标题：Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat
作者：Zhou, Xiaojun; Zhang, Rui; Zou, Zhiwei; Shen, Xue; Xie, Tianyue; Xu, Chunmei; Dong, Jianjun; Liao, Lin
作者机构：[Zhou, Xiaojun; Zhang, Rui; Xu, Chunmei; Liao, Lin] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Endocrinol, 16766 Jingshi Rd, Jinan 250000, Sha 更多
通讯作者：Liao, L;Dong, JJ
通讯作者地址：[Liao, L]Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Endocrinol, 16766 Jingshi Rd, Jinan 250000, Shandong, Peoples R China;[Dong, JJ]Shandong U 更多
来源：BRITISH JOURNAL OF PHARMACOLOGY
摘要：Background and Purpose Sulfonylureas (SUs) have been suggested to have an insulin-independent blood glucose-decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrapancreatic blood glucose-lowering activity in vivo. Experimental Approach Sulfonylurea receptor 1 deficient (SUR1(-/-)) rats were created by means of transcription activator-like effector nucleases (TALEN)-mediated gene targeting technology. Type 2 diabetic models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. These rats were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2 weeks. Key Results Glimepiride decreased blood glucose levels and increased insulin sensitivity without elevating insulin levels. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied by the activation of Akt in the liver. Moreover, glimepiride increased both total and membrane glucose transporter 4 (GLUT4) levels in muscle and fat, which might be attributed to insulin receptor-independent IRS1/Akt activation. Conclusion and Implications Glimepiride possesses an extrapancreatic blood glucose-lowering effect in vivo, which might be attributed to its direct effect on insulin-sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injections should not be excluded per se.