Allosteric activators of glucokinase: Potential role in diabetes therapy
Allosteric activators of glucokinase: Potential role in diabetes therapy
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DOI：
10.1126/science.1084073
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发表时间：
2003-07-18
期刊：
影响因子：
56.9
通讯作者：
Grippo, JF
中科院分区：
文献类型：
--
作者：
Grimsby, J;Sarabu, R;Grippo, JF
葡萄糖激酶（GK）通过催化表达该酶的细胞（如胰腺β细胞和肝细胞）中葡萄糖的磷酸化，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），可提高葡萄糖激酶的葡萄糖亲和力和最大反应速度（V-max）。GKAs增强了肝脏葡萄糖代谢以及从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是一致的。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的结果，并增加了肝脏对葡萄糖的摄取。这些发现可能会促使开发新的糖尿病药物疗法。
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 (V-max) 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.