Mouse model of metformin-induced diarrhea. Issue 1 (25th March 2020)

• Record Type: Journal Article
• Authors: Takemori, Hiroshi; Hamamoto, Akie; Isogawa, Kenta; Ito, Masafumi; Takagi, Masanori; Morino, Hirofumi; Miura, Takanori; Oshida, Kyoichi; Shibata, Takashi
• Is Part Of: BMJ open diabetes research and care. Volume 8:Issue 1(2020)
• Publication Date: 2020-03-25
• Subjects: metformin -- diarrhea -- mouse model(s) -- oral antidiabetics; Diabetes -- Periodicals; 616.462005
• DOI: 10.1136/bmjdrc-2019-000898
• Languages: English
• ISSNs: 2052-4897

Abstract

Abstract : Objective: 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. Research design and methods: 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 ( db/db ) 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. Results: 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 db/db mice. A reduction in PCR signals for the Firmicutes group was associated with metformin-induced diarrhea. Wood creosote reduced diarrhea (high water-content) without affecting metformin's efficacy or enterobacterial flora levels. Conclusions: We have created the first animal model of metformin-induced diarrhea using db/db mice, which will provide better quality of life for patients suffering from diarrhea caused by metformin.