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Nuclear hormone retinoid X receptor (RXR) negatively regulates the glucose-stimulated insulin secretion of pancreatic ß-cells.

Miyazaki S, Taniguchi H, Moritoh Y, Tashiro F, Yamamoto T, Yamato E, Ikegami H, Ozato K, Miyazaki J - Diabetes (2010)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan.

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.

Research design and 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.

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Related in: MedlinePlus

Experimental protocols for the Dox treatment (A) and OGTT in the dnRXR Tg mice (B and C). The Dox-containing water was given for 2 weeks and renewed every 4 days. The OGTTs were performed after 2 weeks of the Dox treatment (Dox On) and 2 weeks after the withdrawal of the Dox treatment (Dox Off). Compared with the Dox On state, the withdrawal of Dox (Dox Off) deteriorated the glucose tolerance. Plasma insulin levels were also measured at each time point (C). Values are expressed as the mean ± SE. Statistical analyses were carried out by the Student t test. *P < 0.05, **P < 0.01. n = 6.
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Figure 3: Experimental protocols for the Dox treatment (A) and OGTT in the dnRXR Tg mice (B and C). The Dox-containing water was given for 2 weeks and renewed every 4 days. The OGTTs were performed after 2 weeks of the Dox treatment (Dox On) and 2 weeks after the withdrawal of the Dox treatment (Dox Off). Compared with the Dox On state, the withdrawal of Dox (Dox Off) deteriorated the glucose tolerance. Plasma insulin levels were also measured at each time point (C). Values are expressed as the mean ± SE. Statistical analyses were carried out by the Student t test. *P < 0.05, **P < 0.01. n = 6.

Mentions: To investigate the effect of dnRXR expression in β-cells on glucose homeostasis, OGTTs were performed after 2 weeks of Dox treatment (Dox On) and 2 weeks after the withdrawal of Dox treatment (Dox Off) (Fig. 3A). Interestingly, the dnRXR Tg mice showed significantly improved glucose tolerance under the expression of the dnRXRβ (Dox On) compared with after the withdrawal of the Dox treatment (Dox Off) (Fig. 3B). Plasma insulin levels at 10 min after glucose administration were significantly higher under the Dox treatment (Dox On) compared with after the withdrawal of the Dox treatment (Dox Off) (Fig. 3C). The non-Tg control mice showed no significant change in the glucose tolerance with Dox treatment (data not shown). In a separate experiment, we examined whether the Dox treatment affected the body weight of the dnRXR Tg mice. Eight-week-old dnRXR Tg mice were maintained with or without Dox treatment (n = 5 each) for 2 weeks, and their body weights were measured. The result showed that there were no significant changes in the body weight between Dox-treated and Dox-untreated mice. Therefore, the improved glucose tolerance seen under the expression of the dnRXRβ was mostly due to the improved response of β-cells to glucose.


Nuclear hormone retinoid X receptor (RXR) negatively regulates the glucose-stimulated insulin secretion of pancreatic ß-cells.

Miyazaki S, Taniguchi H, Moritoh Y, Tashiro F, Yamamoto T, Yamato E, Ikegami H, Ozato K, Miyazaki J - Diabetes (2010)

Experimental protocols for the Dox treatment (A) and OGTT in the dnRXR Tg mice (B and C). The Dox-containing water was given for 2 weeks and renewed every 4 days. The OGTTs were performed after 2 weeks of the Dox treatment (Dox On) and 2 weeks after the withdrawal of the Dox treatment (Dox Off). Compared with the Dox On state, the withdrawal of Dox (Dox Off) deteriorated the glucose tolerance. Plasma insulin levels were also measured at each time point (C). Values are expressed as the mean ± SE. Statistical analyses were carried out by the Student t test. *P < 0.05, **P < 0.01. n = 6.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2963544&req=5

Figure 3: Experimental protocols for the Dox treatment (A) and OGTT in the dnRXR Tg mice (B and C). The Dox-containing water was given for 2 weeks and renewed every 4 days. The OGTTs were performed after 2 weeks of the Dox treatment (Dox On) and 2 weeks after the withdrawal of the Dox treatment (Dox Off). Compared with the Dox On state, the withdrawal of Dox (Dox Off) deteriorated the glucose tolerance. Plasma insulin levels were also measured at each time point (C). Values are expressed as the mean ± SE. Statistical analyses were carried out by the Student t test. *P < 0.05, **P < 0.01. n = 6.
Mentions: To investigate the effect of dnRXR expression in β-cells on glucose homeostasis, OGTTs were performed after 2 weeks of Dox treatment (Dox On) and 2 weeks after the withdrawal of Dox treatment (Dox Off) (Fig. 3A). Interestingly, the dnRXR Tg mice showed significantly improved glucose tolerance under the expression of the dnRXRβ (Dox On) compared with after the withdrawal of the Dox treatment (Dox Off) (Fig. 3B). Plasma insulin levels at 10 min after glucose administration were significantly higher under the Dox treatment (Dox On) compared with after the withdrawal of the Dox treatment (Dox Off) (Fig. 3C). The non-Tg control mice showed no significant change in the glucose tolerance with Dox treatment (data not shown). In a separate experiment, we examined whether the Dox treatment affected the body weight of the dnRXR Tg mice. Eight-week-old dnRXR Tg mice were maintained with or without Dox treatment (n = 5 each) for 2 weeks, and their body weights were measured. The result showed that there were no significant changes in the body weight between Dox-treated and Dox-untreated mice. Therefore, the improved glucose tolerance seen under the expression of the dnRXRβ was mostly due to the improved response of β-cells to glucose.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Osaka, Japan.

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus