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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在肥胖症和2型糖尿病中，脂肪细胞中GLUT 4葡萄糖转运蛋白的表达选择性降低。脂肪特异性Glut 4（也称为Slc 2a 4）敲除（脂肪-Glut 4-/-）小鼠在肌肉和肝脏中显示继发性胰岛素抵抗。使用DNA阵列，我们最近已经表明，在脂肪-Glut 4-/-小鼠的脂肪组织中，视黄醇结合蛋白-4（RBP 4）的表达升高[Yang等人，2005年]。我们已经表明，血清RBP 4水平在胰岛素抵抗小鼠和肥胖和2型糖尿病患者中升高。在胰岛素抵抗小鼠中，RBP 4水平通过胰岛素增敏药物罗格列酮正常化。转基因过表达人RBP 4或注射重组RBP 4在正常小鼠中引起胰岛素抵抗。相反，RBP 4的基因缺失增强胰岛素敏感性。芬维A胺是一种合成类维生素A，可增加尿中RBP 4的排泄，使血清RBP 4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受不良。增加血清RBP 4诱导肝脏表达的致炎酶磷酸烯醇式丙酮酸羧激酶（PEPCK），并损害肌肉中的胰岛素信号传导。因此，RBP 4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，RBP 4作为与甲状腺素运载蛋白四聚体的复合物转运。[伦讷等人，1983]一些报道已经讨论了这种复合物的结构和蛋白质的相互作用点[Roston等，1998; Naylor和Newcomer，1999]，以及其在糖尿病中的潜在临床意义[Graham等，2006年]。在BUSM MS Resource，用于从血清中免疫沉淀TTR及其变体和翻译后修饰的质谱表征的方法已经在过去十年中开发出来并经常使用[Lim et al.，2002年]。 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。

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.