We have previously shown that oxo-4-methylpentanoate promotes islet GABA (γ-aminobutyric acid) metabolism and stimulates insulin secretion. The main aim of this work was to explore the participation of the transamination of branched-chain 2-oxoacids in these processes with the aid of several inhibitors of this enzyme activity. No correlation was found between the transamination of branched-chain 2-oxoacids in islet homogenates and insulin secretion. However, in vivo transamination rates correlated better with the secretion capacity of the different branched-chain 2-oxoacids. Gabapentin, a specific inhibitor of the cytosolic isoenzyme, showed greater potential to decrease the in vitro transamination rates of oxo-3-methylbutyrate and oxo-3-methylpentanoate than those of oxo-4-methylpentanoate and oxohexanoate; this correlated with its capacity to decrease insulin secretion. 4-Methylvaleric acid very strongly inhibited the transamination of all the branched-chain 2-oxoacids and blocked their capacity to decrease islet GABA and to stimulate insulin secretion. KCl at 70 mM at stimulated islet GABA release, subsequently decreasing its tissue concentration. This ‘non-metabolic’ decrease of GABA suppressed the second phase of insulin secretion triggered by oxo-4-methylpentanoate and oxohexanoate. Oxo-4-methylpentanoate and oxo-3-methylpentanoate suppressed dose-dependent 2-oxoglutarate dehydrogenase activity in islet homogenates. In conclusion, the transamination of branchedchain 2-oxoacids is more important to the stimulation of insulin secretion than their catabolism, and transamination decreases islet GABA concentrations by promoting GABA metabolism. Also, inhibition of 2-oxoglutarate dehydrogenase by branched-chain 2-oxoacids may increase metabolic flux in the ‘GABA-shunt’ at the expense of reduced tricarboxylic acid cycle flux.
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Research Article|
March 27 2009
Branched-chain 2-oxoacid transamination increases GABA-shunt metabolism and insulin secretion in isolated islets
Javier Pizarro-Delgado;
Javier Pizarro-Delgado
*Department of Biochemistry, Medical School, Complutense University, Madrid 28040, Spain
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Inés Hernández-Fisac;
Inés Hernández-Fisac
*Department of Biochemistry, Medical School, Complutense University, Madrid 28040, Spain
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Rafael Martín-Del-Río;
Rafael Martín-Del-Río
†Research Department, Hospital “Ramón y Cajal”, Madrid 28034, Spain
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Jorge Tamarit-Rodriguez
Jorge Tamarit-Rodriguez
1
*Department of Biochemistry, Medical School, Complutense University, Madrid 28040, Spain
1To whom correspondence should be addressed (email tamarit@med.ucm.es).
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Publisher: Portland Press Ltd
Received:
August 26 2008
Revision Received:
January 15 2009
Accepted:
January 22 2009
Accepted Manuscript online:
January 28 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 419 (2): 359–368.
Article history
Received:
August 26 2008
Revision Received:
January 15 2009
Accepted:
January 22 2009
Accepted Manuscript online:
January 28 2009
Citation
Javier Pizarro-Delgado, Inés Hernández-Fisac, Rafael Martín-Del-Río, Jorge Tamarit-Rodriguez; Branched-chain 2-oxoacid transamination increases GABA-shunt metabolism and insulin secretion in isolated islets. Biochem J 15 April 2009; 419 (2): 359–368. doi: https://doi.org/10.1042/BJ20081731
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