BP Figure 3: Chronic attenuation in blood glucose lowering by AZD1656 in the P446L mouse despite sustained islet GK staining.

Experimental details were as in Figure 1. A) Similar blood glucose by genotype at the start (0 wk) of the 20 wk study and sustained blood glucose lowering by AZD1656 (3mg/kg) after 19 wk compared to 2 wk in wild-type (PP) but not in LL mice. B) Difference (delta ∆) in blood glucose by AZD1656 treatment after 2 wk (white stripe) and 19 wk (grey stripe) relative to start of study (0 wk) showing lower efficacy at 19 wk in LL mice. C) Lack of effect of AZD1656 on plasma insulin. D) Glucose tolerance test after 2h food withdrawal determined at 18wk: glucose excursion and area under the curve (AUC). E) Representative immunostaining of pancreas for insulin, glucagon and GK after 20 wk HFHSD -/+ AZD1656 in PP and LL mice. F) Pancreatic islet % area determined from insulin staining. G) Islet GK-staining intensity showing higher intensity by AZD1656 treatment in wild-type, PP mice. *P < 0.005 effect of AZD1656; #P < 0.05 effect of genotype; $P < 0.01; $$ P< 0.005 19 wk versus 2 wk.

实验细节详见图1。A) 在20周研究起始时（0周）按基因型测定的血糖水平相似，AZD1656（3mg/kg）在19周后持续降低血糖的效果，与野生型（PP）小鼠在2周时的效果相比，但在LL小鼠中并未观察到。B) 在2周（白条）和19周（灰条）的AZD1656治疗后相对于研究起始时（0周）的血糖变化（delta ∆），显示LL小鼠在19周时的疗效较低。C) AZD1656对血浆胰岛素无显著影响。D) 在18周食物禁食2小时后的葡萄糖耐量测试：血糖峰值和曲线下面积（AUC）。E) 在PP和LL小鼠中，经过20周HFHSD-/-AZD1656处理后胰腺对胰岛素、胰高血糖素和GK的代表性免疫染色。F) 从胰岛素染色中确定的胰腺胰岛百分比面积。G) 小岛GK染色强度显示野生型、PP小鼠在AZD1656治疗后染色强度更高。*P < 0.005为AZD1656的效果；#P < 0.05为基因型效果；$P < 0.01；$$P < 0.005为19周与2周的对比。