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Effect of Retinoic Acid on Glucokinase Activity and Gene Expression and on Insulin Secretion in Primary Cultures of Pancreatic Islets¹

From the Nutritional Genetics Unit (G.C.V., C.F.M.) Biomedical Research Institute, National University of Mexico, Mexico City, Mexico 04530; Hormone Research Institute (M.S.G., J.W.) University of California San Francisco, San Francisco, California 94143-0534; and Diabetes Research Center (F.M.M.), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6015

Address all correspondence and requests for reprints to: Cristina Fernandez-Mejia, Unidad de Genetica de la Nutricion, Instituto de Investigaciones Biomedicas Universidad Nacional Autónoma de México/Instituto Nacional de Pediatría, Avenida del Iman 1, 4th Floor, Mexico City, C.P. 04530, Mexico. E-mail: crisfern{at}servidor.unam.mx

Retinoic acid has manifold effects on pancreatic ß-cells. Previously we reported that retinoic acid increases glucokinase activity and messenger RNA (mRNA) levels in the insulinoma cell line RIN-m5F; however, we could not rule out the possibility that the effect of retinoic acid on RIN-m5F glucokinase was inherent to the cell line or related to its differentiating capacity. In this report, we demonstrate that physiologic concentrations of retinoic acid stimulate glucokinase activity in both fetal islets and differentiated adult islets in culture. In the adult tissue, the response to the retinoid was less pronounced, achieving about half of the maximal effect produced on the fetal tissue. Using the branched DNA (bDNA) assay, a sensitive signal amplification technique, we detected relative increases in glucokinase mRNA levels of 51.8 ± 13.3% and 62.8 ± 16.1% at 12 and 24 h, respectively, in adult islets treated with ]10^-6 M retinoic acid. In fetal islets, increases of 55 ± 14.9% and 107 ± 30.5% at 12 and 24 h, respectively, were observed. In transfected fetal islets, retinoic acid increased the activity of the -1000 kb rat glucokinase promoter by 51.3%. Because glucokinase activity controls insulin secretion, we also investigated the effect of retinoic acid on insulin secretion. Treatment with 10^-6 M 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 fetal islets. These data show that retinoic acid increases pancreatic glucokinase in cultured islets and that the mechanism may involve a stimulatory effect on the glucokinase promoter.

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