Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5513264 | The Journal of Steroid Biochemistry and Molecular Biology | 2016 | 9 Pages |
â¢Mice with a mutation in the transcriptional activation site of Vdr (VDRÎAF2) were generated.â¢VDRÎAF2 mice have normal fur phenotype but lower body weight than wild type (WT) mice.â¢In vivo glucose tolerance is similar between adult normocalcemic WT, VDRâ/â and VDRÎAF2 mice.â¢Ex vivo glucose stimulated insulin secretion is similar in islets from WT, VDRâ/â and VDRÎAF2 mice.â¢Phosphodiesterase 10a mRNA is upregulated in VDRâ/â and VDRÎAF2 islets, as compared to WT mice
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 (VDRÎAF2), preventing ligand-driven transcriptional activation of vitamin D responsive genes.VDRÎAF2 mice were compared to Vdr full knockout (VDRâ/â) 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 VDRâ/â mice developed extensive alopecia by the age of 24 weeks, the fur of VDRÎAF2 remained normal. All VDRÎAF2 mice weighed significantly less than WT, while male but not female VDRâ/â mice had a lower body weight than WT mice. Dual-energy X-ray absorptiometry showed that both VDRÎAF2 (17.2% (females) and 16.6% (males)) and VDRâ/â (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 VDRÎAF2 (â4.55 fold, P < 0.001) and VDRâ/â (â3.7 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 VDRÎAF2 and VDRâ/â 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 VDRÎAF2 and VDRâ/â islets as compared to WT islets, respectively (P â¤Â 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.