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Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in
Roman Vangoitsenhoven1, Heidi Wolden-Kirk1, Katleen Lemaire2
1Clinical and Experimental Medicine and Endocrinology, KU Leuven, Herestraat 49, Box 902, 3000 Leuven, Belgium.
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.
Insights
Vitamin D deficiency is linked to diabetes risk, but this study found that lacking the vitamin D receptor (VDR) or its ligand activation does not directly impact glucose homeostasis in mice. This suggests VDR
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Research
Background:
- Vitamin D deficiency is associated with beta-cell dysfunction and increased diabetes risk.
- However, mice and humans lacking the vitamin D receptor (VDR) exhibit normal glucose tolerance, creating a paradox.
- The direct impact of VDR absence or its ligand-activated function on beta-cell function remains unclear.
Purpose of the Study:
- To investigate the direct effects of VDR absence or its ligand-activated transcriptional activity on beta-cell function and glucose homeostasis.
- To compare VDR full knockout (VDR-/-) mice with mice harboring a mutation (VDRΔAF2) that prevents ligand-driven VDR transcriptional activation.
- To assess these effects under conditions of normocalcemia to isolate VDR's role.
Main Methods:
- Generated VDRΔAF2 mutant mice to specifically block ligand-driven VDR activation.
- Utilized VDR-/- mice and wild-type (WT) littermates for comparison.
- Maintained mice on a high calcium, high lactose diet to ensure comparable serum calcium levels across all groups.
- Performed in vivo glucose tolerance tests (GTT) and ex vivo glucose-stimulated insulin secretion (GSIS) assays.
- Conducted microarray analysis on isolated islets to assess gene expression changes.
Main Results:
- VDRΔAF2 and VDR-/- mice exhibited lower body fat percentage compared to WT mice.
- Serum 25(OH)D3 levels were reduced, while 1,25(OH)2D3 levels were significantly increased in VDR mutant mice.
- Despite these biochemical changes, both VDRΔAF2 and VDR-/- mice showed no significant differences in glucose tolerance or insulin secretion compared to WT mice.
- Microarray analysis revealed only one differentially expressed gene, phosphodiesterase 10a (Pde10a), in the islets of VDR mutant mice.
Conclusions:
- In normocalcemic conditions, the absence of VDR or its ligand-activated transcription does not directly affect murine glucose homeostasis.
- Beta-cell function and overall glucose regulation appear independent of VDR's transcriptional activity under these specific experimental conditions.
- The study clarifies the role of VDR in glucose metabolism, suggesting other factors may be more critical in the context of vitamin D and diabetes risk.
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