Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice.
Effect of a transcriptional inactive or absent vitamin D receptor on beta-cell function and glucose homeostasis in mice.
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转录失活或缺失的维生素 D 受体对小鼠 β 细胞功能和葡萄糖稳态的影响。
DOI：
10.1016/j.jsbmb.2016.02.011
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Overbergh L.
中科院分区：
文献类型：
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作者：
Vangoitsenhoven R;Wolden-Kirk H;Lemaire K;Verstuyf A;Verlinden L;Yamamoto Y;Kato S;Van Lommel L;Schuit F;Van der Schueren B;Mathieu C;Overbergh L.
维生素D缺乏与β细胞功能障碍和糖尿病风险较高有关，但缺乏维生素D受体（VDR）的小鼠和人类显示正常的葡萄糖耐量。在这里，我们研究了缺乏VDR或缺乏VDR的配体活化对β细胞功能的直接影响。为此，我们在VDR的AF 2结构域（VDRΔ AF 2）中产生突变，阻止配体驱动的维生素D应答基因的转录激活。VDRΔ AF 2小鼠与VDR完全敲除（VDR−/−）和野生型（WT）小鼠进行了比较。为了避免对β细胞功能有直接影响的低钙血症，给小鼠喂食高钙、高乳糖饮食，在所有小鼠中产生相当的血清钙。虽然VDR−/−小鼠在24周龄时出现了广泛的脱发，但VDRΔ AF 2的皮毛保持正常。所有VDRΔ AF 2小鼠的体重均显著低于WT小鼠，而雄性而非雌性VDR−/−小鼠的体重低于WT小鼠。双能X射线吸收测定法显示，VDRΔ AF 2（17.2%（雌性）和16.6%（雄性））和VDR−/−（15.7%和14.8%）小鼠的体脂百分比均较低（WT为19.3%和22.2%）。血清25（OH）D3浓度低于VDRΔ AF 2和（−4.55倍，P < 0.001）和VDR−/−（-3.7倍，P < 0.001），而两种品系的血清1，25（OH）2D 3均增加94.5倍VDRΔ AF 2和VDR−/−分别是WT的92.8倍（P <0.001）和92.8倍（P < 0.001）。在12周龄和24周龄时进行的体内葡萄糖耐受试验，以及在新鲜分离的胰岛上进行的体外葡萄糖刺激胰岛素分泌试验，显示三种菌株之间没有重大差异。对新鲜分离的胰岛进行的微阵列分析显示，只有一个差异表达的基因，磷酸二酯酶10a（Pde 10a），与WT胰岛相比，其在VDRΔ AF 2和VDR−/−胰岛中分别上调2.16和1.75倍（P ≤ 0.001）。我们得出结论，在正常血钙的情况下，VDR或其配体激活的基因转录的缺乏对小鼠葡萄糖稳态或胰岛中的基因表达没有直接的调节作用。
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 ofVdr(VDRΔAF2), preventing ligand-driven transcriptional activation of vitamin D responsive genes.VDRΔAF2 mice were compared toVdrfull 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)D3concentrations 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)2D3was 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 vivoglucose tolerance tests performed at 12 and 24 weeks of age, as well asex vivoglucose 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.