Baker D J, Atkinson A M, Wilkinson G P, Coope G J, Charles A D, Leighton B
Br J Pharmacol. 2014 Apr;171(7):1629-41. doi: 10.1111/bph.12498.
The global heterozygous glucokinase (GK) knockout (gk(wt/del)) male mouse, fed on a high-fat (60% by energy) diet, has provided a robust and reproducible model of hyperglycaemia. This model could be highly relevant to some facets of human type 2 diabetes (T2D). We aimed to investigate the ability of standard therapeutic agents to lower blood glucose at translational doses, and to explore the glucose-lowering potential of novel glucokinase activators (GKAs) in this model.
We measured the ability of insulin, metformin, glipizide, exendin-4 and sitagliptin, after acute or repeat dose administration, to lower free-feeding glucose levels in gk(wt/del) mice. Further, we measured the ability of novel GKAs, GKA23, GKA71 and AZD6370 to control glucose either alone or in combination with some standard agents.
A single dose of insulin (1 unit·kg(-1)), metformin (150, 300 mg·kg(-1)), glipizide (0.1, 0.3 mg·kg(-1)), exendin-4 (2, 20 μg·kg(-1)) and GKAs reduced free-feeding glucose levels. Sitagliptin (10 mg·kg(-1)), metformin (300 mg·kg(-1)) and AZD6370 (30, 400 mg·kg(-1)) reduced glucose excursions on repeat dosing. At a supra-therapeutic dose (400 mg·kg(-1)), AZD6370 also lowered basal levels of glucose without inducing hypoglycaemia.
Standard glucose-lowering therapeutic agents demonstrated significant acute glucose lowering in male gk(wt/del) mice at doses corresponding to therapeutic free drug levels in man, suggesting the potential of these mice as a translatable model of human T2D. Novel GKAs also lowered glucose in this mouse model.
以高脂（能量的60%）饮食喂养的全球杂合型葡萄糖激酶（GK）基因敲除（gk(wt/del)）雄性小鼠，已成为一种可靠且可重复的高血糖模型。该模型可能与人类2型糖尿病（T2D）的某些方面高度相关。我们旨在研究标准治疗药物在转化剂量下降低血糖的能力，并探索新型葡萄糖激酶激活剂（GKA）在该模型中的降血糖潜力。
我们测量了胰岛素、二甲双胍、格列吡嗪、艾塞那肽 - 4和西他列汀在急性或重复给药后降低gk(wt/del)小鼠自由进食血糖水平的能力。此外，我们还测量了新型GKA（GKA23、GKA71和AZD6370）单独或与某些标准药物联合控制血糖的能力。
单剂量的胰岛素（1单位·kg(-1)）、二甲双胍（150、300mg·kg(-1)）、格列吡嗪（0.1、0.3mg·kg(-1)）、艾塞那肽 - 4（2、20μg·kg(-1)）和GKA可降低自由进食血糖水平。西他列汀（10mg·kg(-1)）、二甲双胍（300mg·kg(-1)）和AZD6370（30、400mg·kg(-1)）在重复给药时可降低血糖波动。在超治疗剂量（400mg·kg(-1)）下，AZD6370还可降低基础血糖水平且不诱发低血糖。
标准降血糖治疗药物在与人类治疗性游离药物水平相对应的剂量下，在雄性gk(wt/del)小鼠中显示出显著的急性降血糖作用，表明这些小鼠作为人类T2D可转化模型的潜力。新型GKA在该小鼠模型中也可降低血糖。
