INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES

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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 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. In the current phase of the study, blood samples from mice on normal and fat diets are being analyzed to determine the form of TTR that is present, and to relate this to the phenotype. Patient samples will also be examined.