June 12, 2020
Although metformin is the most widely prescribed medication for type 2 diabetes worldwide, and has been in use for more than 60 years, its mechanism of action has not been fully elucidated, say Yasuko Morita, MD, Kobe University, Japan, and colleagues in their article, published online June 3 in Diabetes Care.
But it is known to reduce gluconeogenesis in the liver and likely affects the gut microbiota, they note.
Experts told Medscape Medical News the new research will help provide a better understanding of how the drug works, although they noted study limitations and said more work is required to confirm the findings. In the meantime, the findings will not change their use of metformin, they noted.
Is Phenomenon Related to Glucose-Lowering Effect of Metformin?
Morita's team performed a retrospective analysis of 48 patients with type 2 diabetes who underwent whole-body positron emission tomography (PET)–magnetic resonance imaging (MRI) with a radioactive 18F-labeled fluorodeoxyglucose (18F-FDG) tracer to detect tumors (as tumors tend to take up more glucose than normal tissue).
They found that the patients receiving metformin had more 18F-FDG uptake in the intraluminal space of the intestine but not the intraluminal wall, compared with control patients who were not receiving metformin — which suggests that metformin promotes excretion of glucose from the circulation to stool.
However, the researchers acknowledge that study limitations include a relatively small sample size as well as possible unmeasured confounders and spillover of radioactive signals between the intestinal wall and intraluminal space.
Further study is needed, they write, to quantify metformin-induced glucose transport and determine "whether the phenomenon uncovered in the current study is related to the glucose-lowering effect of this drug."
"A prospective study with a nonroutine imaging method that allows the quantitative analysis of total absolute radioactivity in the intestine will be required to clarify the clinical relevance of this novel pharmacological phenomenon," the investigators conclude.
Better Understanding of How an Old Drug Works
Invited to comment, Vanita R. Aroda, MD, Brigham and Women's Hospital, Boston, Massachusetts, told Medscape Medical News in an email that the study "broadens our understanding that metformin may have benefits beyond just direct glucose control, possibly through interactions with the gut endocrine cells and system and through influencing the microbiome and intestinal flora."
A recent review of the mechanisms of action of metformin (Diabetologia 2017; 60:1577-1585) describes how a complex picture with multiple modes of action has emerged in the past decade, and how more work is needed to truly understand how the drug works in individuals with type 2 diabetes, she noted.
"While metformin has been shown to reduce hepatic glucose production, many of the mechanisms of potential benefit are still not clearly understood," Aroda added.
"Understanding the underlying mechanisms of metformin will help us understand its effects on the whole body, and the multiple comorbidities associated with diabetes, and perhaps shed light on additional novel targets of therapy in diabetes."
Also invited to comment, Alice Cheng, MD, of the University of Toronto, Ontario, Canada, told Medscape Medical News that metformin remains first-line therapy for people diagnosed with type 2 diabetes worldwide, "and I still use it in that way, although admittedly with initial combination with outcome-reducing therapy in those who need it."
"This new proposed mode of action will not change my clinical use [of metformin]," but the findings can be part of a conversation with patients about the way metformin is believed to work, Cheng said.
Cheng also pointed to the same study caveats that the authors noted, indicating that the results should be interpreted with caution.
"This [research] does not definitely prove that metformin promotes the release of glucose into stool," she said in an email, "but it is certainly suggestive and represents a novel use of imaging to answer mechanistic questions."
PET-MRI Enables Clearer Picture of Glucose Uptake in Intestine
With regard to the specific imaging used, Morita and colleagues explain that PET-computed tomography (PET-CT) with 18F-FDG provides sequential PET and CT images, and studies that use this type of imaging have shown metformin stimulates uptake of 18F-FDG in the intestine.
But it was not clear if uptake occurs in the intestinal wall or intraluminal space, they write.
With PET-MRI, the two types of images are obtained simultaneously, providing superior imaging, especially for organs that move.
The researchers identified 1246 patients who underwent whole body 18F-FDG PET-MRI to detect cancer at Kobe University Hospital between 2016 and 2018.
Of these, 244 patients had type 2 diabetes, including 50 patients who were receiving metformin.
After excluding patients who had stopped metformin 48 hours before the imaging test or had repeat scans or missing information, researchers matched the remaining 24 patients who were receiving metformin with 24 similar patients who were not.
The patients in each group were a mean age of 71 years, had a mean body mass index of 24.5 kg/m2, and had a mean A1c of 7.6%; 56% were men.
Compared with the other patients, those who were receiving metformin had significantly greater 18F-FDG uptake (greater radioactivity) inside the ileum and colon, but not the jejunum, "suggesting that the release of the tracer into the intraluminal space occurs not through biliary tracts but through the intestinal mucosa," Morita and colleagues write.
SGLT1 Transporters May Be Involved
The authors note that SGLT2 inhibitors "promote the transport of 10 to > 100 g of glucose per day into the urine."
Aroda explained that "there is no clear known connection between SGLT2 inhibitors' effect on the urine and metformin's effects of glucose in the intestine."
"However, of interest, there are SGLT1 transporters in intestinal cells (enterocytes) which take up glucose, and these enterocytes, through other transporters (eg, GLUT2)," as suggested by the authors, "may also have a role in the excretion of glucose into the intestinal lumen," she noted.
"Better understanding of all of these mechanisms," she said, "may help identify natural and pharmacologic synergies for the treatment of diabetes and its associated comorbidities."
Similarly, Cheng explained that "SGLT1 is expressed in the gut and is related to glucose transport. Some of the current antihyperglycemic therapies inhibit both SGLT1 and SGLT2. It is proposed that the inhibition of SGLT1 increases glucose delivery further down the intestines which may promote GLP-1 secretion and affect gut microbiota."
"Could this also be part of the mechanism through which metformin works?" she wondered rhetorically.
"There remains more research to be done to confirm the gut glucose properties of metformin, but this is certainly an interesting hypothesis."
Morita has reported no relevant financial relationships. Disclosures of the other authors are listed in the article. Aroda has reported acting as a consultant for Applied Therapeutics, Duke, Liberum, Medscape, Novo Nordisk, and Sanofi, and has received research support (institutional contracts) from Applied Therapeutics, Premier/Fractyl, Novo Nordisk, and Sanofi. Cheng has reported participating in speakers bureaus, advisory boards, and/or acting as a consultant for Abbott, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, Servier, and Takeda, and has received research support from Boehringer Ingelheim and Sanofi.