Straub S G, James R F, Dunne M J, Sharp G W
Department of Biomedical Science, University of Sheffield, UK.
Diabetes. 1998 May;47(5):758-63. doi: 10.2337/diabetes.47.5.758.
Insulin secretion by isolated islets of Langerhans from 19 human donors (9 women and 10 men) was studied in vitro to test the hypothesis that human islets contain both the K(ATP) channel-dependent and the K(ATP) channel-independent signaling pathways. The results demonstrated the presence of both of these major pathways of glucose signaling. Thus, insulin secretion was stimulated by high glucose concentrations, by the sulfonylurea tolbutamide, and by a depolarizing concentration of potassium chloride. Diazoxide, which activates the K(ATP) channel, completely blocked the stimulation of release by glucose. Stimulation of insulin release by tolbutamide, which inhibits the K(ATP) channel and depolarizes the beta-cell, and inhibition of glucose-stimulated release by diazoxide, which activates the channel and repolarizes the beta-cell, confirm the involvement of the K(ATP) channel-dependent pathway in glucose signaling. The participation of the K(ATP) channel-independent pathway in the stimulation of insulin release by glucose was demonstrated for the first time in human islets. This was done in two ways. The first method, in the presence of diazoxide, blocked the action of glucose on the K(ATP) channel in combination with a depolarizing concentration of KCl to raise [Ca2+]i. Under these conditions, glucose stimulated insulin release. A second method to demonstrate the involvement of the K(ATP) channel-independent pathway was to close the K(ATP) channels with tolbutamide. Again, with no possibility of further action on the K(ATP) channel, glucose stimulated insulin release. In a final series of experiments, glucose-stimulated insulin release was profoundly inhibited by somatostatin, clonidine, and prostaglandin E2, but not by galanin.
对来自19名人类供体（9名女性和10名男性）的分离胰岛进行体外胰岛素分泌研究，以检验人类胰岛同时存在依赖ATP敏感性钾通道（K(ATP)通道）和不依赖K(ATP)通道的信号通路这一假说。结果证实了这两种主要葡萄糖信号通路的存在。因此，高葡萄糖浓度、磺脲类药物甲苯磺丁脲以及去极化浓度的氯化钾均可刺激胰岛素分泌。激活K(ATP)通道的二氮嗪完全阻断了葡萄糖对释放的刺激作用。甲苯磺丁脲抑制K(ATP)通道并使β细胞去极化从而刺激胰岛素释放，而二氮嗪激活该通道并使β细胞复极化从而抑制葡萄糖刺激的释放，这证实了依赖K(ATP)通道的信号通路参与葡萄糖信号传导。首次在人类胰岛中证实了不依赖K(ATP)通道的信号通路参与葡萄糖刺激的胰岛素释放。这通过两种方式得以证实。第一种方法是在存在二氮嗪的情况下，结合去极化浓度的氯化钾阻断葡萄糖对K(ATP)通道的作用以提高细胞内钙离子浓度（[Ca2+]i）。在这些条件下，葡萄糖刺激胰岛素释放。证实不依赖K(ATP)通道的信号通路参与的第二种方法是用甲苯磺丁脲关闭K(ATP)通道。同样，在无法对K(ATP)通道产生进一步作用的情况下，葡萄糖刺激胰岛素释放。在最后一系列实验中，生长抑素、可乐定和前列腺素E2可显著抑制葡萄糖刺激的胰岛素释放，但甘丙肽则无此作用。
