Takemori Hiroshi, Hamamoto Akie, Isogawa Kenta, Ito Masafumi, Takagi Masanori, Morino Hirofumi, Miura Takanori, Oshida Kyoichi, Shibata Takashi
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan
Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Gifu, Japan.
BMJ Open Diabetes Res Care. 2020 Mar;8(1). doi: 10.1136/bmjdrc-2019-000898.
Metformin, an oral medication used for type 2 diabetes mellitus, is the most commonly prescribed drug with less economic burden of patients. Although metformin's efficacy and safety have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea as an adverse effect and have to abandon treatment. Because there is no animal model to study metformin-induced diarrhea, it is hard to develop methods to maintain quality of life of patients prescribed with metformin.
Using mouse models, we tried to develop an evaluation system for metformin-induced diarrhea to improve diarrheal symptoms in patients with diabetes. Healthy (C57BL/6J) and diabetic obese () mice were subjected to a stepwise dose escalation of metformin (250 mg/kg/day (125 mg/kg twice daily oral dose)-1000 mg/kg/day (500 mg/kg twice daily oral dose)), and fecal moisture contents and their score were monitored. To evaluate anti-diarrheal medications, wood creosote (a traditional medicine) was tested. Several groups of enterobacteria in fresh feces were examined by using PCR.
1000 mg/kg/day (four times maximal effective dose) of metformin significantly increased fecal moisture content. Although no symptoms of diarrhea were observed in healthy C57BL/6J mice, the same dose of metformin induced severe diarrhea in diabetic obese mice. A reduction in PCR signals for the group was associated with metformin-induced diarrhea. Wood creosote reduced diarrhea (high water-content) without affecting metformin's efficacy or enterobacterial flora levels.
We have created the first animal model of metformin-induced diarrhea using mice, which will provide better quality of life for patients suffering from diarrhea caused by metformin.
二甲双胍是一种用于治疗2型糖尿病的口服药物，是最常用的处方药，患者经济负担较小。尽管二甲双胍的疗效和安全性早已得到认可，但约5%接受该药物治疗的患者会出现严重腹泻这一不良反应，不得不放弃治疗。由于没有动物模型来研究二甲双胍引起的腹泻，因此很难开发出维持服用二甲双胍患者生活质量的方法。
我们使用小鼠模型，试图开发一种二甲双胍诱导腹泻的评估系统，以改善糖尿病患者的腹泻症状。对健康的（C57BL/6J）和糖尿病肥胖（）小鼠进行二甲双胍剂量逐步递增（250mg/kg/天（125mg/kg每日两次口服剂量）-1000mg/kg/天（500mg/kg每日两次口服剂量）），并监测粪便水分含量及其评分。为了评估止泻药物，测试了木馏油（一种传统药物）。使用PCR检测新鲜粪便中的几组肠道细菌。
1000mg/kg/天（最大有效剂量的四倍）的二甲双胍显著增加了粪便水分含量。虽然在健康的C57BL/6J小鼠中未观察到腹泻症状，但相同剂量的二甲双胍在糖尿病肥胖小鼠中诱发了严重腹泻。组PCR信号的降低与二甲双胍诱导的腹泻有关。木馏油减少了腹泻（高含水量），而不影响二甲双胍的疗效或肠道菌群水平。
我们使用小鼠创建了首个二甲双胍诱导腹泻的动物模型，这将为因二甲双胍引起腹泻的患者提供更好的生活质量。
