TIGHT LINKS BETWEEN ADENINE AND GUANINE-NUCLEOTIDE POOLS IN MOUSE PANCREATIC-ISLETS - A STUDY WITH MYCOPHENOLIC-ACID

Glucose metabolism in pancreatic B-cells leads to an increase in the A TP/ADP ratio that might participate in the regulation of insulin secre tion. Good correlations have also been observed between guanine nucleo tide levels in isolated pancreatic islets and insulin secretion. To as sess whether guanine nucleotides have a specific role in stimulus-secr etion coupling, their concentration should be modified selectively. Th is was attempted by culturing mouse islets overnight in the presence o f mycophenolic acid (MPA), an inhibitor of GMP synthesis at the level of IMP dehydrogenase. The drug (25-50 mu g/ml) did not affect the insu lin content but decreased the GTP content of the islets and inhibited insulin secretion during subsequent incubation in the presence of 15 m M glucose. However, MPA also decreased the ATP/ADP ratio in the islets . The addition of guanine to the culture medium (to stimulate the salv age pathway of GTP synthesis) restored normal GTP levels, corrected th e ATP/ADP ratio and partly prevented the inhibition of insulin release . In contrast, attempts to stimulate ATP synthesis specifically (by pr ovision of adenine or adenosine) failed to reverse any of the effects of MPA. It is concluded that guanine and adenine nucleotide pools are tightly linked and cannot be specifically affected by MPA in pancreati c islet cells, probably because of the activity of nucleoside diphosph ate kinase and because of the role of GTP in several reactions leading to adenine nucleotide generation. Contrary to previous claims, MPA is not an adequate tool for evaluating a specific role of guanine nucleo tides in the control of insulin secretion.