Institute of Applied Health Research, University of Birmingham, Birmingham, UK.
Department of Endocrinology, 424 General Military Hospital, Thessaloniki, Greece.
Drugs. 2020 Apr;80(5):467-475. doi: 10.1007/s40265-020-01278-z.
Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a "glucose-sensor" or "glucose receptor" in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose "gate-keeper" in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs) may increase insulin secretion from the pancreas and promote glycogen synthesis in the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and a novel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.
肝葡萄糖输出增加是 2 型糖尿病（T2DM）的主要肝脏失调，除二甲双胍外，目前可用的降血糖药物类别并不能直接或有效地针对这一失调。这种未满足的需求可能通过激活己糖激酶家族的特定酶成员，即葡萄糖激酶（GK）来实现。GK 在胰腺细胞中充当“葡萄糖传感器”或“葡萄糖受体”，引发葡萄糖刺激的胰岛素分泌，在肝细胞中充当葡萄糖“门控”，促进肝葡萄糖摄取和糖原合成和储存。小分子激活 GK 提供了一种替代方法，可以恢复/改善 T2DM 患者的血糖控制。GK 激活剂（GKAs）可能会增加胰腺胰岛素分泌并促进肝脏糖原合成，从而减少肝葡萄糖输出。尽管在开发过程中遇到了一些挫折，但对 GKA 类药物的兴趣已经重新燃起，特别是自从引入新型双重作用的全 GKA 多扎格列净和新型肝选择性分子替格列汀之后。在本文中，我们概述了 GKA 在 T2DM 管理中的作用、疗效、安全性和未来发展。
