Skeletal Muscle Lipid and Insulin Resistance in Aging

衰老过程中的骨骼肌脂质和胰岛素抵抗

• 批准号: 7086147
• 负责人: Bret H Goodpaster
• 金额: $ 31.7万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7086147
• 关键词: aerobic exercise; aging; biopsy; ceramides; clinical research; diacylglycerols; fatty acid metabolism; histochemistry /cytochemistry; human old age (65+); human subject; human therapy evaluation; insulin sensitivity /resistance; magnetic resonance imaging; mitochondria; muscle metabolism; noninsulin dependent diabetes mellitus; oxidation; patient oriented research; striated muscles; triglycerides

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.

描述（由申请人提供）：骨骼肌内的代谢失调，包括胰岛素抵抗，是老年人面临的主要健康问题。这是2型糖尿病（T2DM）的关键因素，这种疾病遭受了每四个老年人中近一个。因此，有关这些代谢性疾病的病因，预防和治疗的研究至关重要。迄今为止，缺乏研究，这些研究已经解决了骨骼肌脂质含量的改变以及干预诱导的脂肪氧化能力是否可以预测胰岛素抵抗的改善。 许多研究表明，升高的肌肉甘油三酸酯或细胞内脂质（IMCL）含量与胰岛素抵抗有关。但是，我们小组以及其他人的最新证据表明，IMCL和胰岛素抵抗之间存在更复杂的关联，这可能涉及脂肪氧化的能力。 我们的研究支持以下假设：脂肪酸代谢失调和肌肉脂质的积累可能是先前久坐的老年人胰岛素抵抗的机制。此外，我们将提供有关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由。 我们将采用一项随机对照运动干预试验来检验总体假设，即运动引起的骨骼肌脂肪氧化能力的改善是预测胰岛素抵抗的改善的主要因素。我们将利用新型的磁共振成像（MRI），组织化学和生化方法来量化肌肉脂质含量和分布的变化以及收缩组织（肌肉）本身的量。这些变化将与体内和体外测量脂肪氧化能力以及体内胰岛素抵抗的能力一起测量。 该项目将提供有关特定机制的新信息，锻炼可以增强脂肪酸氧化代谢的能力，并改善对T2DM发育高风险的老年人的胰岛素抵抗。最终，这应该有助于确定与骨骼肌代谢失调有关的机制和治疗靶标。