New Technology Leads to Breakthrough in Metformin Mechanism of Action 

A new study shows that metformin may have a previously unknown mechanism of action that could lead to new and improved diabetes medications. 

Kobe University Graduate School of Medicine’s Professor Ogawa Wataru (the Division of Diabetes and Endocrinology) and Project Associate Professor Nogami Munenobu (the Department of Radiology) came together to utilize a newer form of imaging to study metformin’s mechanism of action. A new bio-imaging apparatus, called the PET-MRI, has improved researchers’ abilities to look at bodily structures that were not previously observable with PET-CT imaging (the previous mainstay of diabetes imaging research).  

FDG-PET is an imaging test that can show how much and where F.D.G. (fluorodeoxyglucose, a substance that acts similar to sugar) accumulates in the body after injection. Previously researchers used PET-CT imaging to look at F.D.G. accumulation. However, the new PET-MRI imaging device allows researchers to see more than they were able to with the C.T. portion. The PET-MRI unit is still very new, to the point that there are only nine available for use in all of Japan (where this research occurred). 

This research team utilized this new imaging device on patients with diabetes, some who were taking metformin and some who were not, and observed the movement of sugar throughout their bodies. The team found that sugar slowly accumulated in the intestines of patients taking metformin. The team then investigated the intestinal wall and the inside of the intestines via stools “and other contents” to fully understand where the sugar was accumulating. Through these tests, they found that the patients taking metformin had more sugar accumulation “in the areas inside the intestine that are distal to the ileum (the anal side part of the small intestine).” However, they did not observe any difference between the two patient groups in sugar accumulation in the intestinal wall. 

These observed results show that metformin use results in the release of sugars in the blood from the intestines into the stool. Previous studies showed that metformin caused F.D.G. accumulation in the intestines with PET-CT imaging. These findings led to the assumption that this was just on the intestinal wall since C.T. scans could not show the inside of the intestines. It is also worth noting that it is a new finding that the intestines excrete sugar into the stools.  

Based on this research, researchers believe metformin alters the intestinal flora to create its blood sugar-lowering effects, but how it alters the flora is still a mystery. Because sugar consumption and exposure can affect bacterial growth, metformin’s ability to draw sugar into the intestine may be related to the changes in the intestinal flora. Further research is likely needed, though, to get a full picture of what is happening to the flora of the intestine. 

This new information gives us further insight into how we can lower the blood sugar of patients with diabetes. We may see new drugs developed around this mechanism now that we have a deeper understanding of how metformin treats high blood sugars. The author of this review notes the similarities of this mechanism to that of SGLT2 inhibitors, and how this may be important in future studies to obtain a deeper understanding of how glucose excretion occurs through stools in patients taking metformin. The researchers were also unable to see how much glucose was excreted through these patients’ stools, so further research may be warranted here to maximize the extraction of blood sugars if the development of new medications using this mechanism will occur. As a whole, though, these findings are fascinating and provide a new understanding of metformin, and also provide an opportunity to develop new and improved diabetes medications. 

Practice Pearls: 

• The new imaging technology of the PET-MRI device was able to show a previously unknown mechanism of action for metformin in diabetes treatment, in excreting blood sugars in patients’ stools. 
• This new finding may make it possible to begin the development of a new drug that enhances this mechanism of action. 
• Further research is needed to determine the amount of glucose excreted via stools and the significance of this mechanism of action overall.  

Reference for “New Technology Leads to Breakthrough in Metformin Mechanism of Action”:
Kobe University, “A New Method of Action for an Older Anti-Diabetic Drug Discovered.” Medical Press, June 3, 2020, https://medicalxpress.com/news/2020-06-method-action-older-anti-diabetic-drug.html. 

Jacob Roberts, 2021 PharmD. Candidate, University of Colorado Denver Skaggs School of Pharmacy and Pharmaceutical Sciences 

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