以葡萄糖激酶为靶点的2型糖尿病药物研究现状

Current status of research on glucokinase targeting drugs for type 2 diabetes

葡萄糖激酶(glucokinase,GK)参与糖酵解第1步反应,催化MgATP2-依赖的葡萄糖磷酸化,主要存在于肝细胞和胰腺β细胞,促进葡萄糖代谢和胰岛素分泌,有效控制体内的血糖平衡。其活性受葡萄糖激酶调节蛋白(glucokinase regulatory protein,GKRP)、6-磷酸果糖-2-激酶/果糖-2,6-双磷酸化酶(6-phos-phofructo-2-kinase/fructose-2,6-bisphosphatase,PFK-2/FBPase-2)和促凋亡蛋白BAD等的调节。目前已发现多种GK激活剂,包括酰胺类、苯并咪唑类、喹唑啉类、脲类和吡啶类等,能够有效增强GK活性,改善多种糖尿病模型动物的血糖水平,且有些化合物已经进入Ⅰ期和Ⅱ期临床试验,将在2型糖尿病的治疗中发挥重要作用。

Glucokinase（GK） is the enzyme in the first step of the glycolysis,catalyzing the MgATP2——dependent phosphorylation of glucose.It mainly exists in hepatocytes and pancreatic beta-cells.It can promote glucose metabolism and insulin secretion,and plays an important role in glucose homeostasis.Its activity is regulated by several proteins,including glucokinase regulatory protein（GKRP）,6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase（PFK-2/FBPase-2）,and pro-apoptotic BAD.Many GK activators have been found,including amides,benzimidazoles,quinazolines,ureas,pyridines and so on,which potently increase GK activity and ameliorate blood glucose level in several diabetes animal models.Some GK activators are undergoing phase Ⅰand phase Ⅱ clinical trials.In the future,they may become an important part of the treatment of type 2 diabetes mellitus.