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

• 批准号: 8170910
• 负责人: BARBARA B. KAHN
• 金额: $ 0.54万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170910
• 关键词: Adipocytes; Adipose tissue; Affect; Blood Circulation; Blood specimen; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; 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; Institution; Insulin Resistance; Knock-out; Liver; Methods; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Patients; Phase; Phenotype; Phosphoenolpyruvate Carboxylase; Post-Translational Protein Processing; Prealbumin; Proteins; Recombinants; Reporting; Research; Research Personnel; Resources; Retinoids; Retinol Binding Proteins; Sampling; Serum; Signal Transduction; Source; Structure; Transgenic Organisms; United States National Institutes of Health; Variant; human RBP4 protein; improved; insulin sensitivity; insulin sensitizing drugs; insulin signaling; overexpression; rosiglitazone; urinary

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. In the current phase of the study, blood samples from mice on normal and fat diets are being analyzed to determine the form of TTR that is present, and to relate this to the phenotype. Patient samples are also being examined.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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有选择性降低。脂肪特异性GLUT4（也称为SLC2A4）基因敲除（脂肪-Glut4 - / - ）小鼠在肌肉和肝脏中显示出胰岛素抵抗。使用DNA阵列，我们已经表明，在脂肪 - glut4 - / - 小鼠的脂肪组织中，视黄醇结合蛋白4（RBP4）的表达升高[Yang等，2005]。我们还表明，耐肥胖和2型糖尿病的胰岛素小鼠和人类中血清RBP4水平升高。在耐胰岛素的小鼠中，RBP4水平通过胰岛素敏感药物的罗格列酮标准化。人RBP4的转基因过表达或正常小鼠中重组RBP4的注射会引起胰岛素抵抗。相反，RBP4的遗传缺失增强了胰岛素敏感性。芬雷丁是一种合成性类维生素，可增加RBP4的尿液排泄，使血清RBP4水平归一化，并改善了由高脂饮食诱导的肥胖症小鼠的胰岛素耐药性和葡萄糖不耐症。增加血清RBP4会诱导糖原酶磷酸烯醇丙酮酸羧基酶（PEPCK）的肝表达，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型糖尿病的发病机理。在循环中，RBP4作为与经硫代蛋白四聚体的复合物一起运输。 [Ronne等，1983]几份报告讨论了这种复合物的结构以及蛋白质的相互作用[Roston等，1998; Naylor and Newcomer，1999]及其在糖尿病中的潜在临床意义[Graham等，2006]。在BUSM MS资源中，在过去的十年中开发了TTR免疫沉淀TTR和其变体和翻译后修饰的质谱表征的方法，并经常使用[Lim等，2002]。 该项目研究了RBP和TTR的相互作用，因为它可能会影响2型糖尿病的发展。在研究的当前阶段，正在分析来自正常和脂肪饮食的小鼠的血液样本，以确定存在的TTR形式，并将其与表型联系起来。病人样本也正在检查。