Athletes paradox: Mechanisms evaluated in muscle cell culture

运动员悖论：肌肉细胞培养中评估的机制

• 批准号: 7895118
• 负责人: BRYAN C BERGMAN
• 金额: $ 7.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895118
• 关键词: 1,2-diacylglycerol; Acute; Biopsy; Cell Culture Techniques; Data; Development; Diabetes Mellitus; Diglycerides; Disease; Evaluation; Exercise; Fatty acid glycerol esters; First Degree Relative; Funding; General Population; Health; Human; Individual; Insulin; Insulin Resistance; Intramuscular; K-Series Research Career Programs; Label; Link; Lipids; Location; Membrane; Methods; Muscle; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Participant; Phenotype; Play; Recovery; Rest; Role; Saturated Fatty Acids; Skeletal Muscle; Techniques; Time; Training; Triglycerides; Work; diabetes risk; diabetic; glucose transport; human subject; in vivo; insulin sensitivity; insulin signaling; novel; prevent; public health relevance; sedentary

DESCRIPTION (provided by applicant): Insulin resistance is one of the hallmarks in the progression to Type 2 diabetes, however the fundamental mechanisms that underlie insulin resistance are poorly understood. Intramuscular triglyceride (IMTG) appears an important predictor of diabetes as it is high, with low insulin sensitivity in the general population. Paradoxically, endurance trained athletes have a high concentration of IMTG, but are very insulin sensitive, which has been called the "athlete's paradox". Studies in my K award are aimed at determining how IMTG synthesis rates and utilization are different between athletes, controls, and individuals with type 2 diabetes (T2D) during rest, exercise, and recovery. I hope to elucidate differences between groups which may help explain the athlete's paradox. Preliminary data from my K award indicates that in addition to increased insulin action, athletes have decreased saturated fatty acid species within diacylglycerol (DAG), and 2-fold higher fractional synthesis rates for IMTG and DAG. These changes may influence insulin sensitivity within skeletal muscle. Studies proposed in this RO3 will be carried out in primary human cell cultures isolated from athletes, type 2 diabetics and sedentary control subjects in my K award. Primary human cell cultures retain the phenotype of the donor, and will allow a mechanistic evaluation of the potential links between intramuscular lipid saturation and synthesis and insulin action. Specific Aim 1: To determine the role of saturated DAG localization on insulin sensitivity. We hypothesize that saturated DAG localized to membranes decreases insulin sensitivity by increasing PKC activation. Thus, changes in the location of saturated DAG, independent of total concentration, may alter skeletal muscle insulin sensitivity. Specific Aim 2: To determine whether acute changes in IMTG and DAG synthesis influence insulin sensitivity. Our hypothesis is that IMTG and DAG turnover, rather than concentration, is a critical link between intramuscular lipids and insulin action. Thus, acute changes in intramuscular lipid synthesis rates may alter skeletal muscle insulin sensitivity. These studies are vital to determine if either saturated DAG and/or synthesis rates of intramuscular lipid alter insulin sensitivity, or are simply correlated in vivo. Results from these studies will further our understanding of the athlete's paradox, and provide key preliminary data for my first RO1 submission. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is considered one of the greatest health crises of our time, making it vital to understand more about this disease. Fat stored in muscle appears to influence diabetes risk, but exactly how this happens is not clear. This study will examine if the type of fat, or how quickly fat is stored in muscle can influence diabetes risk in muscle cells that are isolated from muscle biopsies from human subjects.

描述（由申请人提供）：胰岛素抵抗是2型糖尿病的进展的标志之一，但是基于胰岛素抵抗的基本机制知之甚少。肌内甘油三酸酯（IMTG）似乎是糖尿病的重要预测因子，因为它的糖尿病很高，一般人群中的胰岛素敏感性较低。矛盾的是，耐力训练的运动员具有高度浓度的IMTG，但非常胰岛素敏感，这被称为“运动员的悖论”。我的K奖中的研究旨在确定运动员，对照组和患有2型糖尿病（T2D）在休息，运动和恢复期间的运动员，对照组（T2D）之间的IMTG合成率和利用率如何不同。我希望阐明群体之间的差异，这可能有助于解释运动员的悖论。 我的K奖的初步数据表明，除了增加胰岛素作用外，运动员还减少了二酰基甘油（DAG）内的饱和脂肪酸物种，而IMTG和DAG的分数合成速率则降低了2倍。这些变化可能会影响骨骼肌内的胰岛素敏感性。 在此RO3中提出的研究将在我的K奖中从运动员，2型糖尿病患者和久坐的控制对象分离出来的原代人细胞培养物中进行。原代人细胞培养物保留了供体的​​表型，并将允许对肌内脂质脂质饱和度与合成和胰岛素作用之间的潜在联系进行机械评估。 特定目的1：确定饱和DAG定位在胰岛素敏感性中的作用。我们假设将饱和的DAG定位在膜上，从而通过增加PKC激活来降低胰岛素敏感性。因此，与总浓度无关的饱和DAG位置的变化可能会改变骨骼肌胰岛素敏感性。 特定目的2：确定IMTG和DAG合成的急性变化是否影响胰岛素敏感性。我们的假设是，IMTG和DAG更新而不是集中度是肌内脂质与胰岛素作用之间的关键联系。因此，肌内脂质合成速率的急性变化可能会改变骨骼肌胰岛素敏感性。 这些研究对于确定肌肉内脂质改变胰岛素敏感性的饱和DAG和/或合成速率是至关重要的，还是在体内仅相关。这些研究的结果将进一步了解我们对运动员的悖论，并为我的第一次RO1提交提供关键的初步数据。 公共卫生相关性：2型糖尿病被认为是我们这个时代最大的健康危机之一，这使得更多了解这种疾病至关重要。存储在肌肉中的脂肪似乎会影响糖尿病的风险，但尚不清楚这种情况的确。这项研究将检查脂肪的类型或在肌肉中存储的速度是否会影响从人类受试者肌肉活检中分离出的肌肉细胞中的糖尿病风险。