INTRAMUSCULAR TRIGLYCERIDE IN IMPAIRED GLUCOSE TOLERANCE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。胰岛素抵抗被定义为胰岛素刺激外周葡萄糖摄取的能力受损，以及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。胰岛素抵抗形成的机制尚不清楚。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）的含量和转化，特别是，已经成为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，健康男性和女性使用IMTG的方式可能不同，尤其是在运动时。我们推测，在IGT的发展过程中，这种依赖性别的IMTG使用机制丢失了。我们的第一个目标是描述IGT患者在基线和急性运动期间的IMTG含量和转换。该研究的第二个和第三个目标将试图解释男性和女性一旦患上IGT就失去转换IMTG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，正如动物研究中所显示的那样。为了区分这些机制，患有IGT的男性和女性将被随机分为运动训练计划（增加氧化能力）或贝特治疗（激活PPAR），为期12周。我们是否将血液和组织取样、稳定同位素方法和胰岛素敏感性测量相结合来追求这些目标？更好地了解IMTG含量和转化在男性和女性胰岛素抵抗发展中的作用，可以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.