Metformin induces diarrhea in mice under over-eating conditions

Metformin, an oral medication for type 2 diabetes, causes severe diarrhea in approximately 5% of individuals with diabetes in Japan, leading them to discontinue treatment despite the drug efficacy, safety, and low economic burden. Given the absence of animal models for diarrhea, we previously proposed a mouse model for metformin-induced diarrhea using diabetic obese db/db mice. The diarrhea model exhibited elevated gene expression of glucagon-like peptide-1 (GLP-1), which was followed by increased expression of the Cl⁻ channel CFTR. However, it remains unclear which specific risk factors in the db/db mouse model are associated with the development of diarrhea. In this study, healthy C57BL/6 J mouse models with dietary modifications were used to replace db/db mice. Unexpectedly, C57BL/6 J mice fed diets containing 10% cellulose consumed more feed and gained weight more rapidly. Overnight fasting led to increased food intake once feeding resumed. The combination of these feeding conditions and metformin administration resulted in increased water content in their feces. Furthermore, the enhanced expression of GLP-1 and CFTR, the decrease in the abundance of the gut microbial Firmicutes family, and the alleviation of diarrhea symptoms by wood creosote share similarities with metformin-induced diarrhea in db/db mice. Although the administration of the GLP-1 receptor agonist Exendin-4 did not induce diarrhea in mice without metformin treatment, the GLP-1 receptor antagonist Exendin-3 (9-39) inhibited the development of diarrhea in mice treated with metformin. These results suggest that overeating, coupled with abnormal regulation of GLP-1 signaling, may be associated with an increased risk of metformin-induced diarrhea in mice.

The online version contains supplementary material available at 10.1007/s13340-025-00822-0.