葡萄糖激酶激活剂研究进展.PDF

PROGRESS IN PHARMACEUTICAL SCIENCES 2016,40 3 :168-177 168 ( ) 葡萄糖激酶激活剂研究进展 余刚* （华领医药技术（上海）有限公司，上海 201203） [ 摘要 ] 葡萄糖激酶分布在体内多个脏器中，可感应葡萄糖和调节糖代谢激素，在稳定血糖水平方面起到重要作用。葡萄糖激酶激活剂系 针对这一靶点而开发，能够通过葡萄糖浓度刺激的胰岛素分泌、降低胰高血糖素浓度和肝糖输出、促进肝糖原合成以及调控肠促胰素释 放等机制来稳定体内血糖水平，近年来已成为 2 型糖尿病新型药物研发的热点。介绍现有葡萄糖激酶激活剂药物的开发策略、作用特点 及临床研究进展。 [ 关键词 ] 葡萄糖激酶；葡萄糖激酶激活剂；葡萄糖激酶调控蛋白；异位调节；葡萄糖刺激的促胰岛素释放 [ 中图分类号 ] R977.15 [ 文献标志码 ] A [ 文章编号 ] 1001-5094（2016）03-0168-10 Research Progress in Glucokinase Activators YU Gang (Hua Medicine (Shanghai) Ltd, Shanghai 201203, China) [Abstract] With wide distribution in multiple organs, glucokinase (GK) senses glucose level and regulates hormones involved in glucose metabolism, playing an important role in stabilizing blood glucose. As GK targeting agents, GK activators (GKAs) have been developed to stabilize glucose level in vivo through various mechanisms including glucose-stimulated insulin release (GSIR), decreased glucagon concentration and hepatic glucose output, enhanced hepatic glycogen synthesis and incretin release regulation, becoming a hot spot in recent medicinal researches for type 2 diabetes. The development strategies, characteristics of drug action and advances in clinical studies of GKAs have been reviewed in this paper. [Key words] glucokinase; glucokinase activator; glucokinase regulatory protein; ectopic regulation; glucose-stimulated insulin release 1 葡萄糖激酶的结构和异位调节作用 2 葡萄糖激酶的体内分布和糖代谢调节作用 葡萄糖激酶（Glucokinase，GK）是一个相对分子 GK 存在于包括人体肝脏、胰腺、肠道、中枢神经 质量为 50 000 的细胞内间质酶，又称己糖激酶Ⅳ。GK 在内的多个脏器系统，通过感应葡萄糖浓度变化调控脏 作为体内葡萄糖代谢的限速酶，在胰腺β细胞决定着葡 器中糖代谢激素的释放。GK 在肝细胞核内与葡萄糖激