Muroyama Akiko, Uehara Shunsuke, Yatsushiro Shouki, Echigo Noriko, Morimoto Riyo, Morita Mitsuhiro, Hayashi Mitsuko, Yamamoto Akitsugu, Koh Duk-Su, Moriyama Yoshinori
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
Diabetes. 2004 Jul;53(7):1743-53. doi: 10.2337/diabetes.53.7.1743.
Many metabolic factors affect the secretion of insulin from beta-cells and glucagon from alpha-cells of the islets of Langerhans to regulate blood glucose. Somatostatin from delta-cells, considered a local inhibitor of islet function, reduces insulin and glucagon secretion by activating somatostatin receptors in islet cells. Somatostatin secretion from delta-cells is increased by high glucose via glucose metabolism in a similar way to insulin secretion from beta-cells. However, it is unknown how low glucose triggers somatostatin secretion. Because L-glutamate is cosecreted with glucagon from alpha-cells under low-glucose conditions and acts as a primary intercellular messenger, we hypothesized that glutamate signaling triggers the secretion of somatostatin. In this study, we showed that delta-cells express GluR4c-flip, a newly identified splicing variant of GluR4, an (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptor of rat. After treatment with L-glutamate, AMPA, or kainate, secretion of somatostatin from isolated islets was significantly stimulated under low-glucose conditions. The glutamate-dependent somatostatin secretion was Ca(2+) dependent and blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. Somatostatin in turn inhibited the secretion of L-glutamate and glucagon from alpha-cells. These results indicate that L-glutamate triggers somatostatin secretion from delta-cells by way of the GluR4c-flip receptor under low-glucose conditions. The released somatostatin may complete the feedback inhibition of alpha-cells. Thus, alpha- and delta-cells may communicate with each other through L-glutamate and somatostatin signaling.
许多代谢因子会影响胰岛β细胞分泌胰岛素以及胰岛α细胞分泌胰高血糖素，从而调节血糖水平。胰岛δ细胞分泌的生长抑素被认为是胰岛功能的局部抑制剂，它通过激活胰岛细胞中的生长抑素受体来减少胰岛素和胰高血糖素的分泌。与胰岛β细胞分泌胰岛素的方式类似，高血糖通过葡萄糖代谢增加胰岛δ细胞分泌生长抑素。然而，目前尚不清楚低血糖是如何触发生长抑素分泌的。由于在低血糖条件下，L-谷氨酸与胰高血糖素一起从胰岛α细胞共分泌，并作为主要的细胞间信使，因此我们推测谷氨酸信号传导会触发生长抑素的分泌。在本研究中，我们发现胰岛δ细胞表达GluR4c-flip，这是一种新鉴定的GluR4剪接变体，GluR4是大鼠的一种（RS）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型离子型谷氨酸受体。在低葡萄糖条件下，用L-谷氨酸、AMPA或海人酸处理后，分离的胰岛中生长抑素的分泌受到显著刺激。谷氨酸依赖性生长抑素分泌依赖于Ca(2+)，并被6-氰基-7-硝基喹喔啉-2,3-二酮阻断。生长抑素反过来又抑制胰岛α细胞分泌L-谷氨酸和胰高血糖素。这些结果表明，在低葡萄糖条件下，L-谷氨酸通过GluR4c-flip受体触发胰岛δ细胞分泌生长抑素。释放的生长抑素可能完成对胰岛α细胞的反馈抑制。因此，胰岛α细胞和δ细胞可能通过L-谷氨酸和生长抑素信号传导相互通讯。
