866-P: Quantitative Analysis of Metformin-Induced Glucose Excretion in the Intestine

Abstract

The enhancement of the uptake of 18F-labeled fluorodeoxyglucose (FDG) during [18F]FDG PET is a recently found metformin action in the gut. Taking advantage of PET-MRI, which provides better tissue registration and soft-tissue contrast than conventional PET-CT, we revealed that metformin enhanced FDG accumulation in the intestinal lumen. We now quantitatively analyzed the phenomenon with a newly developed protocol of PET-MRI. We also analyzed the intestinal glucose dynamics using 13C-labeled glucose and mass spectrometry in mice. We adopted imaging sequences of MR enterography to create 3D images of the intestinal tract, then superimposed the [18F]FDG PET images to obtain the 3D distribution of radioactivity. We conducted this test on type 2 diabetes subjects treated (N=5) or not (control, N=5) with metformin. Radioactivity was detected in the wall and lumen at similar extents in the control. However, in the metformin group, the radioactivity in the lumen, but not the wall, was three to four-fold greater than that in the control. We mathematically analyzed the data using a compartment model and calculated the glucose excretion rate (GER). GER of the control and metformin groups were 6.8 ± 1.2 mg/min and 26.1 ± 2.9 mg/min, respectively, the latter being comparable to glucose excretion into the urine induced by SGLT2 inhibitors. For mouse experiments, we intravenously injected 13C-glucose into C57/B6 mice and analyzed the feces 1 hour after injection with a gas chromatography-quadrupole mass spectrometry. We could not detect 13C-glucose in the feces, possibly because gut microbiota metabolizes glucose in the intestine. However, the content of 13C in short-chain fatty acids (SCFAs) was increased by the injection of 13C-glucose, and metformin augmented the incorporation of 13C into SCFAs. These results suggest that glucose in the circulation transfers to the intestinal lumen at a considerable rate and is metabolized by microbiota, at least partly, into SCFAs and that metformin augments the processes. Disclosure Y.Hosokawa: None. K.Sakaguchi: Research Support; Sumitomo Dainippon Pharma Co., Ltd. J.Ito: None. K.Sugawara: None. Y.Morita: None. W.Ogawa: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Novo Nordisk, Teijin Pharma Limited, Kowa Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Abbott Japan Co., Ltd., Speaker's Bureau; Sumitomo Dainippon Pharma Co., Ltd. Funding Japan Society for the Promotion of Science (21K08578, 22K18393)