RBP4-Transthyretin Interactions in Insulin Resistant States

胰岛素抵抗状态下 RBP4-运甲状腺素蛋白的相互作用

• 批准号: 8011746
• 负责人: TIMOTHY E. GRAHAM
• 金额: $ 7.53万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011746
• 关键词: Adipose tissue; Affinity; Animal Model; Binding; Biochemical; Blood Circulation; Blood Glucose; Cardiovascular Diseases; Cessation of life; Cultured Cells; Cysteine; Development; Diabetes Mellitus; Fatty acid glycerol esters; Fenretinide; Genetic Predisposition to Disease; Glucose Intolerance; Human; In Vitro; Insulin; Insulin Resistance; Laboratories; Metabolic; Modification; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pattern; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Prealbumin; Production; Resistance; Retinol Binding Proteins; Risk Factors; Role; Series; Serum; Serum Proteins; Source; Testing; Work; glucose tolerance; improved; in vivo; insulin sensitivity

DESCRIPTION (provided by applicant): Resistance to the action of insulin (i.e., insulin resistance) is a key pathogenic feature of type 2 diabetes. Even without diabetes, insulin resistance is a major risk factor for cardiovascular disease and early death. The two major causes of insulin resistance are obesity and genetic predisposition. We recently discovered that serum retinol binding protein (RBP4) concentrations are elevated in insulin resistant mice and humans. In a series of animal models we demonstrated that increasing serum RBP4 causes insulin resistance and glucose intolerance, whereas lowering serum RBP4 improves insulin sensitivity and glucose tolerance. Therefore, RBP4 may play a causal role in insulin resistance. Increased expression of RBP4 in adipose tissue may be partly responsible for elevated serum RBP4 in insulin resistant states. However, other factors may regulate serum concentrations of RBP4. The serum protein, transthyretin, binds RBP4 and plays a critical role in stabilizing RBP4 in serum. Treating mice with a drug (fenretinide) that blocks binding of RBP4 to transthyretin lowers circulating RBP4 levels, improves insulin sensitivity, and lowers blood glucose. Therefore, factors that determine how strongly RBP4 binds transthyretin may be important in the development of insulin resistance. Preliminary studies indicate that transthyretin levels are elevated in insulin resistant mice and in humans. Transthyretin is known to undergo several different post-translational modifications that could potentially influence its binding affinity with RBP4. Preliminary findings indicate that the pattern of these modifications is altered in obesity and insulin resistance. The hypothesis to be tested is whether transthyretin concentrations or post- translational modifications regulate serum RBP4 concentrations and/or RBP4 action in insulin resistant states. Both in vitro and in vivo studies in mice are proposed to evaluate the role of transthyretin in regulating RBP4. Insulin resistance is a major cause of type 2 diabetes and cardiovascular disease. Recent work in our laboratory has identified serum retinol binding protein (RBP4) as a potential cause of insulin resistance in humans and in mice. Insulin resistance is associated with increased levels of RBP4 in the circulation. Increased production of RBP4 in fat appears to be an important source of increased circulating RBP4 in humans and in mice. However, the serum protein, transthyretin, also plays a role in stabilizing RBP4 in circulation. The proposed work will study the interaction between transthyretin and RBP4 in terms of their biochemical interactions, metabolic effects in cultured cells, and metabolic effects in mice.

描述（由申请人提供）： 对胰岛素作用的抵抗（即，胰岛素抵抗）是2型糖尿病的关键致病特征。即使没有糖尿病，胰岛素抵抗也是心血管疾病和过早死亡的主要危险因素。胰岛素抵抗的两个主要原因是肥胖和遗传易感性。我们最近发现，血清视黄醇结合蛋白（RBP 4）浓度升高，在胰岛素抵抗的小鼠和人类。在一系列动物模型中，我们证明了血清RBP 4升高会导致胰岛素抵抗和葡萄糖耐受不良，而血清RBP 4降低会改善胰岛素敏感性和葡萄糖耐受。因此，RBP 4可能在胰岛素抵抗中发挥因果作用。脂肪组织中RBP 4表达增加可能是胰岛素抵抗状态下血清RBP 4升高的部分原因。然而，其他因素可能会调节RBP 4的血清浓度。血清蛋白，甲状腺素运载蛋白，结合RBP 4，并在稳定血清中的RBP 4中发挥关键作用。用阻断RBP 4与甲状腺素运载蛋白结合的药物（芬维A胺）治疗小鼠，可降低循环中的RBP 4水平，改善胰岛素敏感性，并降低血糖。因此，决定RBP 4结合甲状腺素运载蛋白的强度的因素可能在胰岛素抵抗的发展中很重要。初步研究表明，甲状腺素运载蛋白水平在胰岛素抵抗小鼠和人类中升高。已知甲状腺素运载蛋白经历几种不同的翻译后修饰，这可能潜在地影响其与RBP 4的结合亲和力。初步研究结果表明，这些修饰的模式在肥胖和胰岛素抵抗中发生改变。待检验的假设是甲状腺素运载蛋白浓度或翻译后修饰是否调节胰岛素抵抗状态中的血清RBP 4浓度和/或RBP 4作用。在体外和在小鼠体内的研究提出了评估的作用，甲状腺素运载蛋白在调节RBP 4。 胰岛素抵抗是2型糖尿病和心血管疾病的主要原因。我们实验室最近的工作已经确定血清视黄醇结合蛋白（RBP 4）是人类和小鼠胰岛素抵抗的潜在原因。胰岛素抵抗与循环中RBP 4水平的增加有关。脂肪中RBP 4的产生增加似乎是人类和小鼠中循环RBP 4增加的重要来源。然而，血清蛋白，甲状腺素运载蛋白，也发挥作用，稳定循环中的RBP 4。拟议的工作将研究转甲状腺素蛋白和RBP 4之间的相互作用，包括它们的生化相互作用、培养细胞中的代谢效应以及小鼠中的代谢效应。