Small elevations of glucose concentration redirect and amplify the synthesis of guanosine 5'-triphosphate in rat islets.
Open Access
- 1 August 1993
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 92 (2), 872-882
- https://doi.org/10.1172/jci116662
Abstract
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.Keywords
This publication has 54 references indexed in Scilit:
- Lack of Glyconeogenesis in Pancreatic Islets: Expression of Gluconeogenic Enzyme Genes in IsletsHormone and Metabolic Research, 1992
- RS-61443—A PHASE I CLINICAL TRIAL AND PILOT RESCUE STUDY 1Transplantation, 1992
- Guanine ribonucleotide depletion inhibits T cell activation. Mechanism of action of the immunosuppressive drug mizoribine.JCI Insight, 1991
- Inosine monophosphate dehydrogenase inhibitors. Probes for investigations of the functions of guanine nucleotide binding proteins in intact cellsCellular Signalling, 1990
- Regulation of RNA metabolism in relation to insulin production and oxidative metabolism in mouse pancreatic islets in vitroBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1986
- Synthesis of Phosphoribosylpyrophosphate in Mammalian CellsPublished by Wiley ,1979
- Isolated mouse pancreatic islets in culture: Effects of serum and different culture media on the insulin production of the isletsDiabetologia, 1978
- Transport and Oxidation of Glycine in Mammalian Pancreatic Islets with Reference to the Mechanism of Amino Acid-Induced Insulin ReleaseHormone Research in Paediatrics, 1972
- Regulation of the synthesis of 5-phosphoribosyl-i-pyrophosphate in intact red blood cells and in cell-free preparationsBiochimica et Biophysica Acta (BBA) - General Subjects, 1969
- The Renal Excretion of Oxypurines*JCI Insight, 1965