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: 8090404
• 负责人: OWEN P MCGUINNESS
• 金额: $ 33.65万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090404
• 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. PUBLIC HEALTH RELEVANCE: Hyperglycemia is very common in hospitalized patients and clinical trials suggest if the hyperglycemia can be minimized morbidity and mortality are improved. A major cause of the hyperglycemia is insulin resistance of skeletal muscle glucose uptake This proposal will determine where the defect is and address the questions is it due simply to a failure of insulin to activate it signaling pathway or are underlying defects in the mitochondria caused by the inflammation aggravating and limiting the ability of insulin to exert is beneficial effects.

描述（由申请人提供）：即使没有糖尿病病史，高血糖也很常见。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。对MGU的控制分布在葡萄糖向肌肉，葡萄糖转运到肌肉之间的分布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所致。肥胖对MGU的影响已经由许多组研究，但是炎症对MGU控制分布的影响尚不清楚。该提案中描述的实验将检查脂多糖（LPS）诱导的炎症在多大程度上重新分布了MGU的控制。在此提案中，将通过使用种系操纵（部分敲除或过度表达）的运输和磷酸化能力（例如己糖激酶）调节单个步骤或多个步骤并测量对MGU的影响来评估控制MGU在控制MGU中的作用和磷酸化的作用。我们假设葡萄糖磷酸化能力的缺陷在炎症引起的胰岛素抵抗中起着核心作用。实验将在长期导管插入意识的小鼠中进行。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。实验策略是扰动控制MGU的蛋白质或过程，并测量扰动对葡萄糖流入的影响。全身葡萄糖的摄取和MGU将分别使用[3-3H]葡萄糖和[14C] 2-脱氧葡萄糖，结合对血液和组织的取样和测量肌肉血流的方法结合使用。 MGU与长链脂肪酸（LCFA）摄取的关系将使用放射标记的脂肪酸类似物同时测量。将使用31NMR光谱法评估肌肉ATP通量。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。我们的具体目的是确定：1​​。LPS对确定MGU 2的相对控制运输和葡萄糖磷酸化的影响。如果LPS放大了NEFA和葡萄糖可用性在调节MGU 3中具有的影响。如果在LPS上调节氧化应激（无效和NF-激活），则可以通过增强MGU的远程和MGU的距离，并将MGU延伸到MGU上。目标是确定控制受炎症影响的MGU的步骤，并评估哪些步骤对氧化应激变化的反应更敏感。然后，未来的疗法可以在诸如败血症等炎症应激期间更正MGU具有更有针对性的方法。公共卫生相关性：高血糖在住院的患者中非常普遍，临床试验表明，是否可以最大程度地减少高血糖症并提高死亡率。 A major cause of the hyperglycemia is insulin resistance of skeletal muscle glucose uptake This proposal will determine where the defect is and address the questions is it due simply to a failure of insulin to activate it signaling pathway or are underlying defects in the mitochondria caused by the inflammation aggravating and limiting the ability of insulin to exert is beneficial effects.