RETINOIC ACID RECEPTOR TRANSCRIPTS AND EFFECTS OF RETINOL AND RETINOIC ACID ON GLUCAGON-SECRETION FROM RAT ISLETS AND GLUCAGON-SECRETING CELL-LINES

Using intact rat islets, hamster In-R1-G9 cells, and mouse alpha TC-1 clone 9 transgenic tumoral glucagon-secreting cells, we determined the effects of retinol (ROH) and retinoic acid (RA) on glucagon secretion . Since vitamin A effects may be mediated through nuclear RA receptors (RARs) and cytoplasmic ROH- and RA-binding proteins (CRBP and CRABP), cells were also assayed for RARs, CRBP, and CRABP mRNA by Northern bl ot analyses. Islets and cells were cultured in 2.8 mmol/L glucose and vitamin A-deficient (A-def) medium or in different concentrations of R OH and RA. Using intact islets, RA 10 and 100 nmol/L inhibited glucago n secretion to approximately 60% of control levels. Using In-R1-G9 cel ls, ROH 0.175 to 5.0 mu mol/L inhibited glucagon secretion to 60% to 8 3% of control levels, and RA 100 and 1,000 nmol/L inhibited glucagon s ecretion from 72% to 43% of control levels, respectively. Using alpha TC-1 cells. ROH 1.75 mu mol/L inhibited glucagon secretion to 80% of c ontrol levels, and RA 1 to 100 nmol/L inhibited secretion from 83% to 68% of control levels. Inhibition of secretion was dose-dependent. RAR alpha RNA transcripts were detected in alpha TC-1 and In-R1-G9 total RNA extracts; RAR gamma transcripts were detected in alpha TC-1 cells. We conclude the following: (1) ROH and RA inhibit glucagon secretion in cultured rat islets and glucagon-secreting cell lines, and in cell lines the effect of RA is dose-dependent; (2) on a molar basis, RA is on the order of 10- to 100-fold more potent than ROH, a finding consis tent with RA being the active metabolite of ROH at the ct-cell level; and (3) this inhibition may be mediated through classic pathways of re tinoid action involving nuclear RARs and gene expression of specific p roteins. Copyright (C) 1996 by W.B. Saunders Company