Nuclear hormone retinoid X receptor (RXR) negatively regulates the glucose-stimulated insulin secretion of pancreatic ß-cells.
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.
Miyazaki
Satsuki
S
Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan.
Taniguchi
Hidenori
H
Moritoh
Yusuke
Y
Tashiro
Fumi
F
Yamamoto
Tsunehiko
T
Yamato
Eiji
E
Ikegami
Hiroshi
H
Ozato
Keiko
K
Miyazaki
Jun-ichi
J
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
D017931:DNA Primers; D018076:DNA, Complementary; D007328:Insulin; D047490:Retinoid X Receptor alpha; D049230:Retinoid X Receptor beta; D047488:Retinoid X Receptors; D005947:Glucose
FEBS Lett. 2008 Jan 9;582(1):32-8
18068127
Diabetologia. 1999 May;42(5):545-54
10333046
Diabetes. 2008 Sep;57(9):2413-20
18599525
FEBS J. 2007 Dec;274(23):6094-105
17970749
Endocrinology. 2006 Feb;147(2):1044-53
16269450
Science. 2007 Feb 9;315(5813):820-5
17255476
Diabetes. 2004 Feb;53 Suppl 1:S60-5
14749267
Genes Dev. 1994 May 1;8(9):1007-18
7926783
Mol Cell Biol. 2003 Sep;23(17):6049-62
12917329
Nature. 1997 Mar 27;386(6623):407-10
9121558
Genes Dev. 2005 Mar 1;19(5):614-25
15741322
Endocrinology. 2007 Apr;148(4):1843-9
17194744
Endocrinology. 1990 Jul;127(1):126-32
2163307
Genes Dev. 1996 Jan 1;10(1):80-92
8557197
J Biol Chem. 1994 Jan 28;269(4):3081-7
8300643
Gene. 1989 Jul 15;79(2):269-77
2551778
Cell Death Differ. 2004 Dec;11 Suppl 2:S126-43
15608692
J Clin Invest. 1997 Nov 15;100(10):2501-11
9366564
Biochem Soc Trans. 2008 Oct;36(Pt 5):891-900
18793157
Endocrinology. 2005 Aug;146(8):3266-76
15878969
Nat Rev Neurosci. 2001 Mar;2(3):175-84
11256078
J Mol Med (Berl). 2001 Jun;79(5-6):321-8
11485027
Cell Biochem Funct. 2001 Sep;19(3):159-69
11494305
Science. 1995 Jun 23;268(5218):1766-9
7792603
Gene Ther. 2003 Jan;10(1):15-23
12525833
Diabetes. 2007 Jun;56(6):1534-43
17369526
Diabetes. 2004 Dec;53 Suppl 3:S75-8
15561926
Endocrinology. 1992 Mar;130(3):1660-8
1537314
N Engl J Med. 2005 Aug 11;353(6):604-15
16093469
Metabolism. 1997 Jun;46(6):656-60
9186301
J Endocrinol. 2010 Mar;204(3):233-40
19837721
Endocrinology. 1999 Jul;140(7):3091-6
10385401
Cell Metab. 2006 Jan;3(1):59-65
16399505
Genes Cells. 1996 Feb;1(2):209-21
9140065
Development. 2005 Jul;132(13):3139-49
15944193
Biochem Biophys Res Commun. 1994 Feb 28;199(1):327-33
8123030