Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
Diabetes Obes Metab. 2012 Jan;14 Suppl 1:9-13. doi: 10.1111/j.1463-1326.2011.01507.x.
It is well known that sulphonylureas (SUs), commonly used in the treatment of type 2 diabetes mellitus, stimulate insulin secretion by closing ATP-sensitive K(+) (K(ATP) ) channels in pancreatic β-cells by binding to the SU receptor SUR1. SUs are now known also to activate cAMP sensor Epac2 (cAMP-GEFII) to Rap1 signalling, which promotes insulin granule exocytosis. For SUs to exert their full effects in insulin secretion, they are required to activate Epac2 as well as to inhibit the β-cell K(ATP) channels. As Epac2 is also necessary for potentiation of glucose-induced insulin secretion by cAMP-increasing agents, such as incretin, Epac2 is a target of both cAMP and SUs. The distinct effects of various SUs appear to be because of their different actions on Epac2/Rap1 signalling as well as K(ATP) channels. Differently from other SUs, gliclazide is unique in that it is specific for β-cell K(ATP) channel and does not activate Epac2.
众所周知，磺酰脲类药物（SUs）通过与 SU 受体 SUR1 结合，关闭胰腺β细胞中的 ATP 敏感性 K(+) (K(ATP) )通道，从而刺激胰岛素分泌。现在也知道 SUs 还可以激活 cAMP 传感器 Epac2（cAMP-GEFII），从而促进 Rap1 信号转导，促进胰岛素颗粒胞吐。为了使 SUs 在胰岛素分泌中发挥其全部作用，它们不仅需要激活 Epac2，还需要抑制β细胞 K(ATP)通道。由于 Epac2 也是 cAMP 增加剂（如肠促胰岛素）增强葡萄糖诱导的胰岛素分泌所必需的，因此 Epac2 是 cAMP 和 SUs 的共同靶标。各种 SUs 的不同作用似乎是由于它们对 Epac2/Rap1 信号转导以及 K(ATP) 通道的不同作用。与其他 SUs 不同，格列齐特的独特之处在于它是专门针对β细胞 K(ATP)通道的，并且不会激活 Epac2。
