INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在肥胖和2型糖尿病中，GLUT4葡萄糖转运体在脂肪细胞中的表达选择性降低。脂肪特异性GLUT4(也称为SLC2a4)基因敲除(脂肪-GLUT4-/-)小鼠在肌肉和肝脏继发表现出胰岛素抵抗。利用DNA阵列，我们已经证明视黄醇结合蛋白-4(RBP4)在脂肪-GLUT4-/-小鼠的脂肪组织中的表达增加[Yang等，2005]。我们还表明，在胰岛素抵抗的小鼠和患有肥胖症和2型糖尿病的人类中，血清RBP4水平升高。在胰岛素抵抗的小鼠中，RBP4水平被胰岛素增敏药物罗格列酮正常化。人RBP4转基因过表达或正常小鼠注射重组RBP4可引起胰岛素抵抗。相反，RBP4的基因缺失会增强胰岛素敏感性。芬维甲素是一种合成维甲酸，可以增加尿中RBP4的排泄，使血清RBP4水平正常化，并改善高脂饮食诱导的肥胖小鼠的胰岛素抵抗和葡萄糖耐量异常。增加血清RBP4可诱导肝脏糖异生酶磷酸烯醇式丙酮酸羧激酶(PEPCK)的表达，并损害肌肉中的胰岛素信号。因此，RBP4是一种脂肪细胞产生的信号，可能与2型糖尿病的发病机制有关。在循环中，RBP4作为转运体四聚体的复合体运输。[Ronne等人，1983]一些报告讨论了这种复合体的结构和蛋白质的相互作用点[Roston等人，1998；Nayler和Newcomer，1999]，以及它在糖尿病中的潜在临床意义[Graham等人，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学表征的方法在过去十年中已经开发出来，并被定期使用[Lim等人，2002]。本项目研究RBP和TTR的相互作用，因为它可能影响2型糖尿病的发生。对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TTR的存在形式，并将其与表型联系起来。患者样本也进行了检查。

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.