Unmasking Metformin: Scientists Finally Crack the Code of This “Wonder Drug”

A Northwestern Medicine study has discovered that metformin, a common Type 2 diabetes medication, works by blocking a key part of the mitochondrial energy production, specifically complex I, which helps lower blood glucose levels.

This breakthrough provides insight into the drug’s mechanism which has been unclear despite its broad usage for over 60 years in treating diabetes, reducing inflammation, and slowing cancer growth.

Metformin’s Multifaceted Role

Millions of people use metformin, a medication for Type 2 diabetes that helps lower blood sugar. Beyond diabetes, this “wonder drug” has also been linked to slowing cancer growth, improving COVID-19 outcomes, and reducing inflammation. However, scientists have long struggled to understand exactly how it works.

A new study from Northwestern Medicine has provided clear evidence in mice that metformin lowers blood sugar by disrupting the cell’s energy supply. It does this by interfering with mitochondria, often called the cell’s “powerhouse.”

Specifically, metformin blocks a key part of the mitochondria’s energy-making system known as mitochondrial complex I. This allows the drug to target disease-contributing cells while sparing healthy ones from significant harm.

The findings were published today (December 18) in the journal Science Advances.

New Insights from Northwestern Medicine Study

“This research gives us a clearer understanding of how metformin works,” said corresponding author Navdeep Chandel, the David W. Cugell, MD, Professor of Medicine (Pulmonology and Critical Care), investigator with the Chan Zuckerberg Initiative and a professor of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine. The study’s first author is Colleen Reczek, research assistant professor of medicine (pulmonary and critical care medicine) at Feinberg.

“This research significantly advances our understanding of metformin’s mechanism of action,” Chandel said. “While millions of people take metformin, understanding its exact mechanism has been a mystery. This study helps explain that metformin lowers blood sugar by interfering with mitochondria in cells.”

Historical Context and Ongoing Research

Metformin has been used as a diabetes treatment for more than 60 years. The relatively inexpensive medication, which derives from compounds in the French lilac plant, is the first line of defense for many patients with Type 2 diabetes worldwide, Chandel said. In the U.S., some patients take it alongside other medications like new diabetes and weight-loss drugs — semaglutides such as Ozempic or Mounjaro.

Scientists have many theories about metformin’s effect on cells, but the theories are often grounded in research from distinct fields and have provided only indirect evidence to back hypotheses, Chandel said.

“Every year there’s a new mechanism, a new target of metformin, and the next few years people debate those and don’t come to a consensus,” Chandel said.

Experimental Approach and Future Directions

Because metformin requires a transporter to access the interior of cells — where mitochondria live — it affects only a handful of cell types, mostly in the gut, liver and kidney. To test mitochondrial complex I’s role in glucose reduction, Reczek created mice genetically engineered to express a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to metformin inhibition.

They compared blood glucose levels in mice with and without metformin, and with or without the expressed yeast NDI1 protein. Glucose levels in the control mice lowered upon metformin administration. By contrast, NDI1-expressing mice ameliorated metformin reduction in glucose levels, indicating that metformin targets mitochondrial complex I to reduce glucose levels.

“The NDI1-expressing mice were not completely resistant to its glucose-lowering effects, suggesting metformin may also target other pathways to some extent, but more research is needed,” Chandel said.

Previously, the Chandel group had used NDI1 to demonstrate that metformin anti-cancer effects in cells that express the transporter for metformin were also due to inhibition of mitochondrial complex I in cancer cells.

Moreover, one of the co-authors of the current study, Dr. Scott Budinger, chief of pulmonary and critical care in the department of medicine at Feinberg, has previously shown with Chandel that metformin can decrease pollution-induced inflammation in mice by interfering with mitochondrial complex I.

“We think that the diverse effects metformin has on lowering glucose levels, decreasing inflammation and its potential anti-cancer effects could, in part, be explained by inhibiting mitochondrial complex I,” Chandel said. “Eventually, others will have to corroborate our idea of mitochondrial complex I inhibition as a unifying mechanism to explain how metformin could improve healthspan in humans.”

Reference: “Metformin targets mitochondrial complex I to lower blood glucose levels” by Colleen R. Reczek, Ram P. Chakrabarty, Karis B. D’Alessandro, Zachary L. Sebo, Rogan A. Grant, Peng Gao, G. R. Scott Budinger and Navdeep S. Chandel, 18 December 2024, Science Advances.
DOI: 10.1126/sciadv.ads5466

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