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.

胰岛素通过动员细胞内GLUT4储存囊泡（GSVs）刺激肌肉中的葡萄糖摄取，GSVs在细胞表面融合并将GLUT4葡萄糖转运体插入肌膜。GLUT4在基础细胞和胰岛素刺激细胞中的不同靶向决定了胰岛素反应性。胰岛素抵抗是由GSV调节受损引起的，并参与代谢综合征和2型糖尿病的发病机制。胰岛素信号和囊泡运输的缺陷都可能导致GSV调节受损。信令缺陷已经得到了很好的研究，但传输缺陷尚未被表征。最近的数据表明，GLUT4运输缺陷可能是肌肉中胰岛素抵抗的一个重要因素。然而，即使是正常的GSV贩运途径也没有明确定义。这一建议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池。这些囊泡被TUG保留在细胞内，在未受刺激的细胞中将GSVs与高尔基基质连接起来。胰岛素引起TUG裂解释放GSVs并将GLUT4插入质膜。尽管胰岛素通过多个步骤控制GSV转运，但数据表明，TUG途径是一个主要的调控位点，在小鼠饮食诱导的胰岛素抵抗中受到损害。此外，GSVs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，受损的GSV运输可能不仅导致胰岛素抵抗（相对于葡萄糖摄取），而且有助于其他