title: Oxo-4-methylpentanoic acid directs the metabolism of GABA into the Krebs cycle in rat pancreatic islets.
abstract: 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' [Fernández-Pascual, Mukala-Nsengu-Tshibangu, Martín del Río and Tamarit-Rodríguez (2004) Biochem. J. 379, 721-729]. In the present study, 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. 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-14C]-Glutamine (at 0.5 and 10.0 mM) conversion to 14CO2 was enhanced by 10 mM OMP within 30% and 70% respectively. Gabaculine (250 microM), a GABA transaminase inhibitor, suppressed OMP-induced oxygen consumption but not L-leucine- or 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 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.
authors.affiliation: Biochemistry Department, Medical School, Complutense University, Madrid-28040, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Hernández-Fisac
authors.forename: Sergio
authors.initials: S
authors.lastname: Fernández-Pascual
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
authors.forename: Javier
authors.initials: J
authors.lastname: Pizarro-Delgado
authors.forename: Rafael
authors.initials: R
authors.lastname: Martín del Río
authors.forename: Peter
authors.initials: P
authors.lastname: Bergsten
authors.forename: Jorge
authors.initials: J
authors.lastname: Tamarit-Rodriguez
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002952:Citric Acid Cycle / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007651:Keto Acids / Q000494:pharmacology*; D007930:Leucine / Q000494:pharmacology; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D050644:Succinate-Semialdehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D003509:Cyclohexanecarboxylic Acids; D007328:Insulin; D007651:Keto Acids; D005973:Glutamine; C012987:gabaculine; D005680:gamma-Aminobutyric Acid; C013082:alpha-ketoisocaproic acid; D000445:Aldehyde Oxidoreductases; D050644:Succinate-Semialdehyde Dehydrogenase; D000637:Transaminases; D007930:Leucine; D005947:Glucose; D010100:Oxygen