Enhanced Release of Glucose into the Intraluminal Space of the Intestine Associated with Metformin Treatment as Revealed by [18F]Fluorodeoxyglucose PET-MRI

Abstract

<b>OBJECTIVE</b> <p>Positron emission tomography (PET)–computed tomography has revealed that metformin promotes the intestinal accumulation of [<sup>18</sup>F]fluorodeoxyglucose (FDG), a nonmetabolizable glucose derivative. It has remained unknown, however, whether this accumulation occurs in the wall or intraluminal space of the intestine. We here addressed this question with the use of [<sup>18</sup>F]FDG PET–magnetic resonance imaging (MRI), a recently developed imaging modality with increased accuracy of registration and high soft-tissue contrast.</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>Among 244 individuals with type 2 diabetes who underwent PET-MRI, we extracted 24 pairs of subjects matched for age, BMI, and HbA<sub>1c</sub> level who were (metformin group) or were not (control group) receiving treatment with metformin. We evaluated accumulation of [<sup>18</sup>F]FDG in different portions of the intestine with both a visual scale and measurement of maximum standardized uptake value (SUV<sub>max</sub>), and such accumulation within the intestinal wall or lumen was discriminated on the basis of SUV<sub>max</sub>.</p> <p><b>RESULTS</b></p> <p>SUV<sub>max</sub> of the jejunum, ileum, and right or left hemicolon was greater in the metformin group than in the control group. [<sup>18</sup>F]FDG accumulation in the ileum and right or left hemicolon as assessed with the visual scale was also greater in the metformin group. SUV<sub>max</sub> for the intraluminal space of the ileum and right or left hemicolon, but not that for the intestinal wall, was greater in the metformin group than in the control group.</p> <p><b>CONCLUSIONS</b></p> <p>Metformin treatment was associated with increased accumulation of [<sup>18</sup>F]FDG in the intraluminal space of the intestine, suggesting that this drug promotes the transport of glucose from the circulation into stool.</p>

Dose‐dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by 18F‐labelled fluorodeoxyglucose positron emission tomography‐MRI

“…Taking advantage of the newly developed imaging modality, PET-MRI, we recently showed that metformin treatment is associated with the accumulation of [ 18 F]FDG in the intestinal lumen. 19 In the current study, we show that the accumulation of [ 18 F]FDG in both the wall and lumen of the large intestine is correlated with the dose of metformin. Multivariable analysis also revealed that the dose of metformin was an explanatory factor for such [ 18 F]FDG accumulation after adjustment for potential confounders, whereas BMI, eGFR and BG at the time of examination appeared to influence [ 18 F]FDG accumulation in the wall, and eGFR and BG that in the lumen.…”

“…On the other hand, the accumulation of [ 18 F]FDG in the small intestine was not significantly correlated with any of the variables examined (Table 1), consistent with previous findings that metformin-induced accumulation of [ 18 F]FDG occurs primarily in the large intestine. 14,[19][20][21] SUV max Small r = −0.314 r = 0.082 r = 0.138 r = −0.099 r = −0.310 r = 0.095 P = .118 P = .692 P = .520 P = .631 P = .124 P = .644 Large r = −0.182 r = 0.243 r = 0.024 r = −0.363 r = −0.413 r = 0.552 P = .373 P = .231 P = .912 P = .069 P = .036 P = .003…”

“…Among 1246 individuals who underwent [ 18 F]FDG PET-MRI at Kobe University Hospital from April 2016 to August 2018, in most cases for the detection of tumours, 244 were found to have type 2 diabetes, and 50 of these 244 individuals were receiving treatment with metformin (Figure S1), as described previously. 19 Five, one and one of these 50 individuals were excluded from the study on account of their undergoing repeated PET-MRI examinations, insufficient medical information, or no information regarding the administered metformin dose, respectively. An additional 17 individuals were excluded because of the termination of metformin administration at least 48 hours before the PET-MRI examination, given that such termination markedly diminishes the effect of metformin on the accumulation of [ 18 F]FDG in the intestine.…”

“…Area 1 of the digestive tract was assumed to correspond to the intestinal wall-in particular, the muscle layer of the walland area 2 to intestinal fluid or stool, as described previously. 19 According to this analysis, SUV max was evaluated at both the intestinal wall and lumen in each region of the intestine. For the accumulation of [ 18 F]FDG in the small and the large intestine, the ileum as well as the jejunum, and the right as well as the left hemicolon, respectively, were analysed.…”

“…17,18 Taking advantage of the accurate registration and high soft tissue contrast of PET-MRI, we recently examined the precise location of the metformin-induced accumulation of [ 18 F]FDG in the human intestine, with distinction between the intestinal wall and lumen, and we found that such accumulation occurred in the intestinal lumen. 19 This finding indicated that metformin not only promotes the transfer of glucose from blood to intestinal cells but also the subsequent excretion of glucose into the intestinal lumen. Although the clinical relevance of this previously unrecognized action of metformin remains to be determined, it is possible that the release of glucose into the intestinal lumen is related to the lowering of blood glucose levels, the limitation of body weight gain, the changes to the gut microbiota, and the intestinal adverse effects triggered by metformin.…”