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 年的死亡证明数据，糖尿病是美国第五大死因，其中明确将 2 型糖尿病 (T2DM) 与超过 233,619 例死亡联系起来。超过 2350 万 20 岁及以上的美国人（约占该年龄组人口的 11%）患有糖尿病，2007 年该人群中诊断出 160 万新发 T2DM 病例，2007 年的年度总费用（直接和间接）美国治疗所有糖尿病病例的费用估计超过 1740 亿美元。骨骼肌胰岛素抵抗和 T2DM 已被证明是由遗传起源以及环境因素（例如饮食成分的改变和/或缺乏体力活动）引起的。然而，目前尚未完全解决骨骼肌胰岛素信号传导损伤如何表现以及这些缺陷是否完全可逆的问题。人们注意到，肥胖、慢性低度炎症和骨骼肌胰岛素抵抗之间可能存在联系，我们最近报道了在高脂肪喂养的大鼠的骨骼肌中存在这种联系（胰岛素抵抗的“环境”模型）炎症通路的激活似乎有助于损害胰岛素刺激的磷酸肌醇 3-激酶 [PI3-K] 活性的激活。在这个项目中，我们将把注意力集中在骨骼肌中胰岛素信号传导调节中的炎症机制上，并将特别关注炎症信号级联和 PI3-K 激活之间的时间关系，以及是否减弱由 PI3-K 引起的炎症反应。高脂肪饮食可改善胰岛素刺激的 PI3-K 激活。我们的假设是，在高脂肪喂养的啮齿动物骨骼肌中，炎症通路激活增加与胰岛素刺激的 PI3-K 激活减少之间存在很强的时间关系，但如果炎症通路特定成分的激活可以被破坏，那么胰岛素-刺激的 PI3-K 激活可以被挽救。本申请的具体目标是：1) 确定高脂肪饮食如何暂时激活炎症通路，进而损害 Sprague-Dawley 大鼠骨骼肌中胰岛素刺激的 PI3-K 激活，以及2) 确定必须激活炎症途径的哪些成分才能使高脂肪喂养的啮齿动物骨骼肌中胰岛素刺激的 PI3-K 激活受损。公众健康相关性：高脂肪饮食会降低胰岛素有效调节骨骼肌碳水化合物代谢的能力，但这种效应背后的机制尚不完全清楚。人们认为高脂肪饮食会引起骨骼肌炎症反应，进而损害胰岛素作用。该项目将评估高脂肪喂养大鼠骨骼肌中炎症通路激活增加与胰岛素信号减弱之间的关系，然后系统地检查炎症通路的特定组成部分，以确定哪些炎症信号有助于损害胰岛素信号传导高脂肪喂养的啮齿动物骨骼肌。