Molecular Mechanisms of Cytokine Induced Insulin Resistance

项目总结 炎症是一种免疫反应，保护我们免受感染和伤害。但是，如果未选中或 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。胰岛素抵抗是一种新陈代谢状态，组织对胰岛素不再有反应。一个 胰岛素的主要功能是通过促进外周组织对葡萄糖的吸收来降低血糖水平 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 胰岛素反应组织中富含促进性葡萄糖转运体。在基础条件下，GLUT4为 被隔离在细胞内的储存囊中。在胰岛素刺激下，GLUT4从细胞内重新定位 囊泡进入细胞表面，有助于将多余的血糖吸收到细胞中处理。 GLUT4胞吐功能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有关，是2型糖尿病(T2D)的一个特征。 实验室和临床研究已经证实，炎症在糖尿病的发病机制中起着核心作用。 胰岛素抵抗。尤其是白介素1β(IL-1β)和肿瘤坏死这两种促炎细胞因子 肿瘤坏死因子α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的联系已经确立，但分子 细胞因子诱导的胰岛素抵抗的机制仍然知之甚少。这一行动的主要目标是 一个探索性项目是通过全球识别细胞因子诱导的胰岛素的介体来帮助弥合这一差距 抵抗，使用胰岛素依赖的GLUT4胞吐作为模型系统。在这项工作中，我们将首先确定 IL-1β和肿瘤坏死因子α是否以及如何损害GLUT4贩运调节器。我们还将表演新的 无偏倚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。这些探索性研究将为全面了解细胞因子相关的胰岛素铺平道路。 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 也是了解促炎症细胞因子在免疫中的其他功能的跳板 系统。

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.