1,25-DIHYDROXYVITAMIN-D(3) AND PANCREATIC BETA-CELL FUNCTION - VITAMIN-D RECEPTORS, GENE-EXPRESSION, AND INSULIN-SECRETION
1,25-DIHYDROXYVITAMIN-D(3) AND PANCREATIC BETA-CELL FUNCTION - VITAMIN-D RECEPTORS, GENE-EXPRESSION, AND INSULIN-SECRETION
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DOI：
10.1210/en.134.4.1602
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发表时间：
1994-04-01
期刊：
影响因子：
4.8
通讯作者：
CHRISTAKOS, S
中科院分区：
文献类型：
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作者：
LEE, S;CLARK, SA;CHRISTAKOS, S
先前的研究表明，胰腺具有对1，25-二羟维生素D3 [1，25-（OH）2D 3]特异性的受体，并且1，25（OH）2D 3增加维生素D缺乏大鼠的胰岛素分泌。在这项研究中，我们报告说，在维生素D充足，但钙缺乏，大鼠在其中1，25-（OH）2D 3水平升高，胰岛素分泌没有改变。此外，在体外研究中，一致发现浓度为10（-10）-10（-7）M的1，25-（OH）2D 3可抑制维生素D充足大鼠胰岛或大鼠胰岛素瘤β细胞系RIN 1046-38的胰岛素分泌。发现RIN细胞系含有维生素D受体和钙结合蛋白-D28 k（CaBP-D28 k）蛋白和mRNA。在RIN细胞中，用丁酸钠处理（2 mm，3天）诱导更多的胰岛表型，如通过增加的胰岛素含量和分泌以及增加的胰岛素基因表达所指示的。1，25-（OH）2D 3处理（50-100 nm，48或72 h）对丁酸盐存在下胰岛素分泌水平的提高没有影响。然而，2 mm丁酸钠在RIN细胞系中诱导CaBP-D28 k蛋白（4倍;对照，0.8 ± 0.2;丁酸钠，3.5 ± 0.1 μ g/mg蛋白）和mRNA（3倍），与丁酸盐诱导胰岛素含量和分泌以及β细胞分化雅阁，表明CaBP-D28 k在这些过程中可能起作用。尽管1，25-（OH）2D 3与丁酸盐不同，不增强胰岛素分泌，但1，25-（OH）2D 3（100 nm）和丁酸盐（2 mM）均抑制RIN细胞生长（分别为对照的69%和28%），丁酸盐和1，25-（OH）2D组合导致细胞生长的进一步抑制（为对照的13%）。响应于1，25-（OH）2D 3（10 nM持续72 h），RIN细胞中维生素D受体上调313%[对照，37 +/- 2; 1，25-（OH）2D 3处理，115 +/- 5 fmol/mg蛋白]。总之，1）与先前在维生素D缺乏大鼠中的研究相反，我们的发现表明，1，25-（OH）2D 3作用不一定导致胰岛素分泌增强; 2）1，25-（OH）2D 3抑制细胞生长和上调维生素D受体表明，β细胞中除了胰岛素分泌之外的参数也可受到1，25-（OH）2D 3的影响; 3）RIN β细胞系为研究维生素D内分泌系统对胰岛生理学的影响提供了一种新的体外系统。
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 mug/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)2D, 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.