Baker D J, Wilkinson G P, Atkinson A M, Jones H B, Coghlan M, Charles A D, Leighton B
Br J Pharmacol. 2014 Apr;171(7):1642-54. doi: 10.1111/bph.12504.
Pharmacological activation of glucokinase (GK) lowers blood glucose in animal models and humans, confirming proof of concept for this mechanism. However, recent clinical evidence from chronic studies suggests that the glucose-lowering effects mediated by glucokinase activators (GKAs) are not maintained in patients with type 2 diabetes (T2D). Existing preclinical data with GKAs do not explain this loss of sustained glucose-lowering efficacy in patients. Here, we have assessed the effects of chronic (up to 11 months) treatment with two different GKAs in two models of T2D.
Two validated animal models of T2D, insulin-resistant obese Zucker rats and hyperglycaemic gk(wt/del) mice, were treated with two different GKAs for 1 or 11 months respectively at exposures that translate to clinical exposures in humans. Blood glucose, cholesterol, triglycerides and insulin were measured. GKA pharmacokinetics were also determined.
Treatment with either GKA provided sustained lowering of blood glucose for up to 1 month in the Zucker rat and up to 11 months in hyperglycaemic gk(wt/del) mice, with maintained compound exposures. This efficacy was achieved without increases in plasma or hepatic triglycerides, accumulation of hepatic glycogen or impairment of glucose-stimulated insulin secretion.
Chronic treatment with two GKAs in two animal models of diabetes provided sustained lowering of blood glucose, in marked contrast to clinical findings. Therefore, either these animal models of T2D are not good predictors of responses in human T2D or we need a better understanding of the consequences of GK activation in humans.
在动物模型和人类中，葡萄糖激酶（GK）的药理学激活可降低血糖，证实了该机制的概念验证。然而，近期慢性研究的临床证据表明，葡萄糖激酶激活剂（GKA）介导的降糖作用在2型糖尿病（T2D）患者中无法持续。现有的GKA临床前数据无法解释患者中这种持续降糖疗效的丧失。在此，我们评估了两种不同的GKA在两种T2D模型中进行长达11个月的慢性治疗的效果。
两种经过验证的T2D动物模型，即胰岛素抵抗的肥胖Zucker大鼠和高血糖gk（wt/del）小鼠，分别用两种不同的GKA进行治疗，治疗时间分别为1个月或11个月，给药剂量相当于人类临床用药剂量。测量血糖、胆固醇、甘油三酯和胰岛素水平。同时也测定了GKA的药代动力学。
在Zucker大鼠中，使用任何一种GKA治疗均可使血糖持续降低长达1个月，在高血糖gk（wt/del）小鼠中可长达11个月，且化合物暴露量保持稳定。在不增加血浆或肝脏甘油三酯、不积累肝糖原或不损害葡萄糖刺激的胰岛素分泌的情况下达到了这种疗效。
在两种糖尿病动物模型中使用两种GKA进行慢性治疗可使血糖持续降低，这与临床研究结果形成显著对比。因此，要么这些T2D动物模型不能很好地预测人类T2D的反应，要么我们需要更好地了解GK激活在人类中的后果。
