Metformin-regulated glucose flux from the circulation to the intestinal lumen

Background: 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. Methods: 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. Results: 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. Conclusions: 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.