Skeletal muscle insulin resistance: High fat diet and inflammatory pathways

骨骼肌胰岛素抵抗：高脂肪饮食和炎症途径

基本信息

批准号：
7881805
负责人：
BEN B YASPELKIS
金额：
$ 21.75万
依托单位：
CALIFORNIA STATE UNIVERSITY NORTHRIDGE
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：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881805
关键词：
1-Phosphatidylinositol 3-Kinase 20 year old Address American Animal Feed Animals Attention Attenuated Cause of Death Cessation of life Chronic Co-Immunoprecipitations Complex Data Death Certificates Defect Diabetes Mellitus Diagnosis Diet Environmental Risk Factor Family Fatty acid glycerol esters Genetic Impairment Inflammation Inflammatory Inflammatory Response Insulin Insulin Receptor Insulin Resistance Link MAP Kinase Gene Modeling Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Phosphatidylinositols Phosphorylation Phosphotransferases Physical activity Population Protein-Serine-Threonine Kinases Proteins Rattus Regulation Reporting Rodent Serine Signal Transduction Skeletal Muscle Sprague-Dawley Rats Time United States age group attenuation base carbohydrate metabolism cost feeding glucose transport improved insulin signaling member prevent public health relevance response stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): Diabetes is the fifth leading cause of death in the United States based on death certificate data from 2005, which specifically linked type 2 diabetes mellitus (T2DM) to more than 233,619 deaths. Over 23.5 million Americans 20 years of age and older (~11% of the population in this age group) have diabetes, 1.6 million new cases of T2DM were diagnosed in this population in 2007 and the total (direct and indirect) annual cost in 2007 to treat all cases of Diabetes in the United States was estimated at over $174 billion. Skeletal muscle insulin resistance and T2DM have been shown to result from genetic origins as well as from environmental factors such as alterations in dietary composition and/or lack of physical activity. However, it has not been fully resolved exactly how impairments in skeletal muscle insulin signaling are manifested and if these defects are entirely reversible. It has been noted that a link may exist between obesity, chronic low-grade inflammation and skeletal muscle insulin resistance, and we have recently reported that in the skeletal muscle of the high fat-fed rat (an "environmental" model of insulin resistance) that activation of inflammatory pathways appear to contribute to impairing insulin-stimulated activation of phosphoinositide 3-kinase [PI3-K] activity. In this project we will direct our attention on inflammatory mechanisms in the regulation of insulin signaling in skeletal muscle and will specifically focus on the temporal relationship between the inflammatory signaling cascades and PI3-K activation, and if attenuation of the inflammatory response that arises from the provision of a high fat diet improves insulin-stimulated PI3-K activation. Our hypothesis is that there is a strong temporal relationship between increased inflammatory pathway activation and decreased insulin-stimulated PI3- K activation in high fat-fed rodent skeletal muscle, but if the activation of specific components of the inflammatory pathways can be disrupted that insulin-stimulated PI3-K activation can be rescued. The specific aims of this application are: 1) To identify how the provision of a high fat diet temporally activates the inflammatory pathways and in turn contribute to impairing insulin-stimulated PI3-K activation in the skeletal muscle of the Sprague-Dawley rat, and 2) To identify what component(s) of the inflammatory pathways must be activated in order for insulin-stimulated PI3-K activation to be impaired in high fat-fed rodent skeletal muscle. PUBLIC HEALTH RELEVANCE: A high fat diet decreases the ability of insulin to effectively regulate skeletal muscle carbohydrate metabolism, but the mechanism behind this effect is not fully understood. It is thought that a high fat diet causes an inflammatory response in the skeletal muscle that in turn impairs insulin action. This project will evaluate the relationship between increased inflammatory pathway activation and decreased insulin signaling in the skeletal muscle of the high fat-fed rat and then systematically examine specific components of the inflammatory pathways to identify which inflammatory signal(s) contribute to impairing insulin signaling in high fat-fed rodent skeletal muscle.

描述（由申请人提供）：根据2005年的死亡证书数据，糖尿病是美国第五大死亡原因，该死亡证书的数据专门将2型糖尿病（T2DM）与233,619多人死亡联系起来。超过2350万20岁及以上的美国人（该年龄段的人口占约11％）患有糖尿病，2007年该人口中诊断出160万例新的T2DM病例，2007年的年度总成本（直接和间接）为治疗美国的所有糖尿病病例，估计为1740亿美元。骨骼肌胰岛素抵抗和T2DM已证明是遗传起源以及环境因素所致，例如饮食组成和/或缺乏体育活动的改变。但是，尚未完全完全解决骨骼肌胰岛素信号传导的损害，以及这些缺陷是否完全可逆。已经注意到，肥胖症，慢性低度炎症和骨骼肌胰岛素抵抗之间可能存在联系，并且我们最近报道，在高脂肪喂养大鼠的骨骼肌（一种胰岛素耐药性的“环境”模型）中，炎症途径的激活似乎会导致胰岛素刺激性激活磷酸3-磷酸化3-磷酸化的活化症。在这个项目中，我们将注意骨骼肌胰岛素信号传导调节炎症机制的注意力，并将专门关注炎症信号传导级联和PI3-K激活之间的时间关系，如果炎症反应的衰减是由高脂肪饮食提供的炎症反应衰减会改善胰岛素蛋白刺激的PI3-k-k-k-k-k-k-k-k-k ktiment。我们的假设是，在高脂肪喂养的啮齿动物骨骼肌中，炎症途径的激活增加与胰岛素刺激的PI3-k激活之间存在很强的时间关系，但是如果炎症途径的特定成分的激活可能会破坏胰岛素刺激的PI3-K活化的激活。该应用的具体目的是：1）确定如何提供高脂饮食在时间上激活炎症途径，进而有助于损害Sprague-Dawley大鼠骨骼肌中胰岛素刺激的PI3-K激活，以及2）在炎症途径中必须在iNsim stroade中逐步激活PI3，以确定PI3的激活。脂肪喂养的啮齿动物骨骼肌。公共卫生相关性：高脂肪饮食降低了胰岛素有效调节骨骼肌碳水化合物代谢的能力，但是这种作用背后的机制尚未完全理解。人们认为，高脂肪饮食会在骨骼肌中引起炎症反应，从而损害胰岛素作用。该项目将评估炎症途径增加激活与胰岛素信号降低之间的关系，然后系统地检查炎症途径的特定成分，以确定哪种炎症信号（S）有助于高脂肪喂养的啮齿动物固有骨骼骨骼肌肉中的胰岛素信号受损。