Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets
Résumé
4-Oxo-methylpentanoic acid (OMP) stimulates by itself a biphasic secretion of insulin whereas L-leucine requires the presence of L-glutamine. L-glutamine is predominantly converted to GABA in rat islets and L-leucine seems to promote its metabolism in the "GABA shunt" (Fernández-Pascual S. et al, Biochem. J. 379, 721-729, 2004). We have investigated how 10 mM OMP affects L-glutamine metabolism to uncover possible differences with L-leucine that might help to elucidate whether they share a common mechanism of stimulation of insulin secretion. At variance with L-leucine, OMP alone stimulated a biphasic insulin secretion in rat perifused islets and decreased the islet content of GABA without modifying its extracellular release irrespective of the medium L-glutamine concentration. It was transaminated to L-leucine whose intracellular concentration did not change because it was very efficiently transported out of the islet cells. L-[U- 14}C]Glutamine, 0.5 and 10.0 mM, conversion to 14}CO 2} was enhanced by 10 mM OMP within 30 and 70 %, respectively. Gabaculine (250 {mu}M), a GABA transaminase inhibitor, suppressed OMP-induced oxygen consumption but not L-leucine or glucose stimulated respiration. It also suppressed OMP-induced decrease of islet GABA content and OMP-induced increase in insulin release. These results support the view that OMP promotes islet metabolism in the "GABA shunt" generating 2-oxoglutarate, in the branched-chain {alpha}-amino acid transaminase reaction, which would in turn trigger GABA deamination by GABA transaminase. OMP, but not L-leucine, suppressed islet semialdehyde succinic acid reductase activity and this might shift the metabolic flux of the "GABA shunt" from {gamma}-hydroxybutyrate to succinic acid production.
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