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Glucose promotion of GABA metabolism contributes to the stimulation of insulin secretion in beta-cells.

Authors: Pizarro-Delgado, J  Braun, M  Hernandez-Fisac, I  Martin-Del-Rio, R  Tamarit-Rodriguez, J 
Citation: Pizarro-Delgado J, etal., Biochem J. 2010 Nov 1;431(3):381-9. doi: 10.1042/BJ20100714.
Pubmed: (View Article at PubMed) PMID:20695849
DOI: Full-text: DOI:10.1042/BJ20100714

We have demonstrated recently that branched-chain alpha-keto acid stimulation of insulin secretion is dependent on islet GABA (gamma-aminobutyric acid) metabolism: GABA transamination to succinic semialdehyde is increased by 2-oxoglutarate, generated in alpha-keto acid transamination to its corresponding alpha-amino acid. The present work was aimed at investigating whether glucose also promotes islet GABA metabolism and whether the latter contributes to the stimulation of insulin secretion. Glucose (20 mM) decreased both the content and release of islet GABA. Gabaculine (1 mM), a GABA transaminase inhibitor, partially suppressed the secretory response of rat perifused islets to 20 mM glucose at different L-glutamine concentrations (0, 1 and 10 mM), as well as the glucose-induced decrease in islet GABA. The drug also reduced islet ATP content and the ATP/ADP ratio at 20 mM glucose. Exogenous succinic semialdehyde induced a dose-dependent increase in islet GABA content by reversal of GABA transamination and a biphasic insulin secretion in the absence of glucose. It depolarized isolated beta-cells and triggered action potential firing, accompanied by a reduction of membrane currents through ATP-sensitive K(+) channels. The gene expression and enzyme activity of GABA transaminase were severalfold higher than that of 2-oxoglutarate dehydrogenase in islet homogenates. We conclude that, at high glucose concentrations, there is an increased diversion of glucose metabolism from the citric acid cycle into the 'GABA shunt'. Semialdehyde succinic acid is a cell-permeant 'GABA-shunt' metabolite that increases ATP and the ATP/ADP ratio, depolarizes beta-cells and stimulates insulin secretion. In summary, an increased islet GABA metabolism may trigger insulin secretion.

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CRRD Object Information
CRRD ID: 9588550
Created: 2014-10-30
Species: All species
Last Modified: 2014-10-30
Status: ACTIVE



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