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（由申请人提供）：即使没有糖尿病史，高血糖在败血症患者中也很常见。骨骼肌葡萄糖摄取（MGU）的胰岛素抵抗是这种高血糖的主要原因。 MGU 的控制分布在将葡萄糖输送到肌肉、将葡萄糖转运到肌肉中以及肌肉内的葡萄糖磷酸化之间；胰岛素抵抗是由于其中一种或多种缺陷造成的。许多小组已经研究了肥胖对 MGU 的影响，但炎症对 MGU 控制分布的影响尚不清楚。本提案中描述的实验将检查脂多糖 (LPS) 诱导的炎症重新分配 MGU 控制的程度。在本提案中，将通过使用运输和磷酸化能力（例如己糖激酶）的种系操作（部分敲除或过度表达）来评估运输和磷酸化在控制 MGU 中的作用，以调节单​​个步骤或多个步骤并测量对 MGU 的影响。我们假设葡萄糖磷酸化能力的缺陷在炎症诱导的胰岛素抵抗中发挥核心作用。实验将在长期插管、有意识的小鼠中进行。这种方法允许在没有压力的情况下对体内 MGU 进行全面的代谢评估。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流入的影响。将分别使用[3-3H]葡萄糖和[14C]2-脱氧葡萄糖，结合血液和组织取样以及肌肉血流量测量方法来测量全身葡萄糖摄取和MGU。 MGU 与长链脂肪酸 (LCFA) 摄取的关系将同时使用放射性标记的脂肪酸类似物进行测量。肌肉 ATP 通量将使用 31NMR 光谱进行评估。将分析组织的糖原合成、胰岛素信号传导、氧化应激和 GLUT4 易位。我们的具体目标是确定： 1. LPS 对相对控制转运和葡萄糖磷酸化在确定 MGU 方面的影响 2. LPS 是否会放大 NEFA 和葡萄糖可用性在调节 MGU 中的影响 3. LPS 后调节氧化应激（NO 可用性和 NF-:B 激活）是否会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 目标是确定受炎症影响的控制 MGU 的步骤，并评估其中哪些步骤对氧化应激的变化更敏感。未来的治疗可以采用更有针对性的方法来纠正脓毒症等炎症应激期间的 MGU。

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