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Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2006 (English)In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 400, no 1, 81-89 p.Article in journal (Refereed) Published
Abstract [en]

OMP (oxo-4-methylpentanoic acid) stimulates by itself a biphasic secretion of insulin whereas L-leucine requires the presence of L-glutamine. L-Glutamine is predominantly converted into GABA (gamma-aminobutyric acid) in rat islets and L-leucine seems to promote its metabolism in the 'GABA shunt' [Fernandez-Pascual, Mukala-Nsengu-Tshibangu, Martin del Rio and Tamarit-Rodriguez (2004) Biochem. J. 379,721-729]. In the present study, we have investigated how 10mM 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. In contrast 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 concentration of L-glutamine in the medium. GABA was transaminated to L-leucine whose intracellular concentration did not change because it was efficiently transported out of the islet cells. The L-[U-C-14]-Glutamine (at 0.5 and 10.0 mM) conversion to (CO2)-C-14 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-leucineor glucose-stimulated respiration. It also suppressed the OMP-induced decrease in islet GABA content and the OMP-induced increase in insulin release. These results support the view that OMP promotes islet metabolism in the 'GABA shunt' generating 2-oxo-glutarate, in the branched-chain a-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.

Place, publisher, year, edition, pages
2006. Vol. 400, no 1, 81-89 p.
Keyword [en]
alpha-amino acid, gamma-aminobutyric acid (GABA), glucose, pancreatic islet, L-leucine, oxo-4-methylpentanoic acid (OMP)
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-24717DOI: 10.1042/BJ20060173ISI: 000242226600009PubMedID: 16819942OAI: oai:DiVA.org:uu-24717DiVA: diva2:52491
Available from: 2007-03-06 Created: 2007-03-06 Last updated: 2011-05-11Bibliographically approved

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Ortsäter, HenrikBergsten, Peter
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