SMALL ELEVATIONS OF GLUCOSE-CONCENTRATION REDIRECT AND AMPLIFY THE SYNTHESIS OF GUANOSINE 5'-TRIPHOSPHATE IN RAT ISLETS

Recent studies suggest a permissive requirement for guanosine 5'-triph osphate (GTP) in insulin release, based on the use of GTP synthesis in hibitors (such as mycophenolic acid) acting at inosine monophosphate ( IMP) dehydrogenase; herein, we examine the glucose dependency of GTP s ynthesis. Mycophenolic acid inhibited insulin secretion equally well a fter islet culture at 7.8 or 11.1 mM glucose (51% inhibition) but its effect was dramatically attenuated when provided at less-than-or-equal -to 6.4 mM glucose (13% inhibition; P < 0.001). These observations wer e explicable by a stimulation of islet GTP synthesis derived from IMP since, at high glucose: (a) total GTP content was augmented; (b) a gre ater decrement in GTP (1.75 vs. 1.05 pmol/islet) was induced by mycoph enolic acid; and (c) a smaller ''pool'' of residual GTP persisted afte r drug treatment. Glucose also accelerated GTP synthesis from exogenou s guanine (''salvage'' pathway) and increased content of a pyrimidine, uridine 5'-triphosphate (UTP), suggesting that glucose augments produ ction of a common regulatory intermediate (probably 5-phosphoribosyl-1 -pyrophosphate). Pathway-specific radiolabeling studies confirmed that glucose tripled both salvage and de novo synthesis of nucleotides. We conclude that steep changes in the biosynthesis of cytosolic pools of GTP occur at modest changes in glucose concentrations, a finding whic h may have relevance to the adaptive (patho)physiologic responses of i slets to changes in ambient glucose levels.