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Research Article Free access | 10.1172/JCI116662
Department of Medicine, University of Wisconsin, Madison 53792.
Find articles by Metz, S. in: JCI | PubMed | Google Scholar
Department of Medicine, University of Wisconsin, Madison 53792.
Find articles by Meredith, M. in: JCI | PubMed | Google Scholar
Department of Medicine, University of Wisconsin, Madison 53792.
Find articles by Rabaglia, M. in: JCI | PubMed | Google Scholar
Department of Medicine, University of Wisconsin, Madison 53792.
Find articles by Kowluru, A. in: JCI | PubMed | Google Scholar
Published August 1, 1993 - More info
Recent studies suggest a permissive requirement for guanosine 5'-triphosphate (GTP) in insulin release, based on the use of GTP synthesis inhibitors (such as myocophenolic acid) acting at inosine monophosphate (IMP) dehydrogenase; herein, we examine the glucose dependency of GTP synthesis. Mycophenolic acid inhibited insulin secretion equally well after islet culture at 7.8 or 11.1 mM glucose (51% inhibition) but its effect was dramatically attenuated when provided at < or = 6.4 mM glucose (13% inhibition; P < 0.001). These observations were explicable by a stimulation of islet GTP synthesis derived from IMP since, at high glucose: (a) total GTP content was augmented; (b) a greater decrement in GTP (1.75 vs. 1.05 pmol/islet) was induced by mycophenolic acid; and (c) a smaller "pool" of residual GTP persisted after drug treatment. Glucose also accelerated GTP synthesis from exogenous guanine ("salvage" pathway) and increased content of a pyrimidine, uridine 5'-triphosphate (UTP), suggesting that glucose augments production 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 which may have relevance to the adaptive (patho) physiologic responses of islets to changes in ambient glucose levels.