药学学报, 2019, 54(6): 1041-1047
引用本文:
王亚男, 张晓琳, 尹震, 田金英, 李雪晨, 叶菲. 双环醇对2型糖尿病KKAy小鼠治疗作用的实验研究[J]. 药学学报, 2019, 54(6): 1041-1047.
WANG Ya-nan, ZHANG Xiao-lin, YIN Zhen, TIAN Jin-ying, LI Xue-chen, YE Fei. Experimental study of bicyclol for type 2 diabetic treatment using KKAy mice[J]. Acta Pharmaceutica Sinica, 2019, 54(6): 1041-1047.

双环醇对2型糖尿病KKAy小鼠治疗作用的实验研究
王亚男, 张晓琳, 尹震, 田金英, 李雪晨, 叶菲
中国医学科学院、北京协和医学院药物研究所, 新药作用机制研究与药效评价北京市重点实验室, 北京 100050
摘要:
本研究旨在探讨化合物双环醇(bicyclol,By)对2型糖尿病(type 2 diabetes mellitus,T2DM)KKAy小鼠的治疗作用及其作用机制。实验采用雌性KKAy小鼠,灌胃给予双环醇(100、200、400 mg·kg-1·d-1)。阳性对照药为二甲双胍(200 mg·kg-1·d-1)。以空腹血糖水平、非禁食血糖水平、葡萄糖耐量等指标评价药物的控制血糖作用;以空腹血胰岛素水平、胰岛素抵抗指数(HOMA-IR)评价机体的胰岛素敏感性;以胰岛素刺激后胰岛素信号通路的激活评价肝组织对胰岛素的反应性;以蛋白质印记的方法检测肝组织的蛋白表达。动物实验过程遵循中国医学科学院动物伦理委员会的规定。结果显示,KKAy小鼠具有高血糖、胰岛素抵抗等典型的T2DM病理特征。给予双环醇治疗后,KKAy小鼠空腹血糖水平明显降低,并呈一定的剂量依赖性和时间依赖性。同时,其空腹血胰岛素水平、胰岛素抵抗指数值均明显降低;肝组织的胰岛素诱导的胰岛素信号通路的磷酸化水平明显上调,使p-IRβ/IRβ、p-Akt/Akt比值明显升高;糖异生关键蛋白FoxO1的磷酸化水平显著升高。推测双环醇可能通过改善KKAy小鼠全身和肝脏的胰岛素抵抗,抑制肝组织糖异生,从而发挥控制血糖的作用。未发现明显的双环醇对二甲双胍的降血糖作用的影响。
关键词:    双环醇      2型糖尿病      KKAy小鼠      胰岛素抵抗     
Experimental study of bicyclol for type 2 diabetic treatment using KKAy mice
WANG Ya-nan, ZHANG Xiao-lin, YIN Zhen, TIAN Jin-ying, LI Xue-chen, YE Fei
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
To investigate the effects of small molecule compound bicyclol on type 2 diabetes mellitus (T2DM) and its mechanism of action, KKAy mice were treated with various doses of bicyclol (100, 200, and 400 mg·kg-1·d-1) with metformin (200 mg·kg-1·d-1) as a positive control, respectively. Age-matched C57BL/6J mice were used as the non-diabetic control (Con). The effect on hyperglycemia was evaluated by the levels of no-fasting blood glucose, fasting blood glucose (FPG), and glucose tolerance. Whole body insulin sensitivity was evaluated by fasting plasma insulin (FPI) and homeostasis model assessment-insulin resistance (HOMA-IR). The hepatic response to insulin was evaluated by insulin-induced activation of insulin signaling pathway. Western blot was performed to detect hepatic protein expressions. All animal experimental procedures were approved by the Animal Ethics Committee of Chinese Academy of Medical Sciences. KKAy mice showed T2DM characteristics such as hyperglycemia and insulin resistance, including attenuated response to insulin in the liver. A 28-day treatment of bicyclol suppressed both FPG and no-fasting blood glucose, in a dose-and time-dependent manner. Moreover, FPI and HOMA-IR values were both significantly decreased, and hepatic insulin-induced-phosphorylation of IRβ and Akt were up-regulated in KKAy mice after bicyclol treatment. Phosphorylation of FoxO1, the key transcription factor for regulating gluconeogenesis, was also significantly elevated by bicyclol treatment. These results suggested that bicyclol has some therapeutic effects on hyperglycemia in a time-and dose-dependent manner in KKAy mice. Its mechanism might be attributed to improving insulin resistance, enhancing hepatic insulin signaling pathway, and inhibiting gluconeogenesis. No significant interference on the hypoglycemic effect of metformin by bicyclol was observed in this study.
Key words:    bicyclol    type 2 diabetes    KKAy    insulin resistance   
收稿日期: 2019-01-25
DOI: 10.16438/j.0513-4870.2019-0086
基金项目: 国家“重大新药创制”科技重大专项(2012ZX09103-101-063,2018ZX09711001-003-005);国家自然科学基金青年科学基金项目(81600546,81703665);中国医学科学院医学与健康科技创新工程团队项目(CIFMS-2016-I2M-3-012).
通讯作者: 叶菲
Email: yefei@imm.ac.cn
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