Localization of saturated diacylglycerol and insulin sensitivity in humans

人类饱和二酰甘油和胰岛素敏感性的定位

• 批准号: 8122379
• 负责人: BRYAN C BERGMAN
• 金额: $ 25.47万
• 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: 2010-08-06 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122379
• 关键词: 1,2-diacylglycerol; Binding; Body fat; Carbon; Cell Culture Techniques; Cells; Cytosol; Data; Development; Diabetes Mellitus; Diglycerides; Epidemic; Euglycemic Clamping; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Glucose Clamp; Glycerol; Human; In Vitro; Individual; Insulin; Insulin Resistance; Intervention; Intramuscular; K-Series Research Career Programs; Link; Lipids; Literature; Location; Measures; Membrane; Molecular; Muscle; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peripheral; Phospholipids; Prevention; Process; Protein Kinase C; Protein Kinase C Inhibitor; Publishing; Saturated Fatty Acids; Site; Skeletal Muscle; Testing; Therapeutic; Tissues; Training; Triglycerides; Visceral; Work; base; calphostin C; diabetic; insulin sensitivity; interest; outcome forecast; prevent; public health relevance; saturated fat; sedentary; therapeutic target

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.

描述（由申请人提供）：骨骼肌胰岛素抵抗是糖尿病发展的基本先决条件，但是基于胰岛素抵抗的基本机制是多因素且知名度不佳的。增加的骨骼肌二酰基甘油（DAG）浓度是影响人类胰岛素敏感性的一种机制。迄今为止，所有在人类中发表的研究都将肌肉dag视为一组均匀的分子，具有影响胰岛素作用的能力。但是，基于与该分子的前两个碳结合的最普遍的脂肪酸，有20多种DAG物种。体外数据表明，DAG上的脂肪酸可能会影响增加蛋白激酶C（PKC）活性的能力，这是当前接受的DAG影响胰岛素敏感性的机制。但是，关于人类肌肉中DAG的分子组成或细胞位置知之甚少。此外，尚不清楚DAG的分子种类或细胞定位是否会影响PKC活性，因此是胰岛素敏感性。我们在这项研究中检验的假设是，DAG的组成和定位会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，抗胰岛素的个体具有增加含有饱和脂肪酸的DAG。此外，我们的数据表明耐力训练减少了DAG的饱和脂肪组成。该提议的目的是确定：1​​）如果DAG的饱和度与人类的胰岛素敏感性有关，并且2）如果DAG分子物种的细胞定位与PKC的激活和人类中的胰岛素敏感性有关，而3）以确定DAG成分在DAG浓度中的变化是否会影响PKC激活和胰岛素的变化。希望这些研究能够促进我们对肌肉DAG和胰岛素抵抗之间相互作用的理解，从而制定更好的治疗策略来预防和治疗糖尿病。 公共卫生相关性：叙事2型糖尿病患者的预后仍然很差。了解糖尿病的病理生理学，以开发出更好的治疗靶标的治疗和预防靶标。这些研究可以更好地了解促进和预防人类胰岛素抵抗的因素，从而可以开发出更好的治疗靶标。