A molecular basis for endotoxin mediated insulin resistance
内毒素介导的胰岛素抵抗的分子基础
基本信息
- 批准号:8391382
- 负责人:
- 金额:$ 5.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-01 至 2015-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAffectAgonistBacteriaCell WallChronicCoinCollectionDataDevelopmentDiabetes MellitusDietDiseaseEndotoxemiaEndotoxinsEnergy IntakeEpithelialEuglycemic ClampingEventFatty acid glycerol estersGlucose ClampGoalsGram-Negative BacteriaHumanImmune responseInflammationInflammatoryInflammatory ResponseInfusion proceduresInsulinInsulin ResistanceIntestinesIntravenousLaboratoriesLeadLinkLipopolysaccharidesMeasuresMediatingMembraneMetabolicMitogen-Activated Protein KinasesModelingMolecularMorbidity - disease rateMusMuscleMutant Strains MiceMutationNon-Insulin-Dependent Diabetes MellitusNuclearNutrientObesityPathogenesisPathway interactionsPatientsPermeabilityPhosphotransferasesPhysiologicalPlasmaPlayRodentRoleSeriesSeveritiesSignal PathwaySignal TransductionSkeletal MuscleSourceTechniquesTestingTissuesbasecohortfeedingglucose uptakegut microbiotaimprovedin vivoinhibitor/antagonistinsightinsulin sensitivityinsulin signalinginterestmortalitynovel strategiespathogenprebioticspreventreceptorresearch studytoll-like receptor 4
项目摘要
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.
PUBLIC HEALTH RELEVANCE: 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. This proposal will provide insight into the role of increased circulating intestinal- generated endotoxin in skeletal muscle insulin resistance. It is the intent of the proposed project to identiy targets which could lead to the development of novel approaches for the treatment of T2D.
描述(由申请方提供):骨骼肌胰岛素抵抗是2型糖尿病(T2 D)的主要标志,也是该疾病发展过程中的早期可检测异常。然而,T2 D肌肉胰岛素抵抗的分子基础尚未完全了解。我们的实验室(初步数据)和其他人已经发现,胰岛素抵抗(肥胖和T2 D)受试者血浆中脂多糖(LPS或内毒素)浓度增加。LPS是革兰氏阴性细菌细胞壁的外膜的组分,其通过激活Toll样受体-4(TLR 4)诱导炎症反应。已经提出肠道微生物群是在胰岛素抵抗受试者中观察到的过量LPS(代谢性内毒素血症)的来源。TLR 4和炎症信号通路受此受体[抑制剂?B激酶IKK-核因子-?B(?F??)和丝裂原活化蛋白激酶(MAPK)]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浓度增加,但尚不清楚代谢性内毒素血症是否会导致肌肉中的炎症和胰岛素抵抗(胰岛素信号传导受损和胰岛素刺激的葡萄糖摄取),以及这些作用是否由TLR 4介导。拟议的研究将通过利用WT和TLR 4突变小鼠的代谢性内毒素血症模型来解决这一差距。总体假设是代谢性内毒素血症通过激活TLR 4和该受体下游的信号传导途径引起胰岛素抵抗。为了检验这一假设,将讨论以下具体目标。具体目标1将确定高脂肪饮食诱导的胰岛素抵抗是否涉及增加的肠通透性、升高的LPS血浆水平,以及体内LPS的有害作用是否需要TLR 4。具体目标2将确定在生理范围内循环LPS的实验性升高是否在体内引起肌肉胰岛素抵抗,以及这种作用是否由TLR 4介导。总之,拟议的研究将利用高胰岛素,正常血糖钳夹技术在WT和TLR 4突变小鼠进行慢性高脂肪饮食和急性内毒素输注,提供新的见解的分子机制,负责胰岛素抵抗的发病机制。如果是阳性的,我们的结果将表明,旨在降低血浆LPS浓度和/或阻断TLR 4的策略将有助于减少炎症并改善T2 D患者的胰岛素作用。因此,我们的研究结果可能会导致开发治疗这种疾病的新方法。
公共卫生关系:骨骼肌中的胰岛素抵抗是2型糖尿病(T2 D)的主要标志,并且是该疾病发展中的早期可检测的异常。然而,T2 D肌肉胰岛素抵抗的分子基础尚未完全了解。这一建议将提供深入了解增加循环肠产生的内毒素在骨骼肌胰岛素抵抗中的作用。该项目的目的是确定可能导致开发治疗T2 D的新方法的靶点。
项目成果
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Sophie Hussey其他文献
Sophie Hussey的其他文献
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{{ truncateString('Sophie Hussey', 18)}}的其他基金
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 - 财政年份:2012
- 资助金额:
$ 5.4万 - 项目类别:
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