Integrated Control of Muscle Glucose Uptake in Vivo

体内肌肉葡萄糖摄取的综合控制

• 批准号: 8484389
• 负责人: DAVID H WASSERMAN
• 金额: $ 31.37万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-15 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484389
• 关键词: Acids; Address; Adopted; Affect; Biochemical; Blood Vessels; Characteristics; Collagen; Conscious; Defect; Deoxyglucose; Deposition; Diet; Effectiveness; Exercise; Experimental Models; Extracellular Matrix; Fatty acid glycerol esters; Functional disorder; Funding; Genetic; Glucose; Health; Healthcare Systems; Hormones; Human; Image; Insulin; Insulin Resistance; Integrins; Intervention; Lead; Life Style; MMP9 gene; Matrix Metalloproteinases; Metabolic; Metabolic syndrome; Metalloproteases; Mitochondria; Modification; Mus; Muscle; Muscle Mitochondria; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Phenotype; Phosphorylation; Physiological; Play; Progress Reports; Protocols documentation; Quality of life; Regulation; Relative (related person); Relaxation; Resistance; Resources; Rodent Model; Role; Signal Transduction; Site; Skeletal Muscle; Speed; Techniques; Testing; Tissues; Transgenic Organisms; Translating; Weight Gain; Whole Organism; blood glucose regulation; catalase; design; effective therapy; feeding; glucose transport; glucose uptake; in vivo; insulin sensitivity; mouse model; muscle metabolism; novel; phosphoric diester hydrolase; prevent; public health relevance; treatment strategy; Acids; Address; Adopted; Affect; Biochemical; Blood Vessels; Characteristics; Collagen; Conscious; Defect; Deoxyglucose; Deposition; Diet; Effectiveness; Exercise; Experimental Models; Extracellular Matrix; Fatty acid glycerol esters; Functional disorder; Funding; Genetic; Glucose; Health; Healthcare Systems; Hormones; Human; Image; Insulin; Insulin Resistance; Integrins; Intervention; Lead; Life Style; MMP9 gene; Matrix Metalloproteinases; Metabolic; Metabolic syndrome; Metalloproteases; Mitochondria; Modification; Mus; Muscle; Muscle Mitochondria; Muscle function; Non-Insulin-Dependent Diabetes Mellitus; Oxidative Stress; Pathogenesis; Phenotype; Phosphorylation; Physiological; Play; Progress Reports; Protocols documentation; Quality of life; Regulation; Relative (related person); Relaxation; Resistance; Resources; Rodent Model; Role; Signal Transduction; Site; Skeletal Muscle; Speed; Techniques; Testing; Tissues; Transgenic Organisms; Translating; Weight Gain; Whole Organism; blood glucose regulation; catalase; design; effective therapy; feeding; glucose transport; glucose uptake; in vivo; insulin sensitivity; mouse model; muscle metabolism; novel; phosphoric diester hydrolase; prevent; public health relevance; treatment strategy

DESCRIPTION (provided by applicant): Insulin resistance is a hallmark of the metabolic syndrome. Muscle comprises the vast majority of insulin sensitive tissue and is a site of dysregulation in the insulin resistant state. Insulin resistance cannot be understood without defining underlying defects in insulin resistant muscle. Despite the central role of muscle metabolism to overall "metabolic health", the mechanism(s) for its effectiveness in healthy physically active states, the factors responsible for dysfunction, and the means to correct dysfunction are poorly understood. The objective of the proposed studies is to bridge the biochemical and histological characteristics of the insulin resistant muscle with their functional consequences. The proposed studies will expand on three major findings from the last funding cycle. These are that (a) extramyocellular barriers to muscle glucose uptake are an important component of insulin resistance; (b) the myocellular extracellular matrix in the insulin resistant state is characterized by increased collagen deposition and reduced matrix metalloprotease-9 activity; and (c) unique and diverse mechanisms for enhancing insulin sensitivity in insulin resistant muscle also reduce collagen deposition and increase MMP9 activity. The aims of the proposed studies are to study in the whole organism: (i) the magnitude and mechanism whereby selective phosphodiesterae-5A inhibition prevents and reverses high fat (HF) diet-induced muscle insulin resistance; (ii) the means by which genetic expression of mitochondrial-targeted catalase prevents insulin resistance in HF-fed mice; (iii) the means by which a physiological intervention, regular physical exercise, protects against HF-fed insulin resistance; and (iv) the relative importance of endothelial dysfunction and extracellular matrix modifications to the extramyocellular defects associated with insulin resistance and interventions that enhance insulin action. These aims will be addressed using novel experimental models (chronically-catheterized, unstressed mice), genetically modified mouse models, isotopic techniques, and high-speed slit-confocal imaging. Results from these studies will lead to a greater understanding of the sites involved in the dysregulation of muscle glucose uptake associated with insulin resistance and will identify potential treatment strategies.

描述（由申请人提供）：胰岛素抵抗是代谢综合征的标志。肌肉包括绝大多数胰岛素敏感组织，是胰岛素耐药性状态下失调的部位。如果不定义抗胰岛素耐药性肌肉中的潜在缺陷，则无法理解胰岛素抵抗。尽管肌肉代谢对整体“代谢健康”的核心作用，但其在健康的身体活跃状态下的有效性，导致功能障碍的因素以及纠正功能障碍的手段的理解很少。拟议的研究的目的是弥合抗胰岛素抵抗肌肉的生化和组织学特征，其功能后果。拟议的研究将扩大上一个融资周期的三个主要发现。这些是（a）肌肉葡萄糖摄取的细胞外屏障是胰岛素抵抗的重要组成部分； （b）抗胰岛素耐药态的心肌细胞外基质的特征是胶原蛋白沉积增加和基质金属蛋白酶9活性降低； （c）增强胰岛素耐药肌中胰岛素敏感性的独特和多种机制，还减少了胶原蛋白沉积并增加了MMP9活性。拟议的研究的目的是研究整个生物体：（i）选择性磷酸二酯-5a抑制作用可阻止并逆转高脂（HF）饮食诱导的肌肉胰岛素耐药性； （ii）线粒体靶向过氧化氢酶的遗传表达阻止HF喂养小鼠的胰岛素抵抗的手段； （iii）一种生理干预，定期体育锻炼，防止HF喂养的胰岛素抵抗的手段； （iv）内皮功能障碍和细胞外基质对与胰岛素耐药性和干预措施相关的细胞外缺陷的相对重要性，从而增强了胰岛素作用。这些目标将使用新颖的实验模型（长期导入，无重理的小鼠），转基因的小鼠模型，同位素技术和高速缝隙对焦点成像来解决。这些研究的结果将使人们对与胰岛素抵抗相关的肌肉葡萄糖吸收失调的部位有更深入的了解，并将确定潜在的治疗策略。