Interleukin-10 and Regulation of Skeletal Muscle Insulin Action

IL-10 和骨骼肌胰岛素作用的调节

基本信息

批准号：
7688617
负责人：
JASON K KIM
金额：
$ 32.82万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688617
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 3-Phosphoinositide Dependent Protein Kinase-1 Acute Adipose tissue Affect Animals Anti-Inflammatory Agents Anti-inflammatory Apoptosis Architecture Attenuated Breeding C57BL/6 Mouse CCL2 gene Chronic Cytokine Inducible SH2-Containing Protein Data Defect Development Dichloromethylene Diphosphonate Diet Diglycerides Down-Regulation Energy Metabolism Euglycemic Clamping Fatty Acids Fatty acid glycerol esters Figs - dietary Genes Genetic Glucose Glucose Clamp Goals Human Infiltration Inflammation Inflammatory Infusion procedures Insulin Insulin Receptor Insulin Resistance Interleukin-10 Interleukin-10 Overexpression Interleukin-6 Intracellular Accumulation of Lipids Intramuscular JUN gene Label Leptin Lipids Liposomes MAPK8 gene Measures Mediating Metabolic Metabolic syndrome Methods Modeling Molecular Profiling Mus Muscle Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Pathway interactions Phenotype Phosphorylation Phosphotransferases Plasma Play Protein Kinase C Protein-Serine-Threonine Kinases Proteins Regulation Reporting Research Role STAT3 gene Serine Signal Transduction Signaling Protein Skeletal Muscle Testing Transgenic Mice Triglycerides Tumor Necrosis Factor-alpha Tumor Necrosis Factors Wild Type Mouse adenylate kinase attenuation base cytokine diabetic feeding glucose metabolism in vivo insight insulin sensitivity insulin signaling lipid metabolism macrophage migration monocyte mouse model new therapeutic target novel prevent protective effect public health relevance resistance mechanism therapeutic target transgene expression

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle insulin resistance plays a primary role in the development of type 2 diabetes and may be causally associated with inflammation and altered lipid metabolism. Circulating levels of fatty acids and pro-inflammatory cytokines are elevated in obese, diabetic subjects and shown to cause insulin resistance in skeletal muscle. In contrast, plasma levels of IL-10, an anti-inflammatory cytokine, are positively related to insulin sensitivity and reduced in subjects with metabolic syndrome. We have recently shown that acute treatment with IL-10 prevents lipid-mediated insulin resistance in muscle that is associated with increased insulin signaling in mice. To further examine the role of IL-10 in skeletal muscle insulin action, we have recently generated transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10 mice). Our preliminary data indicate that MCK-IL10 mice are protected from lipid- mediated defects in insulin signaling and glucose metabolism in muscle. We also find that diet-induced insulin resistance is associated with increased macrophage infiltration in skeletal muscle, and these effects are attenuated in MCK-IL10 mice. We hypothesize that IL-10 prevents muscle insulin resistance by 1) blocking lipid-mediated activation of PKC-8/JNK/IKK and down regulation of insulin signaling, and/or 2) suppressing obesity-associated macrophage infiltration and inhibiting the deleterious effects of macrophage-derived cytokines on glucose metabolism. Based on our preliminary data showing altered intramuscular lipid levels in IL-10 treated mice, the Aim 1 will examine the effects of muscle IL-10 overexpression on glucose and lipid metabolism. In Aim 2, we will identify the mechanism by which MCK-IL10 mice are protected from lipid-mediated insulin resistance using chronic high-fat feeding, acute lipid infusion, and genetically obese mouse models. The Aim 3 will determine the role of macrophage infiltration in muscle insulin resistance in diet-induced obesity and acute lipid infusion models. We will also observe macrophage migration using monocyte labeling and examine the effects of macrophage depletion using clodronate on lipid-mediated insulin resistance. Lastly, we will investigate the role of alternatively-activated macrophages in MCK-IL10 phenotypes. Overall, our proposed studies will identify a novel role of IL-10 in the regulation of skeletal muscle insulin action and discover new therapeutic targets in the treatment of insulin resistance and type 2 diabetes. PUBLIC HEALTH RELEVANCE. Skeletal muscle insulin resistance plays a major role in the development of type 2 diabetes, which impacts more than 170 million people worldwide and may be causally associated with inflammation and altered lipid metabolism. The proposed studies will examine the mechanisms by which interleukin-10 regulates skeletal muscle insulin action and prevents lipid-mediated insulin resistance in skeletal muscle. Our findings will provide important insights into the role of obesity and inflammation in insulin resistance and further identify novel therapeutic targets in the treatment of type 2 diabetes.

描述（由申请人提供）：骨骼肌胰岛素抵抗在2型糖尿病的发展中起主要作用，并且可能与炎症和脂质代谢改变有关。肥胖，糖尿病患者的脂肪酸和促炎细胞因子的循环水平升高，并显示在骨骼肌中引起胰岛素抵抗。相反，抗炎细胞因子IL-10的血浆水平与胰岛素敏感性呈正相关，并且在代谢综合征的受试者中降低。我们最近表明，用IL-10进行急性治疗可防止肌肉中脂质介导的胰岛素抵抗，这与小鼠中胰岛素信号增加有关。为了进一步研究IL-10在骨骼肌胰岛素作用中的作用，我们最近用IL-10（MCK-IL10小鼠）的肌肉特异性过表达产生了转基因小鼠。我们的初步数据表明，MCK-IL10小鼠免受肌肉中胰岛素信号传导和葡萄糖代谢中脂质介导的缺陷的保护。我们还发现，饮食诱导的胰岛素抵抗与骨骼肌中巨噬细胞浸润的增加有关，并且在MCK-IL10小鼠中这些作用会减弱。 We hypothesize that IL-10 prevents muscle insulin resistance by 1) blocking lipid-mediated activation of PKC-8/JNK/IKK and down regulation of insulin signaling, and/or 2) suppressing obesity-associated macrophage infiltration and inhibiting the deleterious effects of macrophage-derived cytokines on glucose metabolism.基于我们的初步数据，显示了IL-10治疗的小鼠肌内脂质水平发生了变化，目标1将检查肌肉IL-10过表达对葡萄糖和脂质代谢的影响。在AIM 2中，我们将使用慢性高脂进食，急性脂质输注和遗传性肥胖的小鼠模型来确定MCK-IL10小鼠免受脂质介导的胰岛素耐药性的机制。目标3将确定巨噬细胞浸润在肌肉胰岛素抵抗中的作用，在饮食诱导的肥胖和急性脂质输注模型中。我们还将使用单核细胞标记观察巨噬细胞的迁移，并检查使用克氯膦酸盐对脂质介导的胰岛素耐药性的巨噬细胞耗竭的影响。最后，我们将研究替代激活的巨噬细胞在MCK-IL10表型中的作用。总体而言，我们提出的研究将确定IL-10在调节骨骼肌胰岛素作用中的新作用，并在治疗胰岛素抵抗和2型糖尿病时发现新的治疗靶标。公共卫生相关性。骨骼肌胰岛素抵抗在2型糖尿病的发展中起着重要作用，这会影响全球超过1.7亿人，并且可能与炎症和脂质代谢改变有关。拟议的研究将研究白介素10调节骨骼肌胰岛素作用并防止骨骼肌中脂质介导的胰岛素抵抗的机制。我们的发现将提供有关肥胖和炎症在胰岛素抵抗中的作用的重要见解，并进一步确定2型糖尿病治疗的新型治疗靶标。