[摘要]：OBJECTIVE-Retinoid X receptors (RXRs) are members of the nuclear hormone receptor superfamily and are thought to be key regulators in differentiation, cellular growth, and gene expression. Although several experiments using pancreatic beta-cell lines have shown that the ligands of nuclear hormone receptors modulate insulin secretion, it is not clear whether RXRs have any role in insulin secretion. RESEARCH DESIGN AND METHODS-To elucidate the function of RXRs in pancreatic beta-cells, we generated a double-transgenic mouse in which a dominant-negative form of RXR beta was inducibly expressed in pancreatic beta-cells using the Tet-On system. We also established a pancreatic beta-cell line from an insulinoma caused by the beta-cell-specific expression of simian virus 40 T antigen in the above transgenic mouse. RESULTS-In the transgenic mouse, expression of the dominant-negative RXR enhanced the insulin secretion with high glucose stimulation. In the pancreatic beta-cell line, the suppression of RXRs also enhanced glucose-stimulated insulin secretion at a high glucose concentration, while 9-cis-retinoic acid, an RXR agonist, repressed it. High-density oligonucleotide microarray analysis showed that expression of the dominant-negative RXR affected the expression levels of a number of genes, some of which have been implicated in the function and/or differentiation of beta-cells. CONCLUSIONS-These results suggest that endogenous RXR negatively regulates the glucose-stimulated insulin secretion. Given these findings, we propose that the modulation of endogenous RXR in beta-cells may be a new therapeutic approach for improving impaired insulin secretion in type 2 diabetes. Diabetes 59:2854-2861, 2010
