title: Nuclear hormone retinoid X receptor (RXR) negatively regulates the glucose-stimulated insulin secretion of pancreatic ß-cells.
abstract: 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 β-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.
  
  
  METHODS
  To elucidate the function of RXRs in pancreatic β-cells, we generated a double-transgenic mouse in which a dominant-negative form of RXRβ was inducibly expressed in pancreatic β-cells using the Tet-On system. We also established a pancreatic β-cell line from an insulinoma caused by the β-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 β-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 β-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 β-cells may be a new therapeutic approach for improving impaired insulin secretion in type 2 diabetes.
authors.affiliation: Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satsuki
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Moritoh
authors.forename: Fumi
authors.initials: F
authors.lastname: Tashiro
authors.forename: Tsunehiko
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Yamato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikegami
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D017124:Conserved Sequence; D003433:Crosses, Genetic; D017931:DNA Primers; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000502:physiology; D049230:Retinoid X Receptor beta / Q000235:genetics / Q000502:physiology; D047488:Retinoid X Receptors / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D007328:Insulin; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D047488:Retinoid X Receptors; D005947:Glucose
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