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.

项目总结