Mouse model of metformin-induced diarrhea.

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.

• Authors: Hiroshi Takemori, Akie Hamamoto, Kenta Isogawa, Masafumi Ito, Masanori Takagi, Hirofumi Morino, Takanori Miura, Kyoichi Oshida, Takashi Shibata
• Journal: BMJ open diabetes research & care (BMJ Open Diabetes Res Care) Vol. 8 Issue 1 (03 2020) ISSN: 2052-4897 [Electronic] England
• PMID: 32213489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Hypoglycemic Agents
• Metformin

Topics

• Animals
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Diarrhea (chemically induced, drug therapy)
• Humans
• Hypoglycemic Agents
• Metformin
• Mice
• Mice, Inbred C57BL
• Quality of Life