Department of Biochemistry, Complutense University, Madrid, Spain.
Biochem J. 2010 Nov 1;431(3):381-9. doi: 10.1042/BJ20100714.
We have demonstrated recently that branched-chain α-keto acid stimulation of insulin secretion is dependent on islet GABA (γ-aminobutyric acid) metabolism: GABA transamination to succinic semialdehyde is increased by 2-oxoglutarate, generated in α-keto acid transamination to its corresponding α-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 β-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 β-cells and stimulates insulin secretion. In summary, an increased islet GABA metabolism may trigger insulin secretion.
我们最近已经证明，支链α-酮酸刺激胰岛素分泌依赖于胰岛 GABA（γ-氨基丁酸）代谢：GABA 转氨酶到琥珀酸半醛的转氨作用被 2-氧戊二酸增加，该物质由α-酮酸转氨酶到其相应的α-氨基酸生成。本工作旨在研究葡萄糖是否也促进胰岛 GABA 代谢，以及后者是否有助于刺激胰岛素分泌。葡萄糖（20 mM）降低了胰岛 GABA 的含量和释放。GABaculine（1 mM），一种 GABA 转氨酶抑制剂，部分抑制了在不同 L-谷氨酰胺浓度（0、1 和 10 mM）下 20 mM 葡萄糖刺激的大鼠胰岛灌流的分泌反应，以及葡萄糖诱导的胰岛 GABA 减少。该药物还降低了 20 mM 葡萄糖时胰岛的 ATP 含量和 ATP/ADP 比值。外源性琥珀酸半醛通过逆转 GABA 转氨酶诱导胰岛 GABA 含量的剂量依赖性增加，并在没有葡萄糖的情况下引发双峰胰岛素分泌。它使分离的β细胞去极化并引发动作电位发射，同时伴有通过 ATP 敏感的 K（+）通道的膜电流减少。GABA 转氨酶的基因表达和酶活性比胰岛匀浆中的 2-氧戊二酸脱氢酶高几倍。我们得出结论，在高葡萄糖浓度下，葡萄糖代谢从柠檬酸循环中更多地转移到“GABA 分流”。半醛琥珀酸是一种可渗透细胞的“GABA 分流”代谢物，可增加 ATP 和 ATP/ADP 比值，使β细胞去极化并刺激胰岛素分泌。总之，胰岛 GABA 代谢的增加可能触发胰岛素分泌。
