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Scientific article
Open access
English

Mitochondrial GTP regulates glucose-stimulated insulin secretion

Published inCell metabolism, vol. 5, no. 4, p. 253-264
Publication date2007
Abstract

Nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl-CoA synthetase (SCS) catalyze substrate-level synthesis of mitochondrial GTP (mtGTP) and ATP (mtATP). While mtATP yield from glucose metabolism is coupled with oxidative phosphorylation and can vary, each molecule of glucose metabolized within pancreatic beta cells produces approximately one mtGTP, making mtGTP a potentially important fuel signal. In INS-1 832/13 cells and cultured rat islets, siRNA suppression of the GTP-producing pathway (DeltaSCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, while suppression of the ATP-producing isoform (DeltaSCS-ATP) increased GSIS 2-fold. Insulin secretion correlated with increases in cytosolic calcium, but not with changes in NAD(P)H or the ATP/ADP ratio. These data suggest a role for mtGTP in controlling pancreatic GSIS through modulation of mitochondrial metabolism, possibly involving mitochondrial calcium. Furthermore, in light of its tight coupling to TCA oxidation rates, mtGTP production may serve as an important molecular signal of TCA-cycle activity.

Keywords
  • Animals
  • Calcium/metabolism
  • Cells, Cultured
  • Energy Metabolism/physiology
  • Glucose/pharmacology
  • Guanosine Triphosphate/analysis/physiology
  • Insulin/secretion
  • Insulin-Secreting Cells/drug effects/secretion
  • Mitochondria/chemistry/drug effects
  • Models, Biological
  • Oxidation-Reduction
  • RNA, Small Interfering/pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Succinate-CoA Ligases/antagonists & inhibitors/genetics
Citation (ISO format)
KIBBEY, Richard G et al. Mitochondrial GTP regulates glucose-stimulated insulin secretion. In: Cell metabolism, 2007, vol. 5, n° 4, p. 253–264. doi: 10.1016/j.cmet.2007.02.008
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Article (Published version)
accessLevelPublic
Identifiers
ISSN of the journal1550-4131
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