Vesicle translocation and the metabolic syndrome

囊泡易位和代谢综合征

• 批准号: 8518317
• 负责人: JONATHAN BOGAN
• 金额: $ 24.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518317
• 关键词: Accounting; Adipocytes; Adult; Affect; Aminopeptidase; Argipressin; Blood Pressure; Blood Vessels; Blood flow; Bypass; Cell membrane; Cell surface; Cells; Contracts; Data; Defect; Development; Diabetes Mellitus; Diet; Energy Metabolism; Equilibrium; Fasting; Fatty acid glycerol esters; GLUT4 gene; Glucose Transporter; Goals; Golgi Apparatus; Homeostasis; Human; Hypertension; Impairment; Insulin; Insulin Resistance; Integral Membrane Protein; Lead; Life; Light; Link; Lipoproteins; Mediating; Membrane; Metabolic; Metabolic syndrome; Mitochondria; Molecular; Morbidity - disease rate; Movement; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathway interactions; Phenotype; Physiological; Physiology; Prediabetes syndrome; Prevention; Proteins; Public Health; Regulation; Research; Rodent Model; Sarcolemma; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Testing; Time; Tissues; Transgenic Mice; Ubiquitin; United States; Vasopressins; Vesicle; Water; Work; abstracting; basal insulin; base; blood glucose regulation; blood pressure regulation; feeding; glucose metabolism; glucose uptake; insight; insulin sensitivity; insulin signaling; lipid metabolism; mortality; response; sortilin; trafficking; uptake

DESCRIPTION (provided by applicant): Abstract Insulin stimulates glucose uptake in muscle by mobilizing intracellular GLUT4 storage vesicles (GSVs), which fuse at the cell surface and insert GLUT4 glucose transporters into the sarcolemma. The differential targeting of GLUT4 in basal and insulin-stimulated cells determines insulin responsiveness. Insulin resistance results from impaired GSV regulation, and contributes to the pathogenesis of the metabolic syndrome and type 2 diabetes. Defects in both insulin signaling and vesicle trafficking may contribute to impaired GSV regulation. Signaling defects have been well studied, but trafficking defects are not characterized. Recent data suggest that GLUT4 trafficking defects may be an important contributor to insulin resistance in muscle. However, even normal GSV trafficking pathways are poorly defined. This proposal builds on recent work that, for the first time, defines a pool of insulin-regulated GSVs in molecular terms. These vesicles are retained intracellularly by TUG, which links GSVs to the Golgi matrix in unstimulated cells. Insulin causes TUG cleavage to release GSVs and to insert GLUT4 at the plasma membrane. Although GSV trafficking is controlled by insulin at multiple steps, data suggest that the TUG pathway is a major site of regulation, which is compromised in diet- induced insulin resistance in mice. Moreover, GSVs contain proteins other than GLUT4, notably IRAP, which may mediate distinct physiologic actions to control vascular tone and water homeostasis. Thus, impaired GSV trafficking may result not only in insulin resistance (with respect to glucose uptake) but also contribute to other abnormal physiology. Here, we propose to test the contribution of the TUG pathway in muscle to glucose homeostasis and to other aspects of physiology. Using transgenic mice, Aim 1 will test effects of disrupting TUG action in muscle on glucose uptake and turnover, energy expenditure, and other metabolic endpoints. Aim 2 will study mice rendered insulin-resistant by a high-fat diet, and elucidate whether the trafficking and/or signaling defects that contribute to insulin resistance are bypassed by TUG disruption. Aim 3 will study how disruption of TUG action affects water homeostasis and blood pressure. It is anticipated that, together, these studies will provide fundamental new insights that are highly significant for understanding glucose homeostasis, insulin resistance, and the metabolic syndrome. Public Health Significance: Type 2 diabetes and pre-diabetes are an enormous public health burden, estimated to affect >40% of adults in the United States. These metabolic abnormalities frequently occur as part of a constellation of abnormalities, including high blood pressure, which leads to substantial morbidity and mortality. The research proposed here will investigate how these abnormalities occur, and whether distinct features of this metabolic syndrome may have a shared pathophysiologic basis.

描述（由申请人提供）：抽象胰岛素通过动员细胞内Glut4储存囊泡（GSV）刺激肌肉中的葡萄糖摄取，该囊泡在细胞表面融合并插入GLUT4葡萄糖转运蛋白中。 GLUT4在基底和胰岛素刺激的细胞中的差异靶向决定了胰岛素反应。胰岛素抵抗是由GSV调节受损引起的，并有助于代谢综合征和2型糖尿病的发病机理。胰岛素信号传导和囊泡运输的缺陷可能导致GSV调节受损。信号传导缺陷已经进行了充分的研究，但未表征运输缺陷。最近的数据表明，GLUT4运输缺陷可能是肌肉中胰岛素抵抗的重要原因。但是，即使是正常的GSV贩运途径也很差。该提案以最近的工作为基础，该工作首次以分子术语定义了胰岛素调节的GSV池。这些囊泡被拖线在细胞内保留，该囊泡将GSV与未刺激的细胞中的高尔基基质联系起来。胰岛素会导致拖船裂解释放GSV并在质膜上插入GLUT4。尽管GSV运输受胰岛素在多个步骤中控制，但数据表明，TUG途径是调节的主要部位，在小鼠饮食诱导的胰岛素抵抗中受到损害。此外，GSV含有除GLUT4以外的其他蛋白质，尤其是IRAP，它可能介导不同的生理作用以控制血管张力和水稳态。因此，GSV运输受损不仅可能导致胰岛素抵抗（有关葡萄糖的摄取），而且还会导致其他 异常生理学。在这里，我们建议测试肌肉中拖线途径对葡萄糖稳态和生理学其他方面的贡献。 AIM 1使用转基因小鼠，将测试破坏肌肉中拖线作用对葡萄糖吸收和离职，能量消耗和其他代谢终点的影响。 AIM 2将研究通过高脂饮食使胰岛素耐药的小鼠，并阐明是否会因拖离力能破坏而绕过导致胰岛素抵抗的贩运和/或信号传导缺陷。 AIM 3将研究拖线作用的破坏如何影响水稳态和血压。预计这些研究将提供基本的新见解，这些见解对于理解葡萄糖稳态，胰岛素抵抗和代谢综合征非常重要。公共卫生的意义：2型糖尿病和糖尿病前是巨大的公共卫生负担，估计会影响美国> 40％的成年人。这些代谢异常经常出现在异常星座的一部分，包括高血压，这导致了大量的发病率和死亡率。这里提出的研究将研究这些异常是如何发生的，以及该代谢综合征的不同特征是否可能具有共同的病理生理基础。