For over six decades, metformin has been a cornerstone in treating type 2 diabetes, primarily known for its effects on blood sugar regulation. However, recent research reveals the drug operates through a previously unrecognized pathway: direct action within the brain. This discovery could reshape diabetes treatment and potentially broaden metformin’s applications.
The Unexpected Brain Connection
Researchers at Baylor College of Medicine have identified a specific neural mechanism through which metformin appears to work. While traditionally understood to reduce glucose output in the liver and gut, the study demonstrates that metformin also influences glucose metabolism directly in the brain.
“It’s widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut,” says Makoto Fukuda, a pathophysiologist at Baylor. “We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin.”
Key Mechanism: The Rap1 Protein
The study centers on a brain protein called Rap1, located within the ventromedial hypothalamus (VMH). Previous research by the same team indicated Rap1’s involvement in glucose metabolism.
Their 2025 study on mice confirmed that metformin travels to the VMH, where it effectively deactivates Rap1, contributing to the drug’s anti-diabetic effects. When mice were bred without Rap1, metformin lost its efficacy – even while other diabetes drugs remained effective. This establishes that metformin’s action within the brain operates through a distinct mechanism.
SF1 Neurons and Targeted Treatments
Researchers pinpointed specific SF1 neurons within the VMH as being activated by metformin. This suggests that the drug directly influences these neurons, potentially paving the way for more targeted therapies. “We also investigated which cells in the VMH were involved in mediating metformin’s effects,” says Fukuda. “We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action.”
Implications and Future Research
Metformin’s established safety, affordability, and long-term use make this discovery significant. The drug already works by improving insulin efficiency and reducing liver glucose output, but now it’s clear the brain is also a key target.
The research team emphasizes that these findings must be validated in human studies. However, once confirmed, the results could lead to optimized treatments that leverage metformin’s brain-acting mechanisms. This understanding also connects to prior studies showing metformin may slow brain aging and extend lifespan, suggesting broader potential applications.
“This discovery changes how we think about metformin,” Fukuda concludes. “It’s not just working in the liver or the gut, it’s also acting in the brain.” He adds that the brain responds to lower concentrations of metformin than the liver and intestines, indicating a more efficient mechanism.
The findings were published in Science Advances.
This research marks a paradigm shift in understanding metformin, suggesting the drug’s full therapeutic potential has yet to be realized. Further investigation is crucial to translate these findings into improved treatments for diabetes and potentially other age-related conditions.
