First study author Colleen Reczek pipettes liquified metformin. Credit Northwestern University
Metformin, a diabetes drug taken by millions, has long been hailed as a “wonder drug.” Not only does it lower blood sugar for people with Type 2 diabetes, but it’s also been shown to slow cancer growth, reduce inflammation, and even improve COVID-19 outcomes. Despite its widespread use for over 60 years, scientists have never fully understood how metformin works — until now.
In a groundbreaking study published in Science Advances, researchers at Northwestern University have finally cracked the code. They’ve discovered that metformin targets the mitochondria, the energy powerhouses of our cells, to lower blood sugar.
The Mitochondria Connection
Metformin specifically interferes with mitochondrial complex I, a key component of the cell’s energy-making machinery. By doing so, it temporarily disrupts the cell’s energy supply in a way that lowers glucose levels. Importantly, this disruption primarily affects cells in the gut, liver, and kidneys — areas where metformin’s effects are most needed — while leaving healthy cells largely untouched.
“This research gives us a clearer understanding of how metformin works,” said Navdeep Chandel, senior author of the study and a professor at Northwestern University Feinberg School of Medicine. “It’s a mystery we’ve been trying to solve for decades.”
Testing the Theory in Mice
To confirm their findings, the research team created genetically engineered mice with a yeast enzyme (NDI1) that mimics mitochondrial complex I but is resistant to metformin’s effects. When treated with metformin, the blood sugar levels in normal mice dropped, but those in the NDI1-engineered mice didn’t budge. This experiment proved that mitochondrial complex I is a key target of metformin in lowering glucose levels.
While the study showed that metformin primarily works through mitochondrial complex I, researchers noted it might also act on other pathways to a more minor degree, leaving room for future exploration.
Beyond Diabetes: Metformin’s Many Superpowers
Metformin’s effects aren’t limited to diabetes. Previous research from Chandel’s team revealed that the drug’s anti-cancer properties are also linked to its ability to inhibit mitochondrial complex I. Another study by co-author Dr. Scott Budinger found that metformin reduces inflammation caused by pollution exposure.
“We think that metformin’s diverse benefits — from lowering blood sugar to reducing inflammation and possibly fighting cancer — all tie back to its inhibition of mitochondrial complex I,” Chandel explained.
A Glimpse Into the Future
Metformin’s discovery as a mitochondrial disruptor could pave the way for new treatments targeting mitochondrial complex I. It might even explain how metformin improves healthspan (the length of time people live in good health).
While this research brings us closer to understanding metformin’s “secret sauce,” Chandel emphasizes that more studies are needed to confirm and expand on these findings.
This humble drug, derived from the French lilac plant, continues to cement its status as a medical marvel, offering hope not just for diabetes patients but for a broader range of health challenges.
As science digs deeper into metformin’s mechanisms, one thing is clear: this 60-year-old drug still has plenty of surprises.