A recent study by Northwestern Medicine has uncovered new insights into how metformin, a widely used Type 2 diabetes medication, lowers blood sugar levels. The research demonstrates that metformin interferes with mitochondria, the cell's energy producers, to reduce glucose levels. This discovery provides direct evidence in mice that the drug reversibly cuts the cell’s energy supply by blocking mitochondrial complex I.

"This research gives us a clearer understanding of how metformin works," said Navdeep Chandel, corresponding author and professor at Northwestern University Feinberg School of Medicine. "While millions of people take metformin, understanding its exact mechanism has been a mystery."

Metformin has been a staple in diabetes treatment for over 60 years and is derived from compounds found in the French lilac plant. It is often used alongside other medications such as semaglutides like Ozempic or Mounjaro.

Scientists have long speculated about metformin’s effects on cells but lacked concrete evidence until now. Chandel noted that various theories have emerged over the years without reaching consensus.

The study involved genetically engineered mice expressing a yeast enzyme (NDI1) resistant to metformin inhibition. Results showed that these mice were less affected by metformin's glucose-lowering effects compared to control mice, indicating that mitochondrial complex I plays a role in reducing glucose levels.

"The NDI1-expressing mice were not completely resistant to its glucose-lowering effects," Chandel explained, suggesting other pathways might also be involved.

Chandel and co-author Dr. Scott Budinger have previously shown that metformin can decrease pollution-induced inflammation in mice through similar mechanisms. They propose that inhibiting mitochondrial complex I could explain the drug's diverse effects on healthspan improvement.

The study was published on December 18 in Science Advances and received support from several institutions including the National Institutes of Health and Northwestern University Pulmonary and Critical Care Division Cugell Predoctoral Fellowship.