Molecular Mechanisms of Cytokine Induced Insulin Resistance

细胞因子诱导胰岛素抵抗的分子机制

• 批准号: 9388051
• 负责人: Charles anthony Dinarello
• 金额: $ 20.38万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-14 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388051
• 关键词: Adipocytes; Arthritis; Biological Models; Blood Glucose; CRISPR library; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular Diseases; Cell surface; Cells; Characteristics; Chronic Disease; Clinical Research; Communities; Data; Defect; Dimensions; Disease Resistance; Down-Regulation; Equilibrium; Exhibits; Exocytosis; Flow Cytometry; GLUT4 gene; Genes; Genetic Screening; Genetic Transcription; Glucose Transporter; Goals; Hepatocyte; Immune response; Immune system; Impairment; Incidence; Individual; Infection; Inflammation; Injury; Insulin; Insulin Resistance; Interleukin-1 beta; Knock-out; Laboratory Study; Lead; Light; Mediating; Mediator of activation protein; Metabolic; Molecular; Mus; Muscle Cells; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Peripheral; Play; Research; Resources; Role; Scientist; Skeletal Muscle; TNF gene; Therapeutic Intervention; Tissues; Up-Regulation; Vesicle; Work; cytokine; experimental study; genome-wide; global health; glucose uptake; human disease; mutant; new therapeutic target; novel; programs; response; tool; trafficking; transcriptome sequencing; uptake

PROJECT SUMMARY Inflammation is an immune response protecting us from infection and injury. However, unchecked or improperly activated inflammation can result in chronic diseases such as arthritis, cardiovascular diseases and insulin resistance. Insulin resistance is a metabolic condition in which tissues no longer respond to insulin. A major function of insulin is to lower blood glucose levels by promoting glucose uptake into peripheral tissues including skeletal muscles and adipocytes. Insulin-stimulated glucose uptake is mediated by GLUT4, a facilitative glucose transporter enriched in insulin-responsive tissues. Under basal conditions, GLUT4 is sequestered in intracellular storage vesicles. Upon insulin stimulation, GLUT4 is relocated from intracellular vesicles to the cell surface where it facilitates the uptake of excess blood glucose into the cells for disposal. Defects in GLUT4 exocytosis disrupt blood glucose balance and are a hallmark of insulin resistance. Commonly associated with obesity, insulin resistance is a characteristic feature of type 2 diabetes (T2D). Laboratory and clinical studies have established that inflammation plays a central role in the pathogenesis of insulin resistance. In particular, the two proinflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNFα) directly interfere with insulin responses in adipocytes, hepatocytes and skeletal muscles. While the connection of proinflammatory cytokines to insulin resistance is well established, the molecular mechanisms of cytokine-induced insulin resistance remains poorly understood. The major goal of this exploratory project is to help bridge this gap by globally identifying mediators of cytokine-induced insulin resistance, using insulin-dependent GLUT4 exocytosis as a model system. In this work, we will first determine whether and how GLUT4 trafficking regulators are impaired by IL-1β and TNFα. We will also perform new unbiased genome-wide genetic screens to identify suppressors of cytokine-induced impairment in GLUT4 exocytosis. These exploratory studies will pave the path for a full understanding of cytokine-associated insulin resistance and will likely identify novel therapeutic targets for treating insulin resistance and T2D. This work will also serve as a springboard to understanding other functions of proinflammatory cytokines in the immune system.

项目概要 炎症是一种免疫反应，保护我们免受感染和伤害。然而，未经检查或 炎症激活不当会导致慢性疾病，如关节炎、心血管疾病和 胰岛素抵抗。胰岛素抵抗是一种代谢状况，组织不再对胰岛素做出反应。一个 胰岛素的主要功能是通过促进周围组织摄取葡萄糖来降低血糖水平 包括骨骼肌和脂肪细胞。胰岛素刺激的葡萄糖摄取是由 GLUT4 介导的，GLUT4 是一种 在胰岛素反应组织中富集的促进性葡萄糖转运蛋白。在基础条件下，GLUT4为 隔离在细胞内的储存囊泡中。胰岛素刺激后，GLUT4 从细胞内重新定位 囊泡附着在细胞表面，促进细胞吸收多余的血糖并进行处理。 GLUT4 胞吐作用的缺陷会破坏血糖平衡，是胰岛素抵抗的标志。 胰岛素抵抗通常与肥胖相关，是 2 型糖尿病 (T2D) 的一个特征。 实验室和临床研究已证实炎症在疾病的发病机制中起着核心作用 胰岛素抵抗。特别是两种促炎细胞因子白细胞介素 1β (IL-1β) 和肿瘤坏死 α因子（TNFα）直接干扰脂肪细胞、肝细胞和骨骼肌的胰岛素反应。 虽然促炎细胞因子与胰岛素抵抗之间的联系已得到充分证实，但分子 细胞因子诱导的胰岛素抵抗的机制仍知之甚少。此次活动的主要目标 探索性项目旨在通过全球识别细胞因子诱导的胰岛素介质来帮助弥合这一差距 使用胰岛素依赖性 GLUT4 胞吐作用作为模型系统。在这项工作中，我们首先要确定 IL-1β 和 TNFα 是否以及如何损害 GLUT4 运输调节因子。我们还将演绎新的 无偏见的全基因组遗传筛选，以确定细胞因子诱导的 GLUT4 损伤的抑制因子 胞吐作用。这些探索性研究将为全面了解细胞因子相关胰岛素铺平道路 抗性，并可能确定治疗胰岛素抵抗和 T2D 的新治疗靶点。这项工作将 也可以作为了解促炎细胞因子在免疫中的其他功能的跳板 系统。