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Impact of Modulated Exocyst Activity on Glut4 Trafficking in Metabolic Tissues

调节外囊活性对代谢组织中 Glut4 运输的影响

基本信息

批准号：
10252773
负责人：
Noemi Polgar
金额：
$ 20.44万
依托单位：
UNIVERSITY OF HAWAII AT MANOA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10252773
关键词：
Adipocytes Adipose tissue Affect Alleles American Area Blood Glucose Cell Line Cell membrane Cells Centers of Research Excellence Complex Defect Diabetes Mellitus Diabetic mouse Disease Exocytosis Future GLUT 4 protein Generations Genetic study Glucose Transporter Glycogen Goals Hyperglycemia Injections Instruction Insulin Insulin Resistance Insulin deficiency Kinetics Knockout Mice Label Lead LoxP-flanked allele Mediating Metabolic Metabolic Diseases Modeling Molecular Molecular Genetics Mouse Strains Mus Muscle Muscle Fibers Myoblasts Non-Insulin-Dependent Diabetes Mellitus Outcome Pathogenesis Phenotype Phosphorylation Physiological Plasmids Play Regulation Reporting Research Role SLC2A1 gene Secretory Vesicles Skeletal Muscle Specificity Strategic Planning Surface System Tamoxifen Testing Tetracyclines Tissues Transgenes Transgenic Mice United States National Institutes of Health Validation Vesicle base blood glucose regulation cell type design diabetic gene delivery system glucose metabolism glucose tolerance glucose transport glucose uptake improved in vivo insulin signaling insulin tolerance kidney cell knock-down knockout animal mouse model novel overexpression protein complex protein degradation protein transport rab GTP-Binding Proteins recombinase-mediated cassette exchange response therapeutic target trafficking

项目摘要

Abstract Type-2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, relative insulin deficiency and insulin resistance. Insulin resistant cells show defects in insulin-induced exocytosis of the glucose transporter GLUT4, affecting glucose uptake. The exocyst, a highly conserved eight protein trafficking complex was identified in cultured adipocytes as a key regulator of GLUT4 trafficking in response to insulin. However, it is not known if the molecular mechanisms through which the exocyst orchestrates exocytosis of this glucose transporter in adipocytes are conserved in other, insulin-responsive tissues, such as the skeletal muscle. Skeletal muscle cells are responsible for the vast majority of insulin-induced glucose uptake, therefore investigating glucose transporter trafficking in these cells will be key to better understanding the mechanism of glucose homeostasis. Sec10 is a central subunit of the exocyst complex, and its overexpression can lead to overall increased exocyst activity, while its knockdown leads to protein degradation of several of the other subunits. We have recently generated a new transgenic mouse to analyze exocyst-regulated cellular trafficking in vivo: the first mouse strain with a conditional Sec10 allele. This unique model enables us to investigate the consequences of tissue-specific Sec10 inactivation by facilitating generation of adipose and muscle-specific conditional Sec10 knockout animals. We hypothesize that in vivo modulation of the exocyst complex can independently regulate GLUT4 exocytosis and glucose uptake in insulin-responsive cells and tissues, affecting the diabetic phenotype. To test this hypothesis, we propose the following Specific Aims: (1) Determine if the exocyst mediated regulatory mechanism of insulin-induced GLUT4 exocytosis is conserved in skeletal muscle cells. (2) Test for defects in glucose homeostasis in vivo using adipocyte and skeletal muscle-specific Sec10 knockout mouse strains. (3) Determine T2DM-associated metabolic defects in mice can be ameliorated by increasing GLUT4 exocytosis with a novel tissue-specific in vivo gene delivery system. The anticipated outcome of this project is the first in vivo evidence of the exocyst's role in regulating insulin-induced glucose uptake, and verification whether this regulatory mechanism is conserved in muscle tissues as well. These studies will also show if the exocyst, and other molecules that directly control GLUT4 exocytosis, are potential therapeutic targets for insulin resistance and diabetes.

摘要