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Cyclic Adenosine 3',5'-Monophosphate Increases Pancreatic Glucokinase Activity and Gene Expression¹

Nutritional Genetics Unit (C.F.M., J.V., A.R.O.), Biomedical Research Institute, National University of México, and School of Chemistry, National University of Mexico (M.R.D.), México City, C.P. 04530, México; School of Chemical-Biological Sciences (G.R.N.), Autonomous University of Sinaloa, Culiacán, Sinaloa, C.P. 80000, México; Hormone Research Institute, University of California (M.S.G., J.W.), San Francisco, California 94143-0534; and Diabetes Research Center, University of Pennsylvania Medical Center (F.M.M.), Philadelphia, Pennsylvania 19104-6015

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

Comparison of the pancreatic and hepatic glucokinase gene transcripts reveals tissue-specific control of expression and the existence of two distinct promoters in a single glucokinase gene. The existence of alternate promoters suggests that separate factors regulate glucokinase transcription in the two tissues. Hepatic glucokinase expression has been shown to be repressed by cAMP; however, in the pancreatic ß-cell it is unlikely that cAMP represses glucokinase activity, as cAMP is known to positively affect glucose-induced insulin secretion, a process that in mature islets requires pancreatic glucokinase activity. In this work we demonstrate that cAMP indeed has a stimulatory effect on pancreatic glucokinase. The cyclic nucleotide stimulates pancreatic glucokinase activity after 3-h incubation, and maximal effects are observed after 6 and 12 h of treatment. Using the bDNA assay, a sensitive signal amplification technique, we detected relative increases in glucokinase messenger RNA levels of 40.5 ± 7.5% after 3-h incubation with cAMP. This stimulatory effect was increased to 106.3 ± 22% after 6-h incubation and sustained up to 12 h of incubation. Inhibition of gene transcription by actinomycin D abolishes cAMP-induced glucokinase activity. In transfected fetal islets, cAMP increased the activity of the -1000 bp rat glucokinase promoter by 60 ± 6%. These data demonstrate that cAMP has a stimulatory effect on pancreatic glucokinase gene expression and that the nucleotide has opposite effects on pancreatic and hepatic glucokinase, supporting the concept that glucokinase transcription in the liver and that in the ß-cell differ.

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