Effect of age on glucose and lipid metabolism

描述（由申请人提供）：衰老是2型糖尿病（T2DM）发展的主要危险因素。骨骼肌是胰岛素刺激下葡萄糖处理的主要部位，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细胞内脂质积累，从而损害胰岛素的作用。然而，细胞内脂肪积累的分子基础仍不清楚。amp活化蛋白激酶（AMPK）是一种能量感应酶，其激活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。使用胰岛素钳技术和肌肉活检，以及一个原代人肌肉细胞培养系统，我们计划测试一个假设，即与年龄相关的AMPK信号的下降是导致脂肪氧化减少的原因，过度的细胞内脂质积累，以及发生在衰老的人类肌肉中的胰岛素抵抗。本文提出以下具体目的：目的1)确定体内老年受试者肌肉中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，以及体力活动是否通过上调肌肉中AMPK信号改善老年受试者的葡萄糖稳态；目的2)确定体外培养的老年肌管中AMPK信号的年龄相关性下降是否会增加脂肪诱导的胰岛素抵抗的易感性；目的3)研究老年肌管中脂肪氧化和胰岛素作用的年龄相关减少是否可以通过上调AMPK活性来逆转。

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.