Localization of saturated diacylglycerol and insulin sensitivity in humans

描述(申请人提供)：骨骼肌胰岛素抵抗是糖尿病发展的基本先决条件，然而，胰岛素抵抗的基本机制是多因素的，而且知之甚少。骨骼肌二酰甘油(DAG)浓度升高是影响人类胰岛素敏感性的机制之一。到目前为止，所有发表在人类身上的研究都认为肌肉DAG是一组同质的分子，具有同样的影响胰岛素作用的能力。然而，基于与分子前两个碳结合的最普遍的脂肪酸，有超过20种丰富的DAG物种。体外数据表明，DAG上的脂肪酸可能会影响提高蛋白激酶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在人类肌肉中的分子组成或细胞定位，人们知之甚少。此外，目前尚不清楚DAG的不同分子种类或细胞定位是否会影响PKC活性，从而影响胰岛素敏感性。我们在这项研究中检验的假设是，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，与胰岛素敏感的人相比，胰岛素抵抗的人含有更多的饱和脂肪酸的DAG。此外，我们的数据表明，耐力训练降低了DAG的饱和脂肪成分。这项建议的目的是确定：1)DAG的饱和是否与人类的胰岛素敏感性有关；2)DAG分子物种的细胞定位是否与人类的PKC激活和胰岛素敏感性有关；3)确定DAG组成的变化是否影响细胞培养中的PKC激活和胰岛素敏感性。这些研究有望促进我们对肌肉DAG和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。 公共卫生相关性：叙述2型糖尿病患者的预后仍然很差。了解糖尿病的病理生理机制对于开发更好的治疗和预防靶点是至关重要的。这些研究可能会让人们更好地了解促进和预防人类胰岛素抵抗的因素，从而开发更好的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Narrative The prognosis for individuals with type 2 diabetes remains poor. It is vital to understand the pathophysiology of diabetes to develop better therapeutic targets for treatment and prevention. These studies may allow a better understanding of factors which promote and prevent insulin resistance in humans so that better therapeutic targets can be developed.