Takasu Toshiyuki, Hayashizaki Yuka, Tahara Atsuo, Kurosaki Eiji, Takakura Shoji
Tsukuba Research Center, Drug Discovery Research, Astellas Pharma, Tsukuba, Ibaraki, Japan.
Clin Exp Pharmacol Physiol. 2015 Jan;42(1):87-93. doi: 10.1111/1440-1681.12317.
Inhibition of sodium-glucose cotransporter 2 is a novel strategy for glycemic control in type 2 diabetes mellitus patients. As the mechanism of action of sodium-glucose cotransporter 2 inhibitors on plasma glucose levels is distinct from that of existing oral antidiabetic drugs, a combination of the two might provide a therapeutic benefit. Here, we investigated the antihyperglycemic effect of ipragliflozin, a selective sodium-glucose cotransporter 2 inhibitor, alone or in combination with oral antidiabetic drugs in a range of relevant mouse models to analyse the blood glucose-lowering properties of different drug types based on their mechanism of action. Oral glucose tolerance tests in ICR mice were used to evaluate the effect of ipragliflozin in combination with the insulin secretagogues, glibenclamide or nateglinide. Liquid meal tests in ICR mice and diabetic KK-A(y) mice were used to investigate the combined effect of ipragliflozin with the dipeptidyl peptidase-4 inhibitor, sitagliptin, and α-glucosidase inhibitor, voglibose, respectively. Four-week repeated administration tests in KK-A(y) mice were used to examine the combined effect of ipragliflozin with the insulin sensitizers, pioglitazone and metformin. In all mouse models tested, the combination of ipragliflozin and existing oral antidiabetic drugs lowered blood glucose or glycated hemoglobin levels more than either monotherapy. In conclusion, inhibition of sodium-glucose cotransporter 2 by ipragliflozin, alone or in combination with existing oral antidiabetic drugs, has a robust effect on blood glucose levels in a range of mouse models of hyperglycemia.
抑制钠-葡萄糖协同转运蛋白2是2型糖尿病患者血糖控制的一种新策略。由于钠-葡萄糖协同转运蛋白2抑制剂对血糖水平的作用机制与现有口服抗糖尿病药物不同，两者联合使用可能会带来治疗益处。在此，我们研究了选择性钠-葡萄糖协同转运蛋白2抑制剂依帕列净单独或与口服抗糖尿病药物联合使用在一系列相关小鼠模型中的降血糖作用，以根据不同药物类型的作用机制分析其降血糖特性。利用ICR小鼠的口服葡萄糖耐量试验评估依帕列净与胰岛素促泌剂格列本脲或那格列奈联合使用的效果。分别利用ICR小鼠和糖尿病KK-A(y)小鼠的液体餐试验研究依帕列净与二肽基肽酶-4抑制剂西他列汀和α-葡萄糖苷酶抑制剂伏格列波糖联合使用的效果。利用KK-A(y)小鼠进行的为期四周的重复给药试验研究依帕列净与胰岛素增敏剂吡格列酮和二甲双胍联合使用的效果。在所有测试的小鼠模型中，依帕列净与现有口服抗糖尿病药物联合使用比单一疗法更能降低血糖或糖化血红蛋白水平。总之，依帕列净单独或与现有口服抗糖尿病药物联合使用抑制钠-葡萄糖协同转运蛋白2，在一系列高血糖小鼠模型中对血糖水平具有显著作用。
