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

基本信息

批准号：
8712477
负责人：
BRYAN C BERGMAN
金额：
$ 25.67万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/8712477
关键词：
1,2-diacylglycerol Binding Body fat Carbon Cell Culture Techniques Cells Cytosol Data Development Diabetes Mellitus Diet 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

项目摘要

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.

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并且人们知之甚少。骨骼肌二酰甘油（DAG）浓度增加是影响人类胰岛素敏感性的一种机制。迄今为止在人体中发表的所有研究都将肌肉 DAG 视为一组同质分子，具有同等影响胰岛素作用的能力。然而，根据与分子前两个碳结合的最常见脂肪酸，DAG 有 20 多种丰富的种类。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，这是目前公认的 DAG 影响胰岛素敏感性的机制。然而，人们对 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 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。我们在本研究中测试的假设是 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，与胰岛素敏感个体相比，胰岛素抵抗个体中含有饱和脂肪酸的 DAG 含量有所增加。此外，我们的数据表明耐力训练会降低 DAG 的饱和脂肪成分。该提案的目的是确定：1) DAG 的饱和度是否与人类的胰岛素敏感性相关，2) DAG 分子种类的细胞定位是否与人类的 PKC 激活和胰岛素敏感性相关，以及 3)确定 DAG 组成的变化而不改变 DAG 浓度是否会影响细胞培养物中的 PKC 激活和胰岛素敏感性。这些研究希望增进我们对肌肉 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。