Diabetology International
https://doi.org/10.1007/s13340-021-00545-y

COMMENTARY

Metformin action in the gut―insight provided by ­[18F]FDG PET
imaging
Hitomi Tsuchida1 · Yasuko Morita1 · Munenobu Nogami2 · Wataru Ogawa1
Received: 30 August 2021
© The Japan Diabetes Society 2021

Abstract
Suppression of hepatic gluconeogenesis is thought to largely underlie the antidiabetes action of metformin. However, thisdrug also exerts various effects on the gut, one of which is the enhancement of the uptake of 18F-labeled fluorodeoxyglucose(FDG), a nonmetabolizable glucose derivative, during [­ 18F]FDG positron emission tomography (PET)–computed tomography(CT). Whereas the relevance of this effect to the glucose-lowering action of metformin remains unclear, it is of special interest
because it was discovered in humans. Cessation of metformin treatment for several days is required to normalize ­[18F]FDG
uptake in the intestine, suggesting that the enhanced uptake is not a direct effect of the drug in the circulation but rather a
prolonged secondary effect. A recent study with state-of-the-art PET–magnetic resonance imaging (MRI), which provides
better tissue registration and soft-tissue contrast compared with PET-CT, revealed that metformin-induced accumulationof ­[18F]FDG occurs primarily in the lumen of the intestine, indicating that the drug promotes excretion of glucose from thecirculation into this space. This phenomenon does not necessarily imply that metformin stimulates the removal of glucose
from the body in the stool. Instead, it might be related to changes in the abundance and metabolism of the gut microbiota
induced by metformin. Further studies of this effect of metformin might shed light on the unanswered questions that still
remain concerning the clinical action of this old drug.
Keywords Metformin · Intestine · FDG PET · Glucose excretion · PET-MRI · Gut microbiota

Introduction
Whereas suppression of gluconeogenesis in the liver appears
to be of primary importance for the hypoglycemic effect of
metformin [1–4], the entire picture of the pharmacologicalaction of this drug remains unclear. One ambiguity in thisregard is that the half-life of metformin in the circulation isshort, on the order of 2.0 to 6.0 h [5], which is inconsistent
with the impression of clinicians for glucose-lowering effectof this drug, suggestive of the operation of a mechanism(or mechanisms) independent of the drug concentration in
the circulation. Given that orally administered metformin* Wataru Ogawa
ogawa@med.kobe-u.ac.jp
1

Division of Diabetes and Endocrinology, Department
of Internal Medicine, Kobe University Graduate Schoolof Medicine, 7‑5‑1 Kusunoki‑cho, Chuo‑ku, Kobe 650‑0017,
Japan

2

Department of Radiology, Kobe University Graduate Schoolof Medicine, Kobe, Japanremains in the intestine for a relatively long period [6],pharmacological effects on the intestine may explain thisinconsistency. Several effects of metformin on the intestine have been identified, including suppression of glucose
absorption [7, 8], changes in the intestinal flora [9–11],
increased secretion of humoral factors such as glucagonlike peptide–1 (GLP-1) [12–14] and growth/differentiation
factor 15 (GDF15) [15, 16], and stimulation of neural signaling at the duodenum that also results in the inhibition ofhepatic glucose production [17]. How and to what extent
these effects on the gut are responsible for the antidiabetes
action of metformin remain unknown, however.
Positron emission tomography (PET)–computed tomography (CT) with 18F-labeled fluorodeoxyglucose ­([18F]FDG), a
nonmetabolizable glucose derivative, is widely performed todetect malignancy or inflammation, which are associated withincreased uptake of glucose, and hence of [­ 18F]FDG, compared with normal tissues. In 2008, Gontier et al. found thatthe uptake of [­ 18F]FDG in the intestine was enhanced in individuals treated with metformin [18], an observation that was
subsequently confirmed by many other investigators [19, 20]

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and which indicated that metformin promotes the accumulation of glucose in the intestine. Whereas neither the underlying
mechanism of this effect nor its relevance to the antidiabetes
action of metformin is yet fully understood, the finding that
metformin affects glucose handling in the intestine is of particular interest in that it was discovered in humans, whereas
many effects of the drug have been identified and characterized in animals and not validated in humans. In this article, wesummarize findings concerning metformin action in the gut asrevealed by ­[18F]FDG PET.

Antidiabetes medications and intestinal ­[18F]
FDG uptake during [­ 18F]FDG PET‑CT
As the application of ­[18F]FDG PET to the detection of malignant tumors became more common, radiologists noticed thatsome individuals with type 2 diabetes manifested nonpathological enhancement of [­ 18F]FDG uptake in the intestine. Gontier et al. first investigated the relation between treatment withantidiabetes drugs and ­[18F]FDG uptake in individuals who
underwent ­[18F]FDG PET-CT [18]. They thus performed aprospective study to compare [­ 18F]FDG uptake in the intestine
between nondiabetic subjects and patients with type 2 diabetes
treated with or without metformin. They found that intestinal­[18F]FDG uptake was greater in type 2 diabetic patients treatedwith metformin than in those treated without metformin or
in the nondiabetic subjects. This enhanced accumulation of­[18F]FDG in the metformin-treated individuals was observedin both the small and large intestine [18] (Fig. 1).
A subsequent retrospective analysis of ­[18F]FDG PET-CT
images of diabetic and nondiabetic subjects revealed that
metformin use was associated with enhanced accumulationof ­[18F]FDG in all compartments of the intestine analyzed(whole colon, ileum, cecum, and transverse, descending,and sigmoid colon), whereas sulfonylurea administration
was associated with enhanced ­[18F]FDG accumulation in
the ileum and transverse colon [19]. A randomized controlled study confirmed the stimulatory effect of metforminon intestinal ­[18F]FDG uptake. Koffert et al. thus randomly
assigned newly diagnosed type 2 diabetic subjects to groups
treated with metformin, rosiglitazone, or placebo and subjected these individuals to ­[18F]FDG PET-CT before and26 weeks after the onset of treatment [20]. They found thattreatment with metformin increased ­[18F]FDG accumulationin the small and large intestine by a factor of 2 and 3, respectively, whereas rosiglitazone induced only a small increase(~ 15%) in ­[18F]FDG accumulation in the small intestine.

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Fig. 1  Representative ­[18F]FDG PET-MRI image of a metformintreated individual. The image was obtained from a 56-year-old man
with type 2 diabetes who was taking 1,500 mg of metformin daily.
Arrows with vertical stripes indicate the ascending colon, blackarrows the transverse colon, white arrows the descending colon, horizontal-striped arrows the ileum, the dotted arrow the sigmoid colon,
the grey arrow the bladder, and the white circle the terminal ileum

Discontinuation of metformin and intestinal­[18F]FDG accumulation
Given that exaggerated ­[18F]FDG uptake hinders accurate
image evaluation, the effect of discontinuation of metforminon such uptake was studied. Özülker et al. performed ­[18F]
FDG PET-CT with the same type 2 diabetic individuals on
two separate occasions: during treatment with metformin
and after cessation of the drug for 3 days [21]. The uptakeof ­[18F]FDG in both the small and large intestine as assessedby a visual score was reduced after cessation of metformin
treatment. Compartment-specific analysis based on the maximum standardized uptake value (­ SUVmax), a semiquantitative index, revealed that [­ 18F]FDG uptake was decreased
after metformin cessation in the ileum and colon but notin the duodenum and jejunum. A prospective study also
showed that the high intestinal [­ 18F]FDG uptake in both thesmall and large intestine of individuals treated with metformin was markedly attenuated 2 days after drug cessation[22].
Lee et al. retrospectively analyzed ­[18F]FDG PET-CT
images of type 2 diabetic subjects obtained < 24 h, 24 to
48 h, or 48 to 72 h after cessation of metformin treatment
and compared the intestinal ­[18F]FDG uptake of thesesubjects with that of control individuals who did not take

Metformin action in the gut―insight provided by [­ 18F]FDG PET imaging﻿	

metformin [23]. Compared with that in the control subjects,­[18F]FDG uptake was enhanced from the ileum to the rectosigmoid colon, from the transverse to the rectosigmoid
colon, and from the descending to the rectosigmoid colon in
the individuals who had stopped metformin administrationfor < 24 h, 24 to 48 h, or 48 to 72 h, respectively. Schreuder
et al. found that [­ 18F]FDG uptake in the descending and rectosigmoid colon of type 2 diabetic subjects who had stopped
metformin for > 48 h (but < 72 h) was still greater than thatfor individuals not treated with metformin, with the uptake
in the transverse and rectosigmoid colon being greater insubjects who had stopped metformin for < 48 h than in those
who had stopped the drug for > 48 h [24].
The normalization of [­ 18F]FDG uptake observed after
cessation of metformin administration thus provided additional evidence that the enhanced uptake apparent in metformin-treated individuals is triggered by the drug. However, the finding that such normalization remains incomplete
for up to 72 h after drug discontinuation indicates that theenhancement of [­ 18F]FDG uptake is the result not of a direct
effect of metformin in the circulation but of an unidentified and prolonged secondary effect of the drug. How longit takes metformin to induce this intestinal effect remains
unknown. Whereas administration of the drug for 26 weeks
enhanced ­[18F]FDG uptake in the intestine [20], no humanstudy has been performed with a shorter administration
period. Metformin administration in drinking water for 48 h
had no effect on intestinal [­ 18F]FDG uptake in mice, whereasthat for 1 month did enhance the uptake [25].

thus indicated that intravenously administered [­ 18F]FDG istransferred into the intestinal lumen. In addition, Gontier
et al. showed that the accumulation of [­ 18F]FDG in subjects taking metformin was localized, at least in part, to theintestinal lumen [18]. However, it is difficult to accurately
discriminate ­[18F]FDG accumulation in the intestinal wallfrom that in the lumen by PET-CT, given that the PET and
CT images are obtained sequentially and the occurrence of
peristalsis hinders their precise superposition.
PET–magnetic resonance imaging (MRI) is a recently
introduced imaging modality that enables simultaneous acquisition of metabolic information with PET andmorphological information with high soft-tissue contrast
by MRI. PET-MRI thus yields an accurate registration
between PET and MRI images [30] and offers diagnostic
advantages over PET-CT for the organs that move suchas heart, lungs, liver, digestive tracts and skin [31]. Taking advantage of the benefits of PET-MRI, we studied theaccumulation of ­[18F]FDG, with discrimination between
the intestinal wall and lumen, in diabetic individuals [32](Fig. 2). We found that [­ 18F]FDG accumulation in thelumen of the ileum and the right and left hemicolon was
greater in subjects treated with metformin than in those
not treated with the drug. In contrast, ­[18F]FDG accumulation in the wall of any compartment of the intestine examined did not differ significantly between the two treatmentgroups [32]. Further examination of the relation between­[18F]FDG accumulation in the intestinal lumen and various
clinical parameters of subjects who underwent PET-MRI
after taking metformin revealed that the dose of metformin

Compartment of ­[18F]FDG accumulationin the intestinal tract: wall or lumen?
Animal experiments have shown that treatment with metformin stimulates glucose utilization in the small intestine
via anaerobic metabolism [26]. Moreover, lactic acid production in the portal vein is increased in humans taking
metformin [27]. These observations suggested that metformin might increase the uptake and utilization of glucose
in enterocytes, and that the enhanced accumulation of [­ 18F]
FDG detected in the intestine of metformin-treated individuals by PET-CT reflects glucose uptake by these cells.
Treatment with metformin was indeed found to result in theaccumulation of ­[18F]FDG in the wall of the small intestinein rats [20].
In human studies, repeat acquisition of ­[18F]FDG PETCT images after ingestion of food revealed that radioactivity in the intestine appeared to move along the intestinal
tract [28], and feces obtained after such imaging were
found to contain radioactivity at a level corresponding to
3.8% to 54.5% of that in blood [29]. These observations

Fig. 2  Representative images of FDG accumulation at the wall andlumen of the intestine obtained with [­ 18F]FDG PET-MRI. The image
was obtained from the same individual described in Fig. 1. The color
scale on the left side of the images represents SUV range between
1.0 and 10.0. White arrows indicate the intestinal wall and horizontalstriped arrows the intestinal lumen

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H. Tsuchida et al.

was positively correlated with luminal ­[18F]FDG accumulation in the large intestine [33].

Glucose in the intestinal lumen―How doesit arrive and where does it go?
The study by Morita et al. [32] suggested that metformin
stimulates the excretion of glucose into the intestinal
lumen (the compartment containing stool). This phenomenon is thus similar to the excretion of glucose from thebody into urine stimulated by SGLT2 (sodium-glucose
cotransporter 2) inhibitors. However, it is unlikely that all
the glucose excreted into the intestinal lumen is passed out
from the body in the stool. When glucose is administeredinto the large intestine, it is not absorbed as glucose but asmetabolites generated by gut microbiota [34]. Short-chain
fatty acids (SCFAs) are key molecules in the symbiotic
relation between the host and gut microbiota, and theyexert various physiological actions including beneficial
effects on host metabolism [35]. Metformin administration has been shown to increase the amount of SCFAs
in stool [11] or serum [36], although the mechanism bywhich metformin affects SCFA production is unknown. It
is possible that glucose excreted into the intestinal lumen
in response to metformin treatment serves as a substrate
for and thereby increases SCFA production by the gut
microbiota [37]. Moreover, given that changes in energy
source affect the composition of the intestinal flora [35],the excretion of glucose into the intestinal lumen might

Fig. 3  Possible effects of
metformin-induced glucose
excretion into the intestinal
lumen. Glucose excretion into
the intestinal lumen induced by
metformin may contribute toenergy loss and changes in theabundance and metabolism of
the gut microbiota, and thereby
to the effects of the drug on hostmetabolism

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contribute to the metformin-induced changes in such composition (Fig. 3).
The mechanism by which glucose is excreted into theintestinal lumen in response to metformin administrationis unknown. In general, ingested glucose is taken up byenterocytes via SGLT1 expressed at the apical surface of
these cells and is then transported from the cells to thecirculation by glucose transporter 2 (GLUT2) expressed at
the basolateral surface. However, exposure of enterocytes
to high glucose concentrations in the intestinal lumen
induces the translocation of GLUT2 to the apical surfaceof the cells, which likely contributes to the efficient uptakeof large amounts of glucose after meals [38]. Of note,
metformin has also been shown to promote the translocation of GLUT2 to the apical surface of enterocytes bothin vivo [39] and ex vivo [40] in a manner dependent on
5'-AMP–dependent protein kinase (AMPK) [41]. Given
that the glucose transport activity of GLUT2 is bidirectional, the metformin-induced translocation of GLUT2 tothe apical surface of enterocytes might contribute to glucose excretion into the intestinal lumen. A recent study
revealed that Roux-en-Y gastric bypass, a widely adopted
bariatric-metabolic surgery, promoted glucose excretion into the intraluminal space of the intestine in rats,
an effect likely mediated by up-regulation of GLUT1 inenterocytes [42]. GLUT1 might thus also participate in the
glucose excretion into the intraluminal space induced by
metformin. Whichever GLUT isoform is involved in thisprocess, the transport mode of each is passive and dependent on the concentration gradient of glucose. An amountof glucose sufficient to generate a concentration gradientwould thus need to be transferred from the circulation toenterocytes to support glucose excretion into the intestinal

Metformin action in the gut―insight provided by [­ 18F]FDG PET imaging﻿	

lumen, but the mechanism responsible for the establishment of such a gradient remains unknown.

Conclusion
More than a decade after the discovery that metformin
induces the accumulation of ­[ 18F]FDG in the intestine,
the application of PET-MRI, a state-of-the-art imaging
modality, showed that the drug promotes excretion of the
glucose derivative into the intestinal lumen. Althoughmany questions remain regarding the clinical relevance of
this phenomenon, it is of special interest because it was
discovered and has been characterized in humans. Given
that metformin increases luminal glucose accumulationin the large intestine [32, 33] and that the large intestine
contains much greater abundance and diversity of microbiota than other compartments of the gastrointestinal tract[43], it is possible that metformin influences the functionsof gut microbiota through the effect. Further studies are
warranted to provide greater insight into various aspectsof metformin treatment, including the apparent inconsistency between the duration of its clinical action and its
pharmacokinetics as well as the mechanisms by which it
affects the abundance and metabolism of the gut microbiota and additional mechanisms by which it modulates
glucose metabolism.

Declarations
Conflicts of interest WO has received lecture fees from DainipponSumitomo Pharma, Novartis, Nippon Boehringer Ingelheim, Takeda
Pharmaceutical, Mitsubishi Tanabe Pharma, and Abbott Japan aswell as research funding from Noster, Nippon Boehringer Ingelheim,
Boehringer Ingelheim Pharma GmbH & Co. KG, Nippon Eli-Lilly,
Novo Nordisk Pharma, Abbott Japan, Abbott Diabetes Care UK Ltd,
Dainippon-Sumitomo Pharma. WO has received subsidies or donations
from Kowa Pharmaceutical, Novo Nordisk Pharma, Astellas, Dainippon-Sumitomo Pharma, Ono Pharmaceutical, Takeda Pharmaceutical,
Abbott Japan, Novartis, Daiichi Sankyo, Nippon Eli-Lilly, Mitsubishi
Tanabe Pharma, Nippon Boehringer Ingelheim. The remaining authors(HT, YM, and MN) declare that they have no conflict of interest.
Research Involving Human Participants and/or Animals This article
does not contain any studies with human or animal subjects performedby any of the authors.

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