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）：高血压在脓毒症患者中非常常见，即使没有糖尿病史。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的控制分布在葡萄糖向肌肉的递送、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的缺陷。肥胖对MGU的影响已被许多研究小组研究，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，将通过使用转运和磷酸化能力（例如己糖激酶）的种系操作（部分敲除或过表达）来调节单个步骤或多个步骤并测量对MGU的影响，评估转运和磷酸化在控制MGU中的作用。我们推测葡萄糖磷酸化能力的缺陷在炎症诱导的胰岛素抵抗中起着重要作用。实验将在长期插管的清醒小鼠中进行。这种方法允许在没有应激的情况下对MGU进行体内综合代谢评估。实验策略是干扰参与MGU控制的蛋白质或过程，并测量干扰对葡萄糖流入的影响。将分别使用[3- 3 H]葡萄糖和[14 C] 2-脱氧葡萄糖结合血液和组织采样以及测量肌肉血流量的方法测量全身葡萄糖摄取和MGU。将使用放射性标记的脂肪酸类似物同时测量MGU与长链脂肪酸（LCFA）摄取的关系。将使用31 NMR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GLUT 4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的影响在确定MGU 2中起作用。如果LPS放大了NEFA和葡萄糖可用性在调节MGU 3中的影响。如果在LPS后调节氧化应激（NO可用性和NF-：B活化）将通过增加葡萄糖磷酸化和线粒体ATP通量来改善MGU，我们的长期目标是鉴定控制受炎症影响的MGU的步骤，并评估这些步骤中的哪些步骤对氧化应激的变化更敏感。未来的治疗方法可以在炎症应激（如脓毒症）期间更有针对性地纠正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