Grimsby Joseph, Sarabu Ramakanth, Corbett Wendy L, Haynes Nancy-Ellen, Bizzarro Fred T, Coffey John W, Guertin Kevin R, Hilliard Darryl W, Kester Robert F, Mahaney Paige E, Marcus Linda, Qi Lida, Spence Cheryl L, Tengi John, Magnuson Mark A, Chu Chang An, Dvorozniak Mark T, Matschinsky Franz M, Grippo Joseph F
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Science. 2003 Jul 18;301(5631):370-3. doi: 10.1126/science.1084073.
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
葡萄糖激酶（GK）通过催化葡萄糖在表达该酶的细胞（如胰岛β细胞和肝细胞）中的磷酸化作用，在全身葡萄糖稳态中发挥关键作用。我们描述了一类抗糖尿病药物，它们作为非必需的混合型葡萄糖激酶激活剂（GKAs），可增加GK的葡萄糖亲和力和最大反应速度（Vmax）。GKAs可增强肝脏葡萄糖代谢以及分离的啮齿动物胰岛中葡萄糖诱导的胰岛素分泌，这与GK在这两种细胞类型中的表达和功能一致。在几种2型糖尿病啮齿动物模型中，GKAs降低了血糖水平，改善了葡萄糖耐量试验结果，并增加了肝脏葡萄糖摄取。这些发现可能会促成糖尿病新药疗法的开发。
