Lu Min, Li Pingping, Bandyopadhyay Gautam, Lagakos William, Dewolf Walter E, Alford Taylor, Chicarelli Mark Joseph, Williams Lance, Anderson Deborah A, Baer Brian R, McVean Maralee, Conn Marion, Véniant Murielle M, Coward Peter
Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Array BioPharma Inc., Boulder, Colorado, United States of America.
PLoS One. 2014 Feb 12;9(2):e88431. doi: 10.1371/journal.pone.0088431. eCollection 2014.
Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
葡萄糖激酶（GK）是一种己糖激酶同工酶，可催化葡萄糖磷酸化为6-磷酸葡萄糖。由于葡萄糖激酶激活剂对肝脏葡萄糖输出和/或胰岛素分泌有影响，因此正在作为潜在的糖尿病治疗方法进行研究。在此，我们研究了一种新型葡萄糖激酶激活剂GKA23的疗效和作用机制。在体外，GKA23增加了大鼠和小鼠葡萄糖激酶对葡萄糖的亲和力，并增加了原代大鼠肝细胞对葡萄糖的摄取。在体内，GKA23治疗通过增强β细胞胰岛素分泌和抑制肝脏葡萄糖生成来改善大鼠的葡萄糖稳态。对高脂饮食喂养的小鼠进行亚慢性GKA23治疗可改善葡萄糖稳态和脂质谱。
