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Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice.
J Steroid Biochem Mol Biol 2016; 164:309-317JS

Abstract

Vitamin D deficiency is associated with beta-cell dysfunction and a higher risk of diabetes, but mice and humans with an absence of the vitamin D receptor (VDR) display normal glucose tolerance. Here, we investigated the direct effects of absence of VDR or absence of ligand activation of VDR on beta-cell function. For this purpose, we generated mice, with a mutation in the AF2 domain of Vdr (VDRΔAF2), preventing ligand-driven transcriptional activation of vitamin D responsive genes. VDRΔAF2 mice were compared to Vdr full knockout (VDR-/-) and wild type (WT) mice. In order to avoid hypocalcemia, which has a direct effect on beta-cell function, mice were fed a high calcium, high lactose diet yielding comparable serum calcium in all mice. While VDR-/- mice developed extensive alopecia by the age of 24 weeks, the fur of VDRΔAF2 remained normal. All VDRΔAF2 mice weighed significantly less than WT, while male but not female VDR-/- mice had a lower body weight than WT mice. Dual-energy X-ray absorptiometry showed that both VDRΔAF2 (17.2% (females) and 16.6% (males)) and VDR-/- (15.7% and 14.8%) mice have a lower percentage of body fat (vs 19.3% and 22.2% in WT). Serum 25(OH)D3 concentrations were lower for both VDRΔAF2 (-4.55 fold, P<0.001) and VDR-/- (-3.7 fold, P<0.001) as compared to 12 week old WT mice, while serum 1,25(OH)2D3 was increased for both strains 94.5 fold (P<0.01) and 92.8 fold (P<0.001) for VDRΔAF2 and VDR-/- vs WT, respectively). In vivo glucose tolerance tests performed at 12 and 24 weeks of age, as well as ex vivo glucose stimulated insulin secretion on freshly isolated islets, revealed no major differences between the three strains. Microarray analysis on freshly isolated islets showed only 1 differentially expressed gene, phosphodiesterase 10a (Pde10a), which was 2.16 and 1.75 fold up-regulated in VDRΔAF2 and VDR-/- islets as compared to WT islets, respectively (P≤0.001). We conclude that in the presence of normocalcemia, absence of VDR or its ligand-activated transcription of genes has no direct regulatory effect on murine glucose homeostasis or gene expression in islets of Langerhans.

Authors+Show Affiliations

Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.Gene Expression Unit, Dept. of Molecular and Cellular Medicine, KU Leuven, Herestraat 49, Box 901, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.University of Tokyo Hospital, University of Tokyo, 113-8655 Tokyo, Japan.Soma Central Hospital, 976-0016 Fukushima, Japan.Gene Expression Unit, Dept. of Molecular and Cellular Medicine, KU Leuven, Herestraat 49, Box 901, 3000 Leuven, Belgium.Gene Expression Unit, Dept. of Molecular and Cellular Medicine, KU Leuven, Herestraat 49, Box 901, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium. Electronic address: Lutgart.Overbergh@med.kuleuven.be.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26877201

Citation

Vangoitsenhoven, Roman, et al. "Effect of a Transcriptional Inactive or Absent Vitamin D Receptor On Beta-cell Function and Glucose Homeostasis in Mice." The Journal of Steroid Biochemistry and Molecular Biology, vol. 164, 2016, pp. 309-317.
Vangoitsenhoven R, Wolden-Kirk H, Lemaire K, et al. Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice. J Steroid Biochem Mol Biol. 2016;164:309-317.
Vangoitsenhoven, R., Wolden-Kirk, H., Lemaire, K., Verstuyf, A., Verlinden, L., Yamamoto, Y., ... Overbergh, L. (2016). Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice. The Journal of Steroid Biochemistry and Molecular Biology, 164, pp. 309-317. doi:10.1016/j.jsbmb.2016.02.011.
Vangoitsenhoven R, et al. Effect of a Transcriptional Inactive or Absent Vitamin D Receptor On Beta-cell Function and Glucose Homeostasis in Mice. J Steroid Biochem Mol Biol. 2016;164:309-317. PubMed PMID: 26877201.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice. AU - Vangoitsenhoven,Roman, AU - Wolden-Kirk,Heidi, AU - Lemaire,Katleen, AU - Verstuyf,Annemieke, AU - Verlinden,Lieve, AU - Yamamoto,Yoko, AU - Kato,Shigeaki, AU - Van Lommel,Leentje, AU - Schuit,Frans, AU - Van der Schueren,Bart, AU - Mathieu,Chantal, AU - Overbergh,Lut, Y1 - 2016/02/11/ PY - 2015/06/14/received PY - 2015/12/08/revised PY - 2016/02/09/accepted PY - 2016/2/16/pubmed PY - 2017/6/15/medline PY - 2016/2/16/entrez KW - Glucose homeostasis KW - Islets of Langerhans KW - Pancreas KW - Vitamin D KW - Vitamin D receptor SP - 309 EP - 317 JF - The Journal of steroid biochemistry and molecular biology JO - J. Steroid Biochem. Mol. Biol. VL - 164 N2 - Vitamin D deficiency is associated with beta-cell dysfunction and a higher risk of diabetes, but mice and humans with an absence of the vitamin D receptor (VDR) display normal glucose tolerance. Here, we investigated the direct effects of absence of VDR or absence of ligand activation of VDR on beta-cell function. For this purpose, we generated mice, with a mutation in the AF2 domain of Vdr (VDRΔAF2), preventing ligand-driven transcriptional activation of vitamin D responsive genes. VDRΔAF2 mice were compared to Vdr full knockout (VDR-/-) and wild type (WT) mice. In order to avoid hypocalcemia, which has a direct effect on beta-cell function, mice were fed a high calcium, high lactose diet yielding comparable serum calcium in all mice. While VDR-/- mice developed extensive alopecia by the age of 24 weeks, the fur of VDRΔAF2 remained normal. All VDRΔAF2 mice weighed significantly less than WT, while male but not female VDR-/- mice had a lower body weight than WT mice. Dual-energy X-ray absorptiometry showed that both VDRΔAF2 (17.2% (females) and 16.6% (males)) and VDR-/- (15.7% and 14.8%) mice have a lower percentage of body fat (vs 19.3% and 22.2% in WT). Serum 25(OH)D3 concentrations were lower for both VDRΔAF2 (-4.55 fold, P<0.001) and VDR-/- (-3.7 fold, P<0.001) as compared to 12 week old WT mice, while serum 1,25(OH)2D3 was increased for both strains 94.5 fold (P<0.01) and 92.8 fold (P<0.001) for VDRΔAF2 and VDR-/- vs WT, respectively). In vivo glucose tolerance tests performed at 12 and 24 weeks of age, as well as ex vivo glucose stimulated insulin secretion on freshly isolated islets, revealed no major differences between the three strains. Microarray analysis on freshly isolated islets showed only 1 differentially expressed gene, phosphodiesterase 10a (Pde10a), which was 2.16 and 1.75 fold up-regulated in VDRΔAF2 and VDR-/- islets as compared to WT islets, respectively (P≤0.001). We conclude that in the presence of normocalcemia, absence of VDR or its ligand-activated transcription of genes has no direct regulatory effect on murine glucose homeostasis or gene expression in islets of Langerhans. SN - 1879-1220 UR - https://www.unboundmedicine.com/medline/citation/26877201/Effect_of_a_transcriptional_inactive_or_absent_vitamin_D_receptor_on_beta_cell_function_and_glucose_homeostasis_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-0760(16)30024-3 DB - PRIME DP - Unbound Medicine ER -