Effect of retinoic acid on glucokinase activity and gene expression and oninsulin secretion in primary cultures of pancreatic islets

Retinoic acid has manifold effects on pancreatic p-cells. Previously we rep orted that retinoic acid increases glucokinase activity and messenger RNA ( mRNA) levels in the insulinoma cell line RIN-m5F; however, we could not rul e out the possibility that the effect of retinoic acid on RIN-m5F glucokina se was inherent to the cell line or related to its differentiating capacity . In this report, we demonstrate that physiologic concentrations of retinoi c acid stimulate glucokinase activity in both fetal islets and differentiat ed adult islets in culture. In the adult tissue, the response to the retino id was less pronounced, achieving about half of the maximal effect produced on the fetal tissue. Using the branched DNA (bDNA) assay, a sensitive sign al amplification technique, we detected relative increases in glucokinase m RNA levels of 51.8 +/- 13.3% and 62.8 +/- 16.1% at 12 and 24 h, respectivel y, in adult islets treated with10(-6) M retinoic acid. In fetal islets, inc reases of 55 +/- 14.9% and 107 +/- 30.5% at 12 and 24 h, respectively, were observed. In transfected fetal islets, retinoic acid increased the activit y of the - 1000 kb rat glucokinase promoter by 51.3%. Because glucokinase a ctivity controls insulin secretion, we also investigated the effect of reti noic acid on insulin secretion. Treatment with 10-6 hr retinoic acid for 24 h increased insulin secretion in both fetal and adult islets; however, the increases on insulin secretion were more pronounced in the mature islets; in contrast, retinoic acid produced higher levels of insulin mRNA in the fe tal islets. These data show that retinoic acid increases pancreatic glucoki nase in cultured islets and that the mechanism may involve a stimulatory ef fect on the glucokinase promoter.