INTRAMUSCULAR TRIGLYCERIDE IN IMPAIRED GLUCOSE TOLERANCE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 胰岛素抵抗是指胰岛素刺激外周葡萄糖摄取、抑制肝脏葡萄糖输出和脂肪分解的能力受损，是糖耐量受损(IGT)和2型糖尿病的主要特征。胰岛素抵抗的形成机制尚不清楚。骨骼肌是胰岛素作用于外周葡萄糖摄取的主要组织，因此被认为是胰岛素抵抗发生的主要部位。肌内甘油三酯(IMTG)的含量和周转率一直是最近相当感兴趣的话题，因为IMTG的量与胰岛素敏感性密切相关。大量数据表明，健康的男性和女性使用IMTG的方式可能不同，尤其是在锻炼期间。我们推测，这种性别相关的IMTG使用机制在IGT的发展过程中丢失了。我们的第一个目标将描述IGT男性和女性在基线和急性运动期间的IMTG含量和周转情况。 这项研究的第二个和第三个目标将试图解释一旦发生IGT，男性和女性失去IMTG周转能力的机制。我们假设女性依赖于肌肉的氧化能力，而男性依赖于PPAR靶基因的激活，正如动物研究所表明的那样。为了区分这些机制，患有IGT的男性和女性将随机接受运动训练计划(以增加氧化能力)或贝特治疗(以激活PPAR，为期12周)。为了实现这些目标，我们是否会将血液和组织采样、稳定同位素方法学和胰岛素敏感性测量结合起来？更好地了解IMTG含量和周转在男性和女性胰岛素抵抗发生发展中的作用，可能会指导我们预防和治疗糖尿病的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin resistance, defined as an impairment in insulin's ability to stimulate peripheral glucose uptake, as well as suppress hepatic glucose output and lipolysis, are major characteristics of impaired glucose tolerance (IGT) and type 2 diabetes. The mechanisms by which insulin resistance develops are unclear. Skeletal muscle is the major tissue responsible for insulin action on peripheral glucose uptake, and therefore has been implicated as a primary site for the development of insulin resistance. Intramuscular triglyceride (IMTG) content and turnover, specifically, have been the topics of considerable recent interest as the amount of IMTG correlates strongly with insulin sensitivity. Substantial data exists that healthy men and women may use IMTG differently, especially during exercise. We speculate that this gender-dependent mechanism for IMTG use is lost in the development of IGT. Our first aim will describe IMTG content and turnover at baseline and during acute exercise in men and women with IGT. The second and third aims of the study will attempt to explain the mechanisms by which men and women lose the ability to turnover IMTG once they develop IGT. We hypothesize that women rely on oxidative capacity of muscle, whereas men rely on the activation of PPAR target genes, as these have been shown in animal studies. To differentiate these mechanisms, men and women with IGT will be randomized to either an exercise training program (to increase oxidative capacity) or fibrate therapy (to activate PPAR for 12 weeks. Will we combine blood and tissue sampling, stable isotope methodology, and measures of insulin sensitivity in pursuit of these aims? Better understanding the role of IMTG content and turnover in the development of insulin resistance in men and women may guide our therapy in the prevention and treatment of diabetes.