Branched-chain 2-oxoacids transamination increases “GABA-shunt” metabolism and insulin secretion in isolated islets
Résumé
We have previously shown that oxo-4-methylpentanoate promotes islet GABA 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 isozyme, 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. 70 mM KCl 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: 1. The transamination of branched-chain 2-oxoacids is more important to the stimulation of insulin secretion than their catabolism. 2. Transamination decreases islet GABA concentrations by promoting GABA metabolism. 3. Inhibition of 2-oxoglutarate dehydrogenase by branched-chain 2-oxoacids may increase metabolic flux in the “GABA-shunt” at the expense of reduced TCA cycle flux.
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