1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion.
1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion.
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DOI：
10.1210/endo.134.4.8137721
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发表时间：
1994-04
期刊：
影响因子：
4.8
通讯作者：
Sooja Lee;S. Clark;R. Gill;S. Christakos
中科院分区：
文献类型：
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作者：
Sooja Lee;S. Clark;R. Gill;S. Christakos
以前的研究表明，胰腺有1，25-二羟基维生素D3[1，25-(OH)2D3]的受体，1，25-(OH)2D3增加了维生素D缺乏大鼠的胰岛素分泌。在这项研究中，我们报告了在维生素D充足但钙缺乏的大鼠中，1，25-(OH)2D3水平升高的大鼠胰岛素分泌没有改变。此外，在体外研究中，1，25-(OH)2D3在10(-10)-10(-7)M的浓度下一直被发现抑制维生素D充足的大鼠胰岛或大鼠胰岛素瘤β细胞系RIN 1046-38的胰岛素分泌。RIN细胞株同时含有维生素D受体和钙结合蛋白-D28k(CABP-D28k)蛋白和mRNA。在RIN细胞中，丁酸钠(2 mM，持续3天)诱导了更多的胰岛表型，表现为胰岛素含量和分泌增加，胰岛素基因表达增加。1，25-(OH)2D3处理(50-100 nM作用48或72小时)对丁酸盐存在时胰岛素分泌水平的升高没有影响。2 mM丁酸钠诱导RIN细胞CABP-D28k蛋白(4倍；对照组，0.8+/-0.2；丁酸钠，3.5+/-0.1微克/mg蛋白)和mRNA(3倍)，与丁酸钠诱导的胰岛素含量和分泌及β细胞分化相一致，提示CABP-D28k可能在这些过程中起作用。与丁酸不同，1，25-(OH)2D3不能促进胰岛素分泌，但1，25-(OH)2D3(100 NM)和丁酸(2 MM)对RIN细胞生长均有抑制作用(分别为对照组的69%和28%)，丁酸和1，25-(OH)2D3联合应用对细胞生长有进一步的抑制作用(为对照组的13%)。1，25-(OH)2D3作用72 h后，RIN细胞维生素D受体表达上调313%[对照组，37+/-2；1，25-(OH)2D3处理，115+/-5fmol/mg蛋白]。综上所述，1)与以前对维生素D缺乏大鼠的研究相反，我们的发现表明1，25-(OH)2D3的作用并不一定导致胰岛素分泌增加；2)1，25-(OH)2D3抑制细胞生长和上调维生素D受体表明1，25-(OH)2D3在β细胞中除了影响胰岛素分泌外，还可以影响参数；3)RINβ细胞系为研究维生素D内分泌系统对胰岛生理的影响提供了一个新的体外系统。
Previous studies have indicated that the pancreas has receptors specific for 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and that 1,25-(OH)2D3 increases insulin secretion in vitamin D-deficient rats. In this study we report that in vitamin D-replete, but calcium-deficient, rats in which 1,25-(OH)2D3 levels are elevated, insulin secretion is not altered. In addition, in in vitro studies 1,25-(OH)2D3 at concentrations of 10(-10)-10(-7) M was consistently found to inhibit insulin secretion from islets of vitamin D-replete rats or from the rat insulinoma beta-cell line RIN 1046-38. The RIN cell line was found to contain both vitamin D receptors and calbindin-D28k (CaBP-D28k) protein and mRNA. In RIN cells, treatment with sodium butyrate (2 mM for 3 days) induces a more islet phenotype, as indicated by increased insulin content and secretion and increased insulin gene expression. 1,25-(OH)2D3 treatment (50-100 nM for 48 or 72 h) had no effect on the enhanced levels of insulin secreted in the presence of butyrate. However, 2 mM sodium butyrate induced CaBP-D28k protein (4-fold; control, 0.8 +/- 0.2; sodium butyrate, 3.5 +/- 0.1 microgram/mg protein) and mRNA (3-fold) in the RIN cell line, in accord with the induction by butyrate of insulin content and secretion and beta-cell differentiation, suggesting a possible role for CaBP-D28k in these processes. Although 1,25-(OH)2D3, unlike butyrate, did not enhance insulin secretion, both 1,25-(OH)2D3 (100 nM) and butyrate (2 mM) inhibited RIN cell growth (to 69% and 28% of the control, respectively), and butyrate and 1,25-(OH)2D3 in combination led to a further inhibition of cell growth (to 13% of the control). In response to 1,25-(OH)2D3 (10 nM for 72 h), vitamin D receptors were up-regulated 313% in RIN cells [control, 37 +/- 2; 1,25-(OH)2D3 treated, 115 +/- 5 fmol/mg protein]. In conclusion, 1) contrary to previous studies in the vitamin D-deficient rat, our findings indicate that 1,25-(OH)2D3 action does not necessarily result in enhanced insulin secretion; 2) inhibition of cell growth and up-regulation of vitamin D receptors by 1,25-(OH)2D3 suggest that parameters in addition to insulin secretion can be affected by 1,25-(OH)2D3 in the beta-cell; 3) the RIN beta-cell line provides a novel in vitro system for studying the effect of the vitamin D endocrine system on pancreatic islet physiology.