RETINOL BINDING PROTEIN-4 AND INSULIN RESISTANCE

描述（由申请人提供）： 脂肪组织中葡萄糖转运蛋白-4表达的减少是以胰岛素抵抗为特征的人类病症（包括2型糖尿病）中发生的最早变化之一。携带脂肪组织特异性Glut 4基因敲除的小鼠显示脂肪组织中胰岛素刺激的葡萄糖转运减少，并产生影响肝脏葡萄糖产生和骨骼肌葡萄糖转运的全身性胰岛素抵抗。由于在该模型中只有脂肪组织发生了遗传改变，我们假设一种或多种引起全身性胰岛素抵抗的循环因子可能由Glut 4表达降低的脂肪组织分泌到循环中。我们使用Affyssin全局基因分析来鉴定视黄醇结合蛋白-4（RBP 4）作为在该模型中介导全身性胰岛素抵抗的候选分子。RBP 4的mRNA在脂肪组织中上调，但在脂肪-Glut 4敲除小鼠的肝脏中不上调。在脂肪-Glut 4基因敲除小鼠和其他五种胰岛素抵抗小鼠模型中，RBP 4的血清水平增加，表明RBP 4可能是胰岛素抵抗或高胰岛素血症的标志物。然而，我们发现RBP 4基因敲除小鼠表现出对胰岛素敏感性增加的表型。因此，循环RBP 4的升高不仅可以作为标记物，而且可以作为全身性胰岛素抵抗的实际原因。在人类中，我们发现血清RBP 4水平与通过正葡萄糖高胰岛素钳夹测量的胰岛素抵抗之间存在强相关性，表明RBP 4可能是人类全身性胰岛素抵抗的新型内分泌介质。为了验证RBP 4是胰岛素抵抗的原因这一假设，我们将分析RBP 4表达发生遗传改变的小鼠的代谢特征。我们将测试改变循环RBP 4水平的影响，无论是通过使用芬维A胺（一种导致RBP 4尿消耗的药物）治疗，还是通过注射纯化的RBP 4。我们将研究RBP 4可能影响胰岛素-葡萄糖稳态的潜在机制，包括类维生素A依赖性和非依赖性

DESCRIPTION (provided by applicant): Reduction in the expression of the glucose transporter-4 in adipose tissue is one of the earliest changes that occur in human conditions characterized by insulin resistance, including type 2 diabetes. Mice harboring an adipose tissue-specific genetic knockout of Glut4 display reduced insulin-stimulated glucose transport in adipose tissue and develop systemic insulin resistance affecting hepatic glucose production and skeletal muscle glucose transport. Since only adipose tissue is genetically altered in this model, we hypothesized that one or more circulating factors causing systemic insulin resistance may be secreted into the circulation by adipose tissue with reduced Glut4 expression. We used Affymetrix global gene analysis to identify retinol binding protein-4 (RBP4) as a candidate molecule for mediating systemic insulin resistance in this model. The mRNA of RBP4 is up-regulated in adipose tissue, but not in liver, of adipose-Glut4 knockout mice. Serum levels of RBP4 are increased in adipose-Glut4 knockout mice and five other mouse models of insulin resistance, suggesting that RBP4 may be a marker for insulin resistance or hyperinsulinemia. However, we find that RBP4 knockout mice exhibit a phenotype of increased sensitivity to insulin. Thus, elevations of circulating RBP4 may serve not only as a marker but as an actual cause of systemic insulin resistance. In humans we find a strong correlation between serum RBP4 levels and insulin resistance measured by euglycemic hyperinsulinemic clamp, indicating that RBP4 could be a novel endocrine mediator of systemic insulin resistance in humans. To test the hypothesis that RBP4 is a cause of insulin resistance, we will analyze the metabolic features of mice with genetic alterations in RBP4 expression. We will test the effects of pharmacologically altering circulating RBP4 levels, either by treating with fenretinide, a drug that causes urinary wasting of RBP4, or by injecting purified RBP4. We will investigate potential mechanisms, both retinoid-dependent and retinoid-independent, by which RBP4 may influence insulin-glucose homeostasis