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 alphaTC-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 blot analyses. Islets and cells were cultured in 2.8 mmol/L glucose and vitamin A-deficient (A-def) medium or in different concentrations of ROH and RA. Using intact islets, RA 10 and 100 nmol/L inhibited glucagon secretion to approximately 60% of control levels. Using In-R1-G9 cells, ROH 0.175 to 5.0 micromol/L inhibited glucagon secretion to 60% to 83% of control levels, and RA 100 and 1,000 nmol/L inhibited glucagon secretion from 72% to 43% of control levels, respectively. Using alphaTC-1 cells, ROH 1.75 micromol/L inhibited glucagon secretion to 80% of control levels, and RA 1 to 100 nmol/L inhibited secretion from 83% to 68% of control levels. Inhibition of secretion was dose-dependent. RARalpha RNA transcripts were detected in alpha TC-1 and In-R1-G9 total RNA extracts; RAR gamma transcripts were detected in alphaTC-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 consistent with RA being the active metabolite of ROH at the alpha-cell level; and (3) this inhibition may be mediated through classic pathways of retinoid action involving nuclear RARs and gene expression of specific proteins.
Chertow
B S
BS
Research and Medical Services, Huntington Veterans Affairs Medical Center, Huntington, WV 25704, USA.
Driscoll
H K
HK
Primerano
D A
DA
Cordle
M B
MB
Matthews
K A
KA
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D005934:Glucagon / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*; D014801:Vitamin A / Q000494:pharmacology*
D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D014212:Tretinoin; D005934:Glucagon