Effect of age on glucose and lipid metabolism

描述（由申请人提供）：衰老是2型糖尿病（T2 DM）发展的主要风险因素。骨骼肌是胰岛素刺激的葡萄糖代谢的主要场所，衰老以肌肉胰岛素抵抗为特征。已经表明，衰老的胰岛素抵抗是由于与年龄相关的肌细胞内脂质的积累损害了胰岛素的作用。然而，肌细胞内脂肪积累的分子基础仍然未知。AMP活化蛋白激酶（AMPK）是一种能量敏感酶，其活化导致脂肪酸氧化增加。最近，已经确定衰老导致肌肉中AMPK活性降低。使用胰岛素钳技术与肌肉活检，和原代人肌肉细胞培养系统，我们计划测试的假设，年龄相关的下降AMPK信号是负责减少脂肪氧化，过度的肌细胞内脂质积累，和胰岛素抵抗，发生在老化的人肌肉。提出了以下具体目的：目的1）确定老年受试者体内肌肉中AMPK信号传导的减少是否与较低的脂肪氧化速率和胰岛素抗性相关，以及体力活动是否通过上调肌肉中AMPK信号传导来改善老年受试者的葡萄糖稳态;目的2）研究体外培养的老年肌管中AMPK信号的年龄相关性下降是否增加了脂肪诱导的胰岛素抵抗的易感性;和目的3）检测是否可以通过上调AMPK活性来逆转衰老肌管中脂肪氧化和胰岛素作用的年龄相关性降低。 公共卫生相关性：衰老与发展2型糖尿病和糖耐量受损（一种糖尿病前期状态）的高风险相关。然而，老年受试者发生葡萄糖（糖）代谢异常的风险较高的原因尚不清楚。在这项研究中，我们将测试一种名为AMPK的蛋白质的活性降低是否是导致老年受试者葡萄糖代谢异常的原因，以及恢复这种蛋白质的功能是否会改善这些个体的葡萄糖代谢。如果结果是肯定的，我们的研究结果可以帮助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.