Localization of saturated diacylglycerol and insulin sensitivity in humans

描述（由申请人提供）：骨骼肌胰岛素抵抗是糖尿病发展的潜在先决条件，然而，胰岛素抵抗的基本机制是多因素的，目前尚不清楚。骨骼肌二酰基甘油（DAG）浓度增加是影响人类胰岛素敏感性的一种机制。迄今为止发表的所有人体研究都认为肌肉DAG是一组具有相同影响胰岛素作用能力的同质分子。然而，基于与分子的前两个碳结合的最普遍的脂肪酸，有超过20种丰富的DAG。体外数据表明，DAG上的脂肪酸可能影响增加蛋白激酶C （PKC）活性的能力，这是目前公认的DAG影响胰岛素敏感性的机制。然而，关于DAG在人体肌肉中的分子组成或细胞位置知之甚少。此外，尚不清楚不同的分子种类或DAG的细胞定位是否会影响PKC活性，从而影响胰岛素敏感性。我们在这项研究中测试的假设是DAG的组成和定位影响人类的胰岛素敏感性。我们的初步数据表明，与胰岛素敏感的个体相比，胰岛素抵抗的个体含有饱和脂肪酸的DAG含量增加。此外，我们的数据表明耐力训练减少了DAG的饱和脂肪组成。本研究的目的是确定：1)DAG的饱和是否与人的胰岛素敏感性有关，2)DAG分子种类的细胞定位是否与人的PKC激活和胰岛素敏感性有关，3)确定DAG组成的改变是否在DAG浓度不变的情况下影响细胞培养中PKC激活和胰岛素敏感性。这些研究有望促进我们对肌肉DAG与胰岛素抵抗之间相互作用的理解，从而开发出更好的治疗策略来预防和治疗糖尿病。

DESCRIPTION (provided by applicant): Skeletal muscle insulin resistance is an underlying pre-requisite to the development of diabetes, however the fundamental mechanisms that underlie insulin resistance are multi-factorial and poorly understood. Increased skeletal muscle diacylglycerol (DAG) concentration is one mechanism influencing insulin sensitivity in humans. All studies published in humans to date have considered muscle DAG as a homogeneous group of molecules with equal ability to impact insulin action. However, there are over 20 abundant species of DAG based on the most prevalent fatty acids binding to the first two carbons of the molecule. In vitro data suggest fatty acids on DAG may impact the ability to increase protein kinase C (PKC) activity, which is the currently accepted mechanism by which DAG impacts insulin sensitivity. However, little is known regarding the molecular composition or cellular location of DAG in human muscle. Further, it is not known if different molecular species or cellular localization of DAG influence PKC activity, and therefore, insulin sensitivity. The hypothesis we are testing in this study is that the composition and localization of DAG impacts insulin sensitivity in humans. Our preliminary data suggest individuals who are insulin resistant have increased amounts of DAG containing saturated fatty acids compared to insulin sensitive individuals. Additionally, our data suggest endurance training decreases the saturated fat composition of DAG. The aim of this proposal is to determine: 1) if saturation of DAG is related to insulin sensitivity in humans, and 2) if the cellular localization of molecular species of DAG are related to PKC activation and insulin sensitivity in humans, and 3) to determine if alterations in DAG composition without a change in DAG concentration influences PKC activation and insulin sensitivity in cell culture. These studies are hoped to advance our understanding of the interplay between muscle DAG and insulin resistance, allowing development of better therapeutic strategies to prevent and treat diabetes.