Impaired insulin signaling: Mechanisms of and reversibility in two rodent models

胰岛素信号传导受损：两种啮齿动物模型的机制和可逆性

• 批准号: 7252142
• 负责人: BEN B YASPELKIS
• 金额: $ 21.45万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252142
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accounting; Address; Aerobic; Aerobic Exercise; Affect; Age-Years; Alternative Therapies; American; Area; Attention; Attenuated; Cause of Death; Cessation of life; Chronic; Data; Death Certificates; Defect; Diabetes Mellitus; Diagnosis; Disease; Environmental Risk Factor; Exercise; Exhibits; Fatty acid glycerol esters; Genetic; Genetic Models; Human; Impairment; Inflammatory; Insulin; Insulin Resistance; Lead; Link; Mediating; Modeling; Molecular; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Phosphatidylinositols; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Physical activity; Population; Proteins; Rate; Rattus; Resistance; Rodent; Rodent Model; Signal Pathway; Signaling Protein; Skeletal Muscle; Skeletal system; Training; United States; Work; Zucker Rats; abstracting; base; cost; design; feeding; glucose metabolism; glucose transport; improved; insulin signaling; interest; muscle metabolism; novel; prevent; response; stem

DESCRIPTION (provided by applicant): Yaspelkis III, B.B. Project Summary/Abstract Diabetes was the sixth leading cause of death in the United States in 2002 based on death certificate data which specifically linked type 2 diabetes mellitus (T2DM) to more than 213,000 deaths. Over 18.2 million Americans 20 years of age and older (~6.3% of the population) are estimated to have diabetes, 1.3 million new cases of T2DM are diagnosed yearly and the total (direct and indirect) annual cost in 2002 of all cases of Diabetes in the United States was estimated at over $132 billion. Skeletal muscle insulin resistance and T2DM have been shown to result from genetic origins as well as environmental factors such as alterations in dietary composition and/or lack of physical activity. However, it has not been extensively addressed whether defects in skeletal muscle insulin signaling are differentially manifested based on how the disease develops and if these defects are correctable. In this project we will direct our attention to the high fat-fed rat (an "environmental" model) and the obese Zucker rat (a genetic model) and specifically focus on the classical (phosphoinositide 3-kinase [PI3-K] dependent) and novel (purportedly PI3-K independent) insulin signaling cascades in the skeletal muscles of these rodent models. Our hypothesis is that although skeletal muscle insulin resistance is due to impaired insulin signaling, impairments in the insulin signaling cascades are not identical across all models of insulin resistance but the impairments can be improved with any mode of exercise. The specific aims of this application are: 1) To identify if impairments in insulin signaling cascades are manifested similarly in skeletal muscle of two distinct models of insulin resistance, the high fat- fed rat and obese Zucker rat, and 2) To determine if exercise, regardless of mode (i.e., aerobic exercise vs. resistance exercise), will similarly enhance insulin signaling in the skeletal muscle of the high fat fed rat and obese Zucker rat. Yaspelkis III, B.B. Project Narrative We expect to establish whether the mechanisms that contribute to defects in skeletal muscle metabolism in genetic and environmental models of insulin resistance share a commonality or are unique to each particular model and if the defects in skeletal muscle metabolism are reversible. The significance of this approach is that efforts in this area will lead to the discovery of the cellular/molecular pathways underlying how insulin works and in turn will allow for the identification of key targets for which alternative therapies can be designed to reverse insulin resistance and prevent diabetes in humans.

描述（由申请人提供）：基于死亡证明数据，该数据专门将2型糖尿病（T2DM）与超过213,000的死亡联系起来，Yaspelkis III，B.B.项目摘要/摘要糖尿病是2002年美国的第六大死亡原因。据估计，超过1,820万名20岁以上的美国人（占人口的约6.3％）患有糖尿病，每年诊断为130万例T2DM新病例，2002年，美国所有糖尿病病例的总（直接和间接）年费用为132亿美元。骨骼肌胰岛素抵抗和T2DM已显示出遗传起源以及环境因素，例如饮食组成和/或缺乏体育活动的改变。但是，尚未广泛解决骨骼肌胰岛素信号的缺陷是否根据疾病的发展方式差异化表现出来，以及这些缺陷是否可纠正。在这个项目中，我们将把注意力转移到高脂肪喂养的大鼠（一种“环境”模型）和肥胖的Zucker Rat（一种遗传模型）上，特别关注古典（磷酸肌醇3-激酶[pi3-k]依赖性）和新颖（据称是PI3-K独立的PI3-K独立）胰岛素信号库中的胰岛素信号库，这些胰岛素信号库是这些Rodent od rodent odent Rodent of codent od rodent of codent od rodent od rodent of codent of codent of rodent of rodent of rodent of rodent of。我们的假设是，尽管骨骼肌胰岛素抵抗是由于胰岛素信号受损而引起的，但胰岛素信号传导级联反应的损害在所有胰岛素抵抗模型中并不相同，但是通过任何运动方式可以改善损害。该应用的具体目的是：1）确定胰岛素信号传导级联中的损害是否相似地表现在两个不同的胰岛素抵抗模型的骨骼肌中Zucker Rat。 Yaspelkis III，B.B.项目叙事我们期望确定在胰岛素抵抗的遗传和环境模型中导致骨骼肌代谢缺陷的机制是否具有共同点，还是每个特定模型独有的，以及骨骼肌代谢中的缺陷是否可逆。这种方法的意义在于，该领域的努力将导致发现胰岛素如何起作用的细胞/分子途径，进而允许鉴定可以设计替代疗法的关键靶标，以逆转胰岛素耐药性并预防人类中的糖尿病。