Vesicle translocation and the metabolic syndrome

囊泡易位和代谢综合征

• 批准号: 8297209
• 负责人: JONATHAN BOGAN
• 金额: $ 24.91万
• 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 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297209
• 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. PUBLIC HEALTH RELEVANCE: This project will study how glucose metabolism is regulated in muscle, how this regulation becomes defective during the development of diabetes, and how the mechanisms that control glucose metabolism may also contribute to the regulation of blood pressure. The results will shed light on how insulin resistance develops and leads to type 2 diabetes and the metabolic syndrome, and will have importance for the prevention and treatment of diabetes and its complications.

描述（由申请人提供）：摘要胰岛素通过动员细胞内GLUT 4储存囊泡（GSV）刺激肌肉中的葡萄糖摄取，GSV在细胞表面融合并将GLUT 4葡萄糖转运蛋白插入肌膜中。基础细胞和胰岛素刺激细胞中GLUT 4的差异靶向决定胰岛素反应性。胰岛素抵抗是GSV调节受损的结果，并有助于代谢综合征和2型糖尿病的发病机制。胰岛素信号传导和囊泡运输的缺陷可能导致GSV调节受损。信号缺陷已经得到了很好的研究，但运输缺陷的特点。最近的数据表明，GLUT 4运输缺陷可能是肌肉胰岛素抵抗的重要因素。然而，即使是正常的GSV运输途径也很难确定。这项建议建立在最近的工作，第一次，定义了一个池的胰岛素调节GSV的分子方面。这些囊泡被TUG保留在细胞内，TUG将GSV连接到未受刺激的细胞中的高尔基体基质。胰岛素引起TUG裂解以释放GSV并将GLUT 4插入质膜。尽管GSV运输在多个步骤中由胰岛素控制，但数据表明TUG途径是主要的调节位点，其在小鼠中的饮食诱导的胰岛素抗性中受损。此外，GSV含有除GLUT 4以外的蛋白质，特别是IRAP，其可以介导不同的生理作用以控制血管张力和水稳态。因此，受损的GSV运输可能不仅导致胰岛素抵抗（关于葡萄糖摄取），而且还有助于其他的胰岛素抵抗。 异常的生理机能在这里，我们建议测试的TUG途径在肌肉中的葡萄糖稳态和生理学的其他方面的贡献。使用转基因小鼠，目标1将测试在肌肉中破坏TUG作用对葡萄糖摄取和周转、能量消耗和其他代谢终点的影响。目的2将研究小鼠呈现胰岛素抵抗的高脂肪饮食，并阐明是否运输和/或信号转导缺陷，有助于胰岛素抵抗被TUG中断绕过。目的3将研究TUG作用的破坏如何影响水稳态和血压。预计这些研究将为理解葡萄糖稳态、胰岛素抵抗和代谢综合征提供重要的新见解。公共卫生意义：2型糖尿病和前驱糖尿病是巨大的公共卫生负担，估计影响美国>40%的成年人。这些代谢异常经常作为一系列异常的一部分发生，包括高血压，高血压导致大量的发病率和死亡率。本研究将探讨这些异常是如何发生的，以及这种代谢综合征的不同特征是否有共同的病理生理基础。 公共卫生关系：该项目将研究葡萄糖代谢如何在肌肉中调节，这种调节如何在糖尿病的发展过程中变得有缺陷，以及控制葡萄糖代谢的机制如何也有助于血压的调节。这些结果将揭示胰岛素抵抗如何发展并导致2型糖尿病和代谢综合征，并将对预防和治疗糖尿病及其并发症具有重要意义。