INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES

转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用

• 批准号: 8365542
• 负责人: BARBARA B. KAHN
• 金额: $ 0.38万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-08-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8365542
• 关键词: Adipocytes; Adipose tissue; Affect; Biology; Blood Circulation; Blood specimen; Clinical; Complex; DNA; Development; Diabetes Mellitus; Diet; Enzymes; Excretory function; Fatty acid glycerol esters; Fenretinide; Funding; GLUT4 gene; Genetic; Glucose Intolerance; Glucose Transporter; Grant; Hepatic; Human; Immunoprecipitation; Injection of therapeutic agent; Insulin Resistance; Knock-out; Liver; Mass Spectrum Analysis; Medicine; Methods; Mus; Muscle; National Center for Research Resources; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Patients; Phenotype; Phosphoenolpyruvate Carboxylase; Post-Translational Protein Processing; Prealbumin; Principal Investigator; Proteins; Recombinants; Reporting; Research; Research Infrastructure; Resources; Retinoids; Retinol Binding Proteins; Sampling; Serum; Signal Transduction; Source; Structure; Transgenic Organisms; United States National Institutes of Health; Variant; cost; human RBP4 protein; improved; insulin sensitivity; insulin sensitizing drugs; insulin signaling; overexpression; rosiglitazone; urinary

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.

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