INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES

转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用

基本信息

批准号：
8365542
负责人：
BARBARA B. KAHN
金额：
$ 0.38万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2012-08-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8365542
关键词：
Adipocytes Adipose tissue Affect Biology Blood Circulation Blood specimen Clinical Complex DNA Development Diabetes Mellitus Diet Enzymes Excretory function Fatty acid glycerol esters Fenretinide Funding GLUT4 gene Genetic Glucose Intolerance Glucose Transporter Grant Hepatic Human Immunoprecipitation Injection of therapeutic agent Insulin Resistance Knock-out Liver Mass Spectrum Analysis Medicine Methods Mus Muscle National Center for Research Resources Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Patients Phenotype Phosphoenolpyruvate Carboxylase Post-Translational Protein Processing Prealbumin Principal Investigator Proteins Recombinants Reporting Research Research Infrastructure Resources Retinoids Retinol Binding Proteins Sampling Serum Signal Transduction Source Structure Transgenic Organisms United States National Institutes of Health Variant cost human RBP4 protein improved insulin sensitivity insulin sensitizing drugs insulin signaling overexpression rosiglitazone urinary

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4 -/-) mice show insulin resistance secondarily in muscle and liver. Using DNA arrays, we have shown that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4 -/- mice [Yang et al., 2005]. We have also shown that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. In insulin-resistant mice, RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of RBP4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. In circulation, RBP4 is transported as a complex with the transthyretin tetramer. [Ronne et al., 1983] Several reports have discussed the structure of this complex and the points of interaction of the proteins [Roston et al, 1998; Naylor and Newcomer, 1999], and its potential clinical implication in diabetes [Graham et al., 2006]. At the BUSM MS Resource, methods for the immunoprecipitation of TTR from serum and mass spectral characterization of its variants and posttranslational modifications have been developed over the last decade and are in regular use [Lim et al., 2002]. This project investigates the interplay of RBP and TTR as it may affect development of type 2 diabetes. Blood samples from mice on normal and fat diets have been analyzed to determine the form of TTR that is present, and to relate this to the phenotype. Patient samples were also examined.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。在肥胖和 2 型糖尿病中，脂肪细胞中 GLUT4 葡萄糖转运蛋白的表达选择性降低。脂肪特异性 Glut4（也称为 Slc2a4）敲除（adipose-Glut4 -/-）小鼠在肌肉和肝脏中显示出胰岛素抵抗。使用 DNA 阵列，我们发现脂肪-Glut4 -/- 小鼠的脂肪组织中视黄醇结合蛋白 4 (RBP4) 的表达升高 [Yang et al., 2005]。我们还发现，胰岛素抵抗小鼠以及患有肥胖和 2 型糖尿病的人的血清 RBP4 水平升高。在胰岛素抵抗小鼠中，RBP4 水平通过胰岛素增敏药物罗格列酮恢复正常。转基因过表达人 RBP4 或在正常小鼠中注射重组 RBP4 会导致胰岛素抵抗。相反，RBP4 的基因缺失会增强胰岛素敏感性。 Fenretinide 是一种合成类视黄醇，可增加 RBP4 的尿液排泄，使血清 RBP4 水平正常化，并改善高脂饮食引起的肥胖小鼠的胰岛素抵抗和葡萄糖耐受不良。血清 RBP4 增加会诱导糖异生酶磷酸烯醇丙酮酸羧激酶 (PEPCK) 的肝脏表达，并损害肌肉中的胰岛素信号传导。因此，RBP4 是一种脂肪细胞衍生的“信号”，可能有助于 2 型糖尿病的发病机制。在循环中，RBP4 作为与转甲状腺素蛋白四聚体的复合物进行运输。 [Ronne et al., 1983] 一些报告讨论了该复合物的结构和蛋白质的相互作用点 [Roston et al., 1998; Naylor 和 Newcomer，1999] 及其对糖尿病的潜在临床意义 [Graham 等，2006]。在 BUSM MS 资源中，从血清中免疫沉淀 TTR 及其变体和翻译后修饰的质谱表征的方法在过去十年中已经开发出来，并且正在常规使用 [Lim et al., 2002]。该项目研究 RBP 和 TTR 的相互作用，因为它可能影响 2 型糖尿病的发展。对来自正常饮食和脂肪饮食的小鼠的血液样本进行了分析，以确定存在的 TTR 形式，并将其与表型联系起来。还检查了患者样本。