Metformin-regulated glucose flux from the circulation to the intestinal lumen
Kazuhiko SAKAGUCHI, Kenji Sugawara, Yusei Hosokawa, Jun Ito, Yasuko Morita, Hiroshi Mizuma, Yasuyoshi Watanabe, Yuichi Kimura, Shunsuke Aburaya, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hisako Komada, Tomoko Yamada, Yushi Hirota, Masaru Yoshida, Munenobu Nogami, Takamichi Murakami, Wataru Ogawa
Abstract
Through a retrospective analysis of existing FDG PET-MRI images, we recently demonstrated that metformin increases the accumulation of FDG in the intestinal lumen, suggesting that metformin stimulates glucose excretion into the intestine. However, the details of this phenomenon remain unclear. We here investigate the detailed dynamics of intestinal glucose excretion, including the rate of excretion and the metabolism of excreted glucose, in both the presence and absence of metformin. We quantified intestinal glucose excretion using newly developed FDG PET-MRI-based bioimaging in individuals with type 2 diabetes, both treated and untreated with metformin. The metabolism of excreted glucose was analyzed through mass spectrometry of fecal samples from mice intravenously injected with 13C-labeled glucose. Continuous FDG PET/MRI image taking reveals that FDG is initially observed in the jejunum, suggesting its involvement in FDG excretion. Metformin-treated individuals excrete a significant amount of glucose (~1.65 g h–1 per body) into the intestinal lumen. In individuals not receiving metformin, a certain amount of glucose (~0.41 g h–1per body) is also excreted into the intestinal lumen, indicating its physiological importance. Intravenous injection of 13C-labeled glucose in mice increases the content of 13C in short-chain fatty acids (SCFAs) extracted from feces, and metformin increased the incorporation of 13C into SCFAs. A previously unrecognized, substantial flux of glucose from the circulation to the intestinal lumen exists, which likely contributes to the symbiosis between gut microbiota and the host. This flux represents a potential target of metformin’s action in humans. People with diabetes have high levels of a specific sugar, glucose, in the blood, which can cause health problems. Metformin is one of the most widely prescribed drugs to treat diabetes. However, it remains unclear how metformin works. We investigated metformin’s effect on glucose movement within the body. We found that more glucose moves inside the intestine in individuals taking metformin. The glucose is then digested by gut microbiota. These findings help us not only understand how metformin works but also reveal a relationship between humans and the gut microbiota which could be helpful for further development of diabetes treatments. Sakaguchi, Sugawara, Hosokawa, Ito, Morita, et al. quantify the effect of metformin on intestinal glucose excretion using fluorodeoxyglucose PET-MRI based bioimaging in individuals with type 2 diabetes. A substantial amount of glucose is excreted into the intestinal lumen, a process augmented by metformin, which is metabolized by gut microbiota into short-chain fatty acids.