Vesicle translocation and the metabolic syndrome

囊泡易位和代谢综合征

基本信息

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
项目类别：
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

项目摘要

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 GLUT4 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 GLUT4 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 GLUT4 的不同靶向决定了胰岛素反应性。胰岛素抵抗是由 GSV 调节受损造成的，并导致代谢综合征和 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会导致 GSV 调节受损。信号缺陷已得到充分研究，但运输缺陷尚未得到表征。最近的数据表明，GLUT4 运输缺陷可能是肌肉胰岛素抵抗的一个重要因素。然而，即使是正常的 GSV 贩运途径也不清楚。该提案建立在最近的工作基础上，该工作首次从分子角度定义了胰岛素调节的 GSV 库。这些囊泡通过 TUG 保留在细胞内，TUG 将 GSV 与未刺激细胞中的高尔基体基质连接起来。胰岛素引起 TUG 裂解，释放 GSV 并将 GLUT4 插入质膜。尽管 GSV 运输在多个步骤中受到胰岛素的控制，但数据表明 TUG 途径是一个主要的调节位点，在小鼠饮食诱导的胰岛素抵抗中，该途径受到损害。此外，GSV 还含有 GLUT4 以外的蛋白质，特别是 IRAP，它可能介导不同的生理作用来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（相对于葡萄糖摄取），还可能导致其他疾病生理异常。在这里，我们建议测试肌肉中 TUG 通路对葡萄糖稳态和生理学其他方面的贡献。目标 1 将使用转基因小鼠测试破坏肌肉中 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。目标 2 将研究因高脂肪饮食而产生胰岛素抵抗的小鼠，并阐明导致胰岛素抵抗的运输和/或信号传导缺陷是否可以通过 TUG 破坏来绕过。目标 3 将研究 TUG 作用的破坏如何影响水稳态和血压。预计这些研究将共同提供基本的新见解，对于理解葡萄糖稳态、胰岛素抵抗和代谢综合征非常重要。公共卫生意义：2 型糖尿病和糖尿病前期是巨大的公共卫生负担，估计影响美国 40% 以上的成年人。这些代谢异常经常作为包括高血压在内的一系列异常的一部分而发生，高血压会导致大量的发病率和死亡率。这里提出的研究将调查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可能具有共同的病理生理学基础。公共健康相关性：该项目将研究肌肉中葡萄糖代谢的调节方式、这种调节在糖尿病发展过程中如何变得有缺陷，以及控制葡萄糖代谢的机制如何也有助于血压的调节。研究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，并对糖尿病及其并发症的预防和治疗具有重要意义。