Skeletal Muscle Lipid and Insulin Resistance in Aging

描述(申请人提供)：骨骼肌内代谢失调，包括胰岛素抵抗，是老年人面临的一个主要健康问题。这是2型糖尿病(T2 DM)的关键因素，T2 DM是一种几乎每四个老年人中就有一个患有这种疾病的疾病。因此，关于这些老年男性和女性特有的代谢紊乱的病因、预防和治疗的研究是至关重要的。到目前为止，缺乏关于干预引起的骨骼肌脂含量和脂肪氧化能力的变化是否预示着胰岛素抵抗的改善的研究。 许多研究表明，肌肉甘油三酯或心肌细胞内脂质(IMCL)含量升高与胰岛素抵抗有关。然而，来自我们小组和其他小组的最新证据表明，IMCL和胰岛素抵抗之间存在更复杂的关联，可能涉及脂肪氧化能力。 我们的研究支持这一假设，即脂肪酸代谢失调和肌肉脂肪堆积可能是先前久坐不动的老年人胰岛素抵抗的一个机制。此外，我们将提供关于运动可能通过改善氧化脂肪酸代谢来改善老年人胰岛素抵抗的潜在治疗机制的详细理论基础。 我们将采用随机对照运动干预试验来检验总体假设，即运动导致骨骼肌脂肪氧化能力的改善是预测胰岛素抵抗改善的主要因素。我们将利用新的磁共振成像(MRI)、组织化学和生化方法来量化肌肉脂肪含量和分布的变化，以及收缩组织(肌肉)本身的数量。这些变化将与体内和体外脂肪氧化能力的测量以及体内胰岛素抵抗的测量一起测量。 该项目将提供有关运动增强脂肪酸氧化代谢能力和改善老年人胰岛素抵抗的具体机制的新信息，老年人是T2 DM的高危人群。最终，这将有助于确定与骨骼肌代谢失调有关的机制和治疗靶点。

DESCRIPTION (provided by applicant): Metabolic dysregulation within skeletal muscle, including insulin resistance, is a major health problem facing older adults. This is a critical factor for type 2 diabetes mellitus (T2DM), a disease afflicting nearly one in every four older adults. Thus, studies concerning the etiology, prevention and treatment of these metabolic disorders specific to older men and women are crucial. To date, there has been a lack of studies, which have addressed whether alterations in skeletal muscle lipid content and the capacity for fat oxidation induced by intervention predict improvements in insulin resistance. Many studies suggest that elevated muscle triglyceride, or intramyocellular lipid (IMCL) content is associated with insulin resistance. However, recent evidence from our group as well as from others suggests a more complex association between IMCL and insulin resistance, one that likely involves the capacity for fat oxidation. Our studies support the hypothesis that dysregulated fatty acid metabolism and the accumulation of muscle lipid may be a mechanism of insulin resistance in previously sedentary older adults. Further, we will provide a detailed rationale regarding the potential therapeutic mechanisms by which exercise may improve insulin resistance in older adults through improved oxidative fatty acid metabolism. We will employ a randomized controlled exercise intervention trial to test the overall hypothesis that exercise-induced improvement in the capacity for fat oxidation in skeletal muscle is a primary factor which predicts improvements in insulin resistance. We will utilize novel magnetic resonance imaging (MRI), histochemical and biochemical approaches to quantify changes in muscle lipid content and distribution and also the amount of contractile tissue (muscle) itself. These changes in will be measured in conjunction with in vivo and in vitro measures of the capacity for fat oxidation and with in vivo measures of insulin resistance. This project will provide novel information concerning specific mechanisms by which exercise enhances the capacity for oxidative metabolism of fatty acids and improves insulin resistance in older adults who are at high risk for the development of T2DM. Ultimately this should help identify mechanisms and therapeutic targets implicated in skeletal muscle metabolic dysregulation.