Intramuscular Triglyceride Turnover/Insulin Sensitivity

描述(由申请人提供)：糖尿病是心血管疾病死亡率的一个公认的危险因素，在美国每年导致70万人死亡。由于糖尿病带来的巨大经济负担，以及糖尿病对心血管疾病死亡率的巨大贡献，了解胰岛素抵抗的机制具有相当重要的意义。肌内甘油三酯(IMTG)浓度可能是骨骼肌胰岛素抵抗的一个重要中介因素，因为在大多数人群中，IMTG含量与胰岛素刺激的葡萄糖代谢呈负相关。然而，耐力运动员和其他人群的IMTG含量与胰岛素敏感性之间的关系存在二分法，因为运动员的IMTG含量与II型糖尿病患者相似，但对胰岛素非常敏感。这使得研究耐力运动员成为解开骨骼肌IMTG和胰岛素作用之间关系的有用工具。我们的目标是研究耐力训练运动员、未经训练的瘦身对照组和II型糖尿病患者的肌内甘油三酯(IMTG)转化、细胞内降低胰岛素作用的信号与胰岛素敏感性的关系。我们假设在II型糖尿病中IMTG周转减少，导致长链酰辅酶A(LCA-CoA)、神经酰胺和二酰甘油(DAG)的形成增加。这些细胞内信号可以通过降低Akt活性和增加PKC、epsilon和theta活性来减弱胰岛素的作用，这些都可以降低胰岛素信号转导。我们的第一个具体目标是研究肌肉内甘油三酯(IMTG)的转化，细胞内信号降低胰岛素的作用，以及休息、50%VO2max运动和恢复时的胰岛素敏感性。我们假设，与II型糖尿病患者相比，运动员的IMTG周转率增加，而对照组通过降低LCA-CoA、DAG和神经酰胺的浓度来保护通常观察到的IMTG储备量增加所引起的胰岛素作用下降。第二个具体目标涉及在高胰岛素/正常血糖钳夹期间通过脂肪/肝素注射使静息时IMTG含量急剧增加。我们假设IMTG含量在运动员和II型糖尿病患者中将类似地增加，而在耐力运动员中胰岛素作用将更显著地降低。胰岛素作用的显著降低将与LCA-CoA、DAG、神经酰胺和Munc18c含量的增加有关。这些研究的意义将是进一步了解促进胰岛素抵抗的机制，以推进II型糖尿病的治疗和预防。

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.