Intramuscular Triglyceride Turnover/Insulin Sensitivity

肌内甘油三酯周转率/胰岛素敏感性

• 批准号: 7271294
• 负责人: BRYAN C BERGMAN
• 金额: $ 13.04万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271294
• 关键词: 1,2-diacylglycerol; Acute; Acyl Coenzyme A; Attenuated; Cardiovascular Diseases; Ceramides; Cessation of life; Diabetes Mellitus; Diglycerides; Economic Burden; Euglycemic Clamping; Exercise; Exhibits; Fat emulsion; Glucose Clamp; Heparin; Infusion procedures; Insulin; Insulin Resistance; Intramuscular; Lipids; Mediator of activation protein; Non-Insulin-Dependent Diabetes Mellitus; Population; Prevention; Rate; Recovery; Relative (related person); Rest; Risk Factors; Signal Transduction; Signaling Molecule; Skeletal Muscle; Training; Triglycerides; diabetic; glucose disposal; insulin sensitivity; insulin signaling; mortality; protein kinase C epsilon; syntaxin 4; tool

DESCRIPTION (provided by applicant): Diabetes is a well-established risk factor for cardiovascular disease mortality which contributes to >700,000 deaths in the U.S. annually. Due to the considerable economic burden of diabetes, and the sizeable contribution of diabetes to cardiovascular disease mortality, understanding the mechanisms involved in insulin resistance is of considerable importance. Intramuscular triglyceride (IMTG) concentration may be an important mediator of skeletal muscle insulin resistance as the content of IMTG is negatively associated with insulin stimulated glucose disposal in most all populations. However, a dichotomy exists in the relationship between IMTG content and insulin sensitivity in endurance athletes and the rest of the population, as athletes have similar IMTG content as in Type II diabetics, yet are very insulin sensitive. This makes studying endurance athletes a useful tool to unraveling the relationship between skeletal muscle IMTG and insulin action. We aim to study the relationship between intramuscular triglyceride (IMTG) turnover, intracellular signals decreasing insulin action, and insulin sensitivity in endurance trained athletes, untrained lean controls, and Type II diabetics. We hypothesize IMTG turnover is decreased in Type II diabetes, leading to increased formation of long chain acyl-CoA (LCA-CoA), ceramide, and diacylglycerol (DAG). These intracellular signals could then attenuate insulin action by decreasing Akt activity and increasing PKC epsilon and theta activity which all act to decrease insulin signaling. Our first specific aim investigates intramuscular triglyceride (IMTG) turnover, intracellular signals decreasing insulin action, and insulin sensitivity during rest, exercise at 50% VO2max, and recovery. We hypothesize increased IMTG turnover in athletes compared to Type II diabetics and controls protects against decreased insulin action commonly observed with increased IMTG stores by decreasing concentration of LCA-CoA, DAG, and ceramide. The second specific aim involves an acute increase in IMTG content at rest via intralipid/heparin infusion during a hyperinsulinemic/euglycemic clamp. We hypothesize IMTG content will increase similarly in athletes and type II diabetics, while insulin action will decrease more dramatically in endurance athletes. The more dramatic decrease in insulin action will be related to a greater increase in LCA-CoA, DAG, ceramide, and Munc18c content. The significance of these studies will be to further the understanding of mechanisms promoting insulin resistance to advance the treatment and prevention of Type II diabetes.

描述（由申请人提供）：糖尿病是心血管疾病死亡率良好的危险因素，每年在美国造成700,000人死亡。由于糖尿病的巨大经济负担，以及糖尿病对心血管疾病死亡率的巨大贡献，因此了解胰岛素抵抗涉及的机制非常重要。肌内甘油三酸酯（IMTG）浓度可能是骨骼肌胰岛素抵抗的重要介质，因为IMTG的含量与大多数人群中胰岛素刺激的葡萄糖处置负相关。然而，由于运动员具有与II型糖尿病患者相似的IMTG含量，但IMTG含量与胰岛素敏感性之间的关系存在二分法，但对II型糖尿病患者的含量类似，但对胰岛素非常敏感。这使研究耐力运动员成为揭示骨骼肌IMTG和胰岛素作用之间关系的有用工具。我们旨在研究肌内甘油三酸酯（IMTG）周转率，细胞内信号降低胰岛素作用，胰岛素训练的运动员，未经训练的精益控制和II型糖尿病患者的胰岛素敏感性。我们假设II型糖尿病的IMTG周转率降低，导致长链酰基-COA（LCA-COA），神经酰胺和二酰基甘油（DAG）的形成增加。然后，这些细胞内信号可以通过降低AKT活性并增加PKC Epsilon和Theta活性来减轻胰岛素的作用，从而减少胰岛素信号传导。我们的第一个特定目的研究了肌内甘油三酸酯（IMTG）周转率，细胞内信号降低胰岛素作用以及休息期间的胰岛素敏感性，在50％vo2max处运动和恢复。与II型糖尿病患者相比，我们假设运动员的IMTG周转率增加，并且可以通过降低LCA-COA，DAG和CERAMIDE浓度来防止IMTG存储增加的胰岛素作用降低。第二个特定目的是在高胰岛素/euglecememic夹期间通过脂质内/肝素输注在REST中的IMTG含量急性增加。我们假设在运动员和II型糖尿病患者中，IMTG含量将类似地增加，而在耐力运动员中，胰岛素作用将使胰岛素动作更大。胰岛素作用的较大降低将与LCA-COA，DAG，CERAMIDE和MUNC18C含量的增加有关。这些研究的意义将是进一步理解促进胰岛素抵抗的机制，以提高对II型糖尿病的治疗和预防。