Chikama Kotomi, Takemroi Hiroshi, Mizoguchi Momoka, Furukawa Saho, Terada Koutarou, Ito Masafumi, Hirano Hirotsugu, Miura Takanori, Doi Koichi, Horiya Megumi, Kato Takehiro, Yabe Daisuke, Shibata Takashi
Department of Life Science and Chemistry, Graduate School of Natural Science and Technology, Gifu University, Yanagido 1-1, Gifu, 501-1193 Japan.
Taiko Pharmaceutical Co., Ltd., Honnmachi 1-4-1, Nishiku, Osaka 550-0005 Japan.
Diabetol Int. 2025 Jun 5;16(3):568-579. doi: 10.1007/s13340-025-00822-0. eCollection 2025 Jul.
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 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 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 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 family, and the alleviation of diarrhea symptoms by wood creosote share similarities with metformin-induced diarrhea in 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.
二甲双胍是一种用于治疗2型糖尿病的口服药物，在日本约5%的糖尿病患者中会导致严重腹泻，尽管该药物疗效好、安全性高且经济负担低，但仍会使他们停药。由于缺乏腹泻的动物模型，我们之前提出了一种使用糖尿病肥胖小鼠的二甲双胍诱导腹泻的小鼠模型。腹泻模型中胰高血糖素样肽-1（GLP-1）的基因表达升高，随后氯离子通道CFTR的表达增加。然而，尚不清楚小鼠模型中哪些特定风险因素与腹泻的发生有关。在本研究中，使用经过饮食调整的健康C57BL/6 J小鼠模型来替代糖尿病肥胖小鼠。出乎意料的是，喂食含10%纤维素饮食的C57BL/6 J小鼠消耗更多饲料且体重增加更快。过夜禁食导致重新喂食后食物摄入量增加。这些喂食条件与二甲双胍给药相结合导致粪便含水量增加。此外，GLP-1和CFTR表达增强、肠道微生物家族丰度降低以及木馏油缓解腹泻症状与糖尿病肥胖小鼠中二甲双胍诱导的腹泻有相似之处。虽然给予GLP-1受体激动剂艾塞那肽-4在未用二甲双胍治疗的小鼠中未诱导腹泻，但GLP-1受体拮抗剂艾塞那肽-3（9-39）抑制了用二甲双胍治疗的小鼠腹泻的发生。这些结果表明，暴饮暴食与GLP-1信号异常调节可能与小鼠二甲双胍诱导腹泻的风险增加有关。
在线版本包含可在10.1007/s13340-025-00822-0获取的补充材料。
