Until recently, the specific mechanism by which metformin, a medication for Type 2 diabetes that reduces blood sugar levels, operates remained ambiguous. A recent study has provided concrete evidence in mice that this medication temporarily diminishes a cell’s energy supply by disrupting mitochondria, effectively lowering glucose levels.
Across the globe, millions rely on metformin, a medication for Type 2 diabetes known for its ability to lower blood sugar. Dubbed a “wonder drug,” it also appears to inhibit cancer growth, enhance outcomes for COVID-19 patients, and reduce inflammation. However, until now, researchers have struggled to pinpoint its exact mode of action.
A novel study from Northwestern Medicine has established direct evidence in mice that metformin reversibly diminishes the energy production in cells by interfering with mitochondria, which are often called the “powerhouses” of the cell, thus lowering glucose levels.
Specifically, metformin targets a crucial component of the cellular energy production system referred to as mitochondrial complex I. By doing so, it can specifically target cells that might be involved in disease progression without causing substantial damage to normal and healthy cells.
The findings of this study will appear in the journal Science Advances on December 18.
“This research provides us with a clearer view of how metformin functions,” stated Navdeep Chandel, the corresponding author and the David W. Cugell, MD Professor of Medicine (Pulmonology and Critical Care), who is also an investigator with the Chan Zuckerberg Initiative and a professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine. The lead author of the study is Colleen Reczek, a research assistant professor in pulmonary and critical care medicine at Feinberg.
“This study significantly enhances our comprehension of metformin’s action,” Chandel explained. “Although millions take metformin, its precise mechanism has long been a puzzle. This research contributes to our understanding that metformin lowers blood sugar by impacting mitochondrial function in cells.”
Metformin has been employed as a treatment for diabetes for over six decades. The medication, which is relatively low-cost and derives from compounds found in the French lilac plant, is considered the primary treatment for many individuals with Type 2 diabetes globally, Chandel noted. In the U.S., some patients combine it with other medications such as newer diabetes and weight-loss drugs like semaglutides, including Ozempic and Mounjaro.
Researchers have proposed various theories regarding how metformin affects cells, but these theories are often derived from distinct research domains and have only provided indirect support for these conjectures, Chandel remarked.
“Each year brings forth a new proposed mechanism or target of metformin, resulting in ongoing debate without reaching a consensus,” Chandel added.
Due to the requirement of a transporter for metformin to enter the interior of cells, it mainly influences a limited number of cell types, primarily in the gut, liver, and kidney. To investigate the role of mitochondrial complex I in reducing glucose levels, Reczek engineered mice that expressed a yeast enzyme (NDI1) that imitates mitochondrial complex I but is resilient to metformin inhibition.
They compared blood glucose levels in groups of mice—with or without metformin, and with or without the yeast NDI1 protein. In the control mice, blood glucose levels decreased upon administration of metformin. Conversely, the NDI1-expressing mice showed reduced effects of metformin on glucose levels, indicating that metformin specifically targets mitochondrial complex I to lower glucose.
“Although the NDI1-expressing mice did not exhibit total resistance to the glucose-lowering effects, suggesting that metformin may influence other pathways as well, further research is required,” Chandel noted.
Earlier, Chandel’s team had utilized NDI1 to illustrate that metformin’s anti-cancer properties in cells that can transport metformin were also due to mitochondrial complex I inhibition within cancer cells.
Additionally, one of the co-authors of the current study, Dr. Scott Budinger, Chief of Pulmonary and Critical Care Medicine at Feinberg, has previously collaborated with Chandel to show that metformin can reduce inflammation triggered by pollution in mice by interfering with mitochondrial complex I.
“We believe that the various effects of metformin—on lowering glucose levels, decreasing inflammation, and its potential anti-cancer qualities—may partly be elucidated by its inhibition of mitochondrial complex I,” said Chandel. “Ultimately, it’s crucial for others to validate our perspective of mitochondrial complex I inhibition as a comprehensive mechanism to explain how metformin could enhance healthspan in humans.”
