Metformin has been used for decades but it was long believed to work primarily in the liver and gut. New research from Baylor College of Medicine reveals the brain is a critical player in its effectiveness. The drug works by suppressing a protein called the Rap1 located in the ventromedial hypothalamus (VMH), a region that regulates metabolism. Metformin activates specific brain cells called SF1 neurons; researchers found that if Rap1 is missing, Metformin cannot activate these neurons, and its ability to lower blood sugar fails. Interestingly, the brain responds to much lower doses of Metformin than the liver or gut, suggesting the brain is highly sensitive to the drug’s signals.
When scientists injected tiny amounts of Metformin directly into the brains of diabetic mice, their blood sugar dropped significantly-even though the dose was thousands of times lower than a standard oral pill. Mice engineered to lack Rap1 in the VMH did not respond to Metformin treatment, proving that this brain pathway is essential for the drug to function.
In this connection, corresponding author Dr. Makoto Fukuda, associate professor of pediatrics-nutrition at Baylor said: “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.”
This discovery could lead to the development of new diabetes medications that specifically target brain pathways for better results with fewer side effects. Beyond diabetes, researchers believe this same Rap1 signaling might explain why Metformin helps slow brain aging and offers other neuroprotective benefits.