Impact of Inflammation on the Control of Muscle Glucose Uptake

炎症对肌肉葡萄糖摄取控制的影响

• 批准号: 8485594
• 负责人: OWEN P MCGUINNESS
• 金额: $ 32.13万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485594
• 关键词: ATP Synthesis Pathway; Acids; Address; Affect; Blood flow; Blood specimen; Clinical Trials; Complex; Conscious; Coupled; Defect; Deoxyglucose; Diabetes Mellitus; Diet; Distal; Endocrine; Environment; Event; Exercise; Failure; Future; GLUT4 gene; Glucose; Glycogen; Goals; Health; Hexokinase 2; Hormones; Hyperglycemia; Hypertension; Hypotension; Impairment; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knock-out; Knockout Mice; Label; Lipopolysaccharides; Measures; Metabolic; Methods; Mitochondria; Monitor; Morbidity - disease rate; Mus; Muscle; NOS2A gene; Nitric Oxide; Nutrient; Obesity; Oxidative Stress; Patients; Phosphorylation; Physiological; Play; Process; Production; Proteins; Radiolabeled; Reaction; Recording of previous events; Relative (related person); Role; SLC2A1 gene; Sepsis; Signal Pathway; Signal Transduction; Skeletal Muscle; Spectrum Analysis; Stress; System; Tetanus Helper Peptide; Tissues; attenuation; cytokine; fatty acid analog; glucose transport; glucose uptake; hexokinase; improved; in vivo; insulin signaling; long chain fatty acid; mortality; radiotracer; research study; septic; uptake

DESCRIPTION (provided by applicant): Hyperglycemia is very common in patients with sepsis even if there is no history of diabetes. Insulin resistance of skeletal muscle glucose uptake (MGU) is a major cause of this hyperglycemia. Control of MGU is distributed between delivery of glucose to muscle, glucose transport into muscle, and glucose phosphorylation within muscle; insulin resistance is due to defects in one or more of them. The impact of obesity on MGU has been studied by a number of groups, but the impact of inflammation on the distribution of control of MGU is unknown. The experiments described in this proposal will examine the extent to which inflammation induced by lipopolysaccharide (LPS) redistributes the control of MGU. In this proposal the roles transport and phosphorylation play in controlling MGU will be assessed by using germline manipulation (partial knockout or over expression) of transport and phosphorylation capacity (e.g. hexokinase) to modulate a single step or multiple steps and measure the impact on MGU. We hypothesize that defects in glucose phosphorylation capacity play a central role in the inflammation induced insulin resistance. Experiments will be performed in chronically catheterized, conscious mice. This approach allows for comprehensive metabolic assessment of MGU in vivo in the absence of stress. The experimental strategy is to perturb proteins or processes involved in control of MGU and measure the effect of the perturbation on glucose influx. Whole body glucose uptake and MGU will be measured using [3-3H] glucose and [14C] 2- deoxyglucose, respectively, in combination with methods for sampling blood and tissues and measuring muscle blood flow. The relationship of MGU to long chain fatty acid (LCFA) uptake will simultaneously be measured using a radiolabeled fatty acid analog. Muscle ATP flux will be assessed using 31NMR spectroscopy. Tissues will be analyzed for glycogen synthesis, insulin signaling, oxidative stress and GLUT4 translocation. Our specific aims are to determine: 1. The impact of LPS on the relative control transport and glucose phosphorylation have in determining MGU 2. If LPS amplifies the impact NEFA and glucose availability have in modulating MGU 3. If modulating oxidative stress (NO availability and NF-:B activation) following LPS will improve MGU by augmenting glucose phosphorylation and mitochondrial ATP flux Our long term goal is to identify the steps controlling MGU that are impacted by inflammation and assess which of those steps are more responsive to changes in oxidative stress. Future therapies can then have a more targeted approach in correcting MGU during an inflammatory stress such as sepsis.

描述(申请人提供)：高血糖在脓毒症患者中非常常见，即使没有糖尿病病史也是如此。骨骼肌葡萄糖摄取的胰岛素抵抗(MGU)是导致这种高血糖的主要原因。MGU的控制分布在葡萄糖向肌肉的输送、葡萄糖向肌肉的转运和肌肉内的葡萄糖磷酸化之间；胰岛素抵抗是由于其中一个或多个缺陷造成的。肥胖对MGU的影响已被多个小组研究，但炎症对MGU对照分布的影响尚不清楚。这项提案中描述的实验将检验内毒素(LPS)引起的炎症在多大程度上重新分配MGU的控制力。在这个提案中，运输和磷酸化在控制MGU中所起的作用将通过使用胚系操纵(部分敲除或过度表达)运输和磷酸化能力(例如己糖激酶)来调节单步或多步来评估，并测量对MGU的影响。我们假设葡萄糖磷酸化能力缺陷在炎症诱导的胰岛素抵抗中起核心作用。实验将在长期导尿管清醒的小鼠身上进行。这种方法允许在没有应激的情况下对MGU在体内的代谢进行全面的评估。实验策略是扰乱参与MGU控制的蛋白质或过程，并测量扰动对葡萄糖内流的影响。全身葡萄糖摄取量和MGU将分别使用[3-~3H]葡萄糖和[14C]2-脱氧葡萄糖，并结合血液和组织采样和肌肉血流量测量方法进行测量。MGU与长链脂肪酸(LCFA)摄取的关系将同时使用放射性标记脂肪酸类似物进行测量。肌肉的三磷酸腺苷流量将使用31核磁共振波谱进行评估。将对组织进行糖原合成、胰岛素信号、氧化应激和GLUT4转位的分析。我们的具体目标是确定：1.脂多糖对相对控制转运和葡萄糖磷酸化在确定MGU 2中的影响。如果内毒素放大NEFA和葡萄糖可获得性在调节MGU 3中的影响。如果脂多糖后调节氧化应激(无可获得性和核因子：B激活)将通过增加葡萄糖磷酸化和线粒体ATP通量来改善MGU，我们的长期目标是确定控制MGU的步骤受到炎症的影响，并评估这些步骤中哪些步骤对氧化应激的变化更敏感。未来的治疗方法可以有一个更有针对性的方法来纠正炎性应激期间的MGU，如脓毒症。

项目成果

Impaired insulin signaling in the B10.D2-Hc0 H2d H2-T18c/oSnJ mouse model of complement factor 5 deficiency.

补体因子 5 缺乏的 B10.D2-Hc0 H2d H2-T18c/oSnJ 小鼠模型中胰岛素信号传导受损。

• DOI: 10.1152/ajpendo.00042.2019
• 发表时间: 2019
• 期刊: American journal of physiology. Endocrinology and metabolism
• 作者: Peterson,KristinR;Gutierrez,DarioA;Kikuchi,Takuya;Anderson-Baucum,EmilyK;Winn,NathanC;Shuey,MeganM;Bolus,WilliamR;McGuinness,OwenP;Hasty,AlyssaH
• 通讯作者: Hasty,AlyssaH