浓度增加至约30 μ U/ml（低剂量），约80 μ U/ml（餐时剂量），约200 μ U/ml（高剂量）。 为了解决与年龄相关的肌肉蛋白质代谢对胰岛素的反应改变是独立的还是葡萄糖耐量的问题，我们将不仅在健康的年轻和老年志愿者中，而且在年轻和老年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.