Maechler P, Wollheim C B
Department of Internal Medicine, University Medical Centre, Geneva, Switzerland.
Nature. 1999 Dec 9;402(6762):685-9. doi: 10.1038/45280.
The hormone insulin is stored in secretory granules and released from the pancreatic beta-cells by exocytosis. In the consensus model of glucose-stimulated insulin secretion, ATP is generated by mitochondrial metabolism, promoting closure of ATP-sensitive potassium (KATP) channels, which depolarizes the plasma membrane. Subsequently, opening of voltage-sensitive Ca2+ channels increases the cytosolic Ca2+ concentration ([Ca2+]c) which constitutes the main trigger initiating insulin exocytosis. Nevertheless, the Ca2+ signal alone is not sufficient for sustained secretion. Furthermore, glucose elicits a secretory response under conditions of clamped, elevated [Ca2+]c. A mitochondrial messenger must therefore exist which is distinct from ATP. We have now identified this as glutamate. We show that glucose generates glutamate from beta-cell mitochondria. A membrane-permeant glutamate analogue sensitizes the glucose-evoked secretory response, acting downstream of mitochondrial metabolism. In permeabilized cells, under conditions of fixed [Ca2+]c, added glutamate directly stimulates insulin exocytosis, independently of mitochondrial function. Glutamate uptake by the secretory granules is likely to be involved, as inhibitors of vesicular glutamate transport suppress the glutamate-evoked exocytosis. These results demonstrate that glutamate acts as an intracellular messenger that couples glucose metabolism to insulin secretion.
激素胰岛素储存于分泌颗粒中，并通过胞吐作用从胰腺β细胞释放。在葡萄糖刺激胰岛素分泌的共识模型中，线粒体代谢产生ATP，促使ATP敏感性钾（KATP）通道关闭，从而使质膜去极化。随后，电压敏感性Ca2+通道开放，增加胞质Ca2+浓度（[Ca2+]c），这是引发胰岛素胞吐作用的主要触发因素。然而，仅Ca2+信号不足以维持分泌。此外，在钳制的、升高的[Ca2+]c条件下，葡萄糖也能引发分泌反应。因此，必然存在一种不同于ATP的线粒体信使。我们现已确定其为谷氨酸。我们发现葡萄糖可从β细胞线粒体生成谷氨酸。一种膜通透性谷氨酸类似物可使葡萄糖诱发的分泌反应敏感化，作用于线粒体代谢的下游。在通透细胞中，在固定的[Ca2+]c条件下，添加的谷氨酸直接刺激胰岛素胞吐作用，与线粒体功能无关。分泌颗粒对谷氨酸的摄取可能参与其中，因为囊泡谷氨酸转运抑制剂可抑制谷氨酸诱发的胞吐作用。这些结果表明，谷氨酸作为一种细胞内信使，将葡萄糖代谢与胰岛素分泌联系起来。
