Effect of age on glucose and lipid metabolism

描述(申请人提供)：年龄是发展为2型糖尿病(T2 DM)的主要危险因素。骨骼肌是胰岛素刺激的葡萄糖代谢的主要部位，衰老以肌肉胰岛素抵抗为特征。有人认为，衰老的胰岛素抵抗是由于与年龄相关的心肌细胞内脂质的积聚，从而削弱了胰岛素的作用。然而，细胞内脂肪积聚的分子基础仍不清楚。AMP激活的蛋白激酶(AMPK)是一种能量敏感酶，它的激活会导致脂肪酸氧化的增加。最近，人们发现衰老会导致肌肉中AMPK活性降低。利用胰岛素钳夹技术结合肌肉活检和原代人类肌肉细胞培养系统，我们计划检验这一假说，即与年龄相关的AMPK信号的下降是衰老的人类肌肉中脂肪氧化减少、细胞内脂肪过度堆积和胰岛素抵抗发生的原因。提出了以下具体目标：目的1)确定在体内老年人肌肉中AMPK信号的减少是否与较低的脂肪氧化率和胰岛素抵抗有关，以及体育活动是否通过上调肌肉中的AMPK信号来改善老年人的葡萄糖稳态；目的2)确定体外培养的老年肌管中AMPK信号的年龄相关下降是否增加了脂肪诱导的胰岛素抵抗的易感性；以及目的3)研究是否可以通过上调AMPK活性来逆转老年肌管中与年龄相关的脂肪氧化和胰岛素作用的减少。 公共卫生相关性：老龄化与患2型糖尿病和糖耐量受损的高风险有关，糖耐量受损是一种糖尿病前期状态。然而，老年受试者发生这些葡萄糖(糖)代谢异常的高风险的原因尚不清楚。在这项研究中，我们将测试一种名为AMPK的蛋白质活性降低是否与老年人糖代谢异常有关，以及恢复这种蛋白质的功能是否会改善这些人的葡萄糖代谢。如果是阳性的，我们的发现可能有助于设计新的方法来预防老年人的2型糖尿病。

DESCRIPTION (provided by applicant): Aging is a major risk factor for the development of type 2 diabetes (T2DM). Skeletal muscle is the main site of insulin-stimulated glucose disposal and aging is characterized by muscle insulin resistance. It has been suggested that the insulin resistance of aging results from an age-related accumulation of intramyocellular lipids which impair insulin action. However, the molecular basis for the accumulation of intramyocellular fat remains unknown. AMP-activated protein kinase (AMPK) is an energy-sensing enzyme whose activation results in increased fatty acid oxidation. Recently, it has been established that aging leads to reduced AMPK activity in muscle. Using the insulin clamp technique with muscle biopsies, and a primary human muscle cell culture system, we plan to test the hypothesis that age-related declines in AMPK signaling are responsible for the decreases in fat oxidation, excessive intramyocellular lipid accumulation, and insulin resistance that occur in aging human muscle. The following Specific Aims are proposed: Aim 1) To determine whether reduced AMPK signaling in muscle from older subjects, in vivo, is associated with lower fat oxidation rates and insulin resistance, and whether physical activity improves glucose homeostasis in older subjects by upregulating AMPK signaling in muscle; Aim 2) To determine whether age-related declines in AMPK signaling in old myotubes cultured in vitro increases the susceptibility to fat-induced insulin resistance; and Aim 3) To examine whether the age-related reductions in fat oxidation and insulin action in old myotubes can be reversed by upregulating AMPK activity. PUBLIC HEALTH RELEVANCE: Aging is associated with a high risk for developing type 2 diabetes and impaired glucose tolerance, a pre- diabetic state. However, the reason why older subjects are at high risk for developing these abnormalities in glucose (sugar) metabolism is not known. In this study we will test whether reduced activity of a protein called AMPK is responsible for the abnormal glucose metabolism that occurs in older subjects, and whether restoring the function of this protein improves glucose metabolism in these individuals. If positive, our findings could help design new ways to prevent type 2 diabetes in the elderly.