INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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，我们最近发现视黄醇结合蛋白-4(RBP4)在脂肪-GLUT4-/-小鼠的脂肪组织中的表达增加[Yang等，2005]。我们已经证明，在胰岛素抵抗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。

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 recently shown that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4 -/- mice [Yang et al., 2005]. We have 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.