A molecular basis for endotoxin mediated insulin resistance

内毒素介导的胰岛素抵抗的分子基础

• 批准号: 8537751
• 负责人: Sophie Hussey
• 金额: $ 5.25万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8537751
• 关键词: Acute; Address; Affect; Agonist; Bacteria; Cell Wall; Chronic; Coin; Collection; Data; Development; Diabetes Mellitus; Diet; Disease; Endotoxemia; Endotoxins; Energy Intake; Epithelial; Euglycemic Clamping; Event; Fatty acid glycerol esters; Glucose Clamp; Goals; Gram-Negative Bacteria; Human; Immune response; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin Resistance; Intestines; Intravenous; Laboratories; Lead; Link; Lipopolysaccharides; Measures; Mediating; Membrane; Metabolic; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Mutant Strains Mice; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obesity; Pathogenesis; Pathway interactions; Patients; Permeability; Phosphotransferases; Physiological; Plasma; Play; Rodent; Role; Series; Severities; Signal Pathway; Signal Transduction; Skeletal Muscle; Source; Techniques; Testing; Tissues; base; cohort; feeding; glucose uptake; gut microbiota; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; insulin signaling; interest; mortality; novel strategies; pathogen; prebiotics; prevent; receptor; research study; toll-like receptor 4

DESCRIPTION (provided by applicant): Insulin resistance in skeletal muscle is a major hallmark of type 2 diabetes (T2D) and an early detectable abnormality in the development of this disease. However, the molecular basis for the muscle insulin resistance of T2D is not fully understood. Our laboratory (preliminary data) and others have found that insulin resistant (obese and T2D) subjects have increased concentrations of lipopolysaccharide (LPS or endotoxin) in plasma. LPS is a component of the outer membrane of gram negative bacteria cell walls which induces an inflammatory response by activating toll-like receptor-4 (TLR4). It has been proposed that intestinal microbiota is the source of the excessive LPS observed in insulin resistant subjects (metabolic endotoxemia). TLR4 and inflammatory signaling pathways regulated by this receptor [inhibitor ?B kinase IKK-nuclear factor-?B (?F??) and mitogen activated protein kinases (MAPKs)] have been implicated in the pathogenesis of insulin resistance. Despite the accumulating evidence that insulin resistant subjects have increased concentrations of LPS in plasma, it is unclear whether metabolic endotoxemia causes inflammation and insulin resistance (impaired insulin signaling and insulin-stimulated glucose uptake) in muscle and whether these effects are mediated by TLR4. The proposed studies will address this gap by utilizing a model of metabolic endotoxemia in WT and TLR4-mutant mice. The overall hypothesis is that metabolic endotoxemia causes insulin resistance by activating TLR4 and signaling pathways downstream this receptor. To test this hypotheses the following specific aims will be addressed. Specific Aim 1 will determine whether high fat diet-induced insulin resistance involves increased intestinal permeability, elevated plasma levels of LPS, and whether TLR4 is required for the deleterious effects of LPS in vivo. Specific Aim 2 will determine whether an experimental elevation in circulating LPS, within a physiologic range, causes muscle insulin resistance in vivo and whether this effect is mediated by TLR4. In summary, the proposed studies will utilize the hyperinsulinemic, euglycemic clamp technique in WT and TLR4 mutant mice subjected to chronic high fat diet and acute endotoxin infusion, to provide new insights into the molecular mechanisms responsible for the pathogenesis of insulin resistance. If positive, our results would indicate that strategies aimed at lowering plasma LPS concentrations and/or blocking TLR4 will help to reduce inflammation and improve insulin action in patients with T2D. As such, our results could lead to the development of novel approaches for the treatment of this disease.

描述（由申请人提供）：骨骼肌胰岛素抵抗是2型糖尿病（T2D）的主要标志，也是该疾病发展过程中早期可检测到的异常。然而，T2D肌肉胰岛素抵抗的分子基础尚不完全清楚。我们的实验室（初步数据）和其他人发现胰岛素抵抗（肥胖和T2D）受试者血浆中脂多糖（LPS或内毒素）浓度升高。脂多糖是革兰氏阴性菌细胞壁外膜的一种成分，通过激活toll样受体-4 （TLR4）诱导炎症反应。有人提出，肠道微生物群是胰岛素抵抗受试者（代谢性内毒素血症）中观察到的过量LPS的来源。TLR4和这种受体[抑制剂]调控的炎症信号通路？核因子-？B (F)和丝裂原活化蛋白激酶（MAPKs）]与胰岛素抵抗的发病机制有关。尽管越来越多的证据表明胰岛素抵抗受试者血浆中LPS浓度升高，但尚不清楚代谢性内毒素血症是否会导致肌肉炎症和胰岛素抵抗（胰岛素信号受损和胰岛素刺激的葡萄糖摄取），以及这些影响是否由TLR4介导。拟议的研究将利用WT和tlr4突变小鼠的代谢性内毒素血症模型来解决这一空白。总体假设是代谢性内毒素血症通过激活TLR4和该受体下游的信号通路导致胰岛素抵抗。为了验证这一假设，将解决以下具体目标。特异性目的1将确定高脂肪饮食诱导的胰岛素抵抗是否涉及肠通透性增加、血浆LPS水平升高，以及TLR4是否需要参与体内LPS的有害作用。特异性目的2将确定在生理范围内循环LPS的实验升高是否会引起体内肌肉胰岛素抵抗，以及这种作用是否由TLR4介导。综上所述，本研究将利用高胰岛素、正糖钳技术对慢性高脂饮食和急性内毒素输注的WT和TLR4突变小鼠进行研究，为胰岛素抵抗的分子机制提供新的见解。如果结果为阳性，我们的研究结果将表明，旨在降低血浆LPS浓度和/或阻断TLR4的策略将有助于减少t2dm患者的炎症和改善胰岛素作用。因此，我们的结果可能会导致治疗这种疾病的新方法的发展。