Department of Pharmacology & Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moraiya, Ahmedabad 382210, India.
Eur J Pharmacol. 2013 Aug 15;714(1-3):188-92. doi: 10.1016/j.ejphar.2013.06.015. Epub 2013 Jun 25.
The glucokinase activators improve the fasting as well as postprandial glucose control and are important investigational drugs for the treatment of diabetes. However, recent studies have implicated that continuous activation of glucokinase with a small molecule activator can increase hepatic triglycerides and the long term glucose control is not achieved. In this study, we investigated the effect of combination of glucokinase activator (GKA, Piragliatin) with GLP-1 receptor agonist exendin-4 (Ex-4) in male db/db mice. Twelve weeks combination treatment in the db/db mice resulted in a significant decrease in body weight gain, food consumption, random glucose and %HbA1c. The decrease in serum glucose and %HbA1c in combination group was more profound and significantly different than that of individual treatment (GKA or Ex-4) group. GKA treatment increased hepatic triglycerides, whereas combination of Ex-4 with GKA attenuated hepatic steatosis. The combination of GKA with Ex-4 reduced the hepatic lipid accumulation, improved the insulin sensitivity, and reduced hepatic glucose production in db/db mice. Overall, our data indicate that combination of GKA and GLP-1 receptor agonist Ex-4 improves glucose homeostasis, shows antiobesity activity, without causing harmful side effects like fatty liver.
葡萄糖激酶激活剂可改善空腹和餐后血糖控制，是治疗糖尿病的重要研究药物。然而，最近的研究表明，小分子激活剂持续激活葡萄糖激酶会增加肝内甘油三酯，并且无法长期控制血糖。在这项研究中，我们研究了葡萄糖激酶激活剂（GKA，吡格列汀）与 GLP-1 受体激动剂 exendin-4（Ex-4）联合治疗 db/db 雄性小鼠的效果。12 周的联合治疗使 db/db 小鼠的体重增加、食物消耗、随机血糖和%HbA1c 显著下降。与单独治疗（GKA 或 Ex-4）组相比，联合组的血清葡萄糖和%HbA1c 下降更为明显且差异显著。GKA 治疗会增加肝内甘油三酯，而 Ex-4 与 GKA 的联合使用则减轻了肝脂肪变性。GKA 与 Ex-4 的联合使用减少了肝内脂质堆积，改善了 db/db 小鼠的胰岛素敏感性，并降低了肝葡萄糖生成。总的来说，我们的数据表明，GKA 与 GLP-1 受体激动剂 Ex-4 的联合使用可改善葡萄糖稳态，具有抗肥胖活性，且不会产生肝脂肪变性等有害副作用。
