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

基本信息

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
项目类别：
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

项目摘要

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）：Yaspelkis III, B.B. 项目摘要/摘要根据死亡证明数据，2002 年糖尿病是美国第六大死因，该数据明确将 2 型糖尿病 (T2DM) 与超过 213,000 人的死亡联系起来。据估计，超过 1820 万 20 岁及以上的美国人（约占总人口的 6.3%）患有糖尿病，每年诊断出 130 万新发 T2DM 病例，2002 年所有糖尿病病例的年度总费用（直接和间接）美国的估计价值超过 1,320 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（例如饮食结构改变和/或缺乏体力活动）引起的。然而，尚未广泛解决骨骼肌胰岛素信号传导缺陷是否根据疾病的发展方式而有不同的表现以及这些缺陷是否可纠正。在这个项目中，我们将把注意力集中在高脂喂养大鼠（“环境”模型）和肥胖 Zucker 大鼠（遗传模型）上，并特别关注经典模型（磷酸肌醇 3-激酶 [PI3-K] 依赖性）这些啮齿动物模型的骨骼肌中存在新颖的（据称不依赖 PI3-K 的）胰岛素信号级联。我们的假设是，虽然骨骼肌胰岛素抵抗是由于胰岛素信号传导受损造成的，但胰岛素信号级联的损伤在所有胰岛素抵抗模型中并不相同，但任何运动模式都可以改善这种损伤。该应用的具体目的是：1) 确定胰岛素信号级联损伤是否在两种不同胰岛素抵抗模型（高脂喂养大鼠和肥胖 Zucker 大鼠）的骨骼肌中表现相似，以及 2) 确定运动是否无论模式如何（即有氧运动与阻力运动），都会类似地增强高脂肪喂养大鼠和肥胖 Zucker 大鼠骨骼肌中的胰岛素信号传导。 Yaspelkis III，B.B. 项目叙述我们希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性或对于每个特定模型来说是独特的，以及骨骼肌代谢缺陷是否是可逆的。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发挥作用的细胞/分子途径，进而确定关键靶点，设计替代疗法以逆转胰岛素抵抗并预防胰岛素抵抗。人类糖尿病。