1,25-Dihydroxyvitamin D3 and pancreatic beta-cell function: vitamin D receptors, gene expression, and insulin secretion.
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.
Lee
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S
Department of Biochemistry, University of Massachusetts Medical Center, Worcester 01605.
Clark
S A
SA
Gill
R K
RK
Christakos
S
S
D000375:Aging / Q000378:metabolism; D000818:Animals; D000833:Animals, Suckling / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D064092:Calbindin 1; D064026:Calbindins; D002117:Calcitriol / Q000494:pharmacology*; D002118:Calcium / Q000172:deficiency; D015870:Gene Expression / Q000187:drug effects*; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014407:Tumor Cells, Cultured
D002087:Butyrates; C576500:Calb1 protein, rat; D064092:Calbindin 1; D064026:Calbindins; D007328:Insulin; D007329:Insulin Antagonists; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D064030:S100 Calcium Binding Protein G; D020148:Butyric Acid; D002117:Calcitriol; D002118:Calcium