For over 60 years, scientists have been baffled by how metformin, the trusted diabetes drug, works at the cellular level. A new study from Northwestern Medicine uncovers a surprising mechanism tied to the cell’s mitochondria, shedding light on its role in lowering blood sugar and even slowing cancer growth.

Arezki Amiri

Published on

December 20, 2024

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Scientists Finally Crack 60-Year Mystery Behind Diabetes ‘Wonder Drug’ Metformin – © The Daily Galaxy –Great Discoveries Channel

The antidiabetic drug metformin, widely prescribed for managing Type 2 diabetes, has long been recognized for its capacity to reduce blood glucose levels, attenuate inflammation, and slow tumor progression. Despite its widespread use for over 60 years, the precise molecular mechanisms underlying its effects have remained unclear.

A recent study from Northwestern Medicine, published in Science Advances, sheds light on this longstanding question by identifying mitochondrial complex I as a primary target of metformin.

Targeting Mitochondria To Regulate Blood Sugar

Metformin exerts its glucose-lowering effects by disrupting energy production within the mitochondria, a key organelle responsible for cellular metabolism. The study demonstrates that the drug inhibits mitochondrial complex I, a crucial component of the mitochondrial electron transport chain. This disruption impairs cellular energy production in select cell types, including those implicated in disease, while sparing healthy cells.

“While millions of people take metformin, its mechanism of action has remained enigmatic,” said Navdeep Chandel, senior author and professor of medicine and biochemistry at Northwestern University Feinberg School of Medicine. “This research provides clear evidence that metformin lowers blood glucose levels by targeting mitochondrial complex I.”

First study author Colleen Reczek pipettes liquified metformin. Credit: Northwestern University

The Experimental Approach: Using Genetically Engineered Mice

The team conducted experiments on genetically engineered mice expressing NDI1, a yeast-derived enzyme that mimics the function of complex I but is resistant to metformin. By comparing glucose levels in mice treated with metformin, the study uncovered the following key findings:

• In wild-type mice, metformin significantly reduced blood glucose levels.
• Mice expressing NDI1 exhibited reduced sensitivity to metformin, with a less pronounced decrease in blood glucose levels.
• The partial resistance observed in NDI1-expressing mice suggests additional pathways may contribute to metformin’s glucose-lowering effects.

This work builds on earlier research showing metformin’s ability to inhibit mitochondrial complex I in cancer cells, potentially slowing tumor growth.

Metformin’s Broad Applications and Future Research

Metformin’s benefits extend beyond diabetes management. Research has linked it to:

• Cancer therapy: Inhibiting complex I in cancer cells.
• Inflammation reduction: Alleviating pollution-induced inflammation in studies with mice.
• COVID-19 outcomes: Preliminary studies suggest metformin might improve survival rates.

These results strongly implicate mitochondrial complex I as a critical target of metformin in glucose regulation. Furthermore, earlier research from the Chandel lab demonstrated that metformin’s inhibition of complex I also contribute to its anti-cancer effects in cells expressing metformin transporters.

“We believe the diverse effects of metformin—ranging from glucose regulation to inflammation reduction and potential anti-cancer properties—can be partially explained by its inhibition of mitochondrial complex I,” Chandel said. He emphasized the need for further research to corroborate these findings and explore additional mechanisms.

First author Colleen Reczek in the lab at Northwestern University Feinberg School of Medicine. Credit: Northwestern University

A Historic Drug With a Modern Understanding

Metformin, derived from compounds in the French lilac plant, has been a cornerstone of diabetes management since its introduction more than six decades ago. Its low cost and efficacy make it a first-line therapy for millions of patients worldwide. In the United States, it is frequently used alongside newer antidiabetic medications, including semaglutides like Ozempic and Mounjaro.

The drug’s multifaceted effects have prompted numerous hypotheses about its mechanisms over the years. However, many of these theories have lacked definitive experimental evidence or consensus within the scientific community.

What Lies Ahead

The identification of mitochondrial complex I as a primary target of metformin opens new avenues for research. By elucidating the specific pathways involved in its action, scientists can refine therapeutic strategies for diabetes and potentially extend metformin’s application to other diseases.

“Metformin’s interaction with mitochondrial complex I offers a cohesive explanation for its effects across multiple conditions,” Chandel noted. “This understanding provides a foundation for further exploration into how targeting mitochondria can enhance human health.”

This study not only resolves a decades-old question about metformin’s mechanism of action but also underscores the potential of mitochondrial biology as a focal point for developing novel therapeutic interventions.