Metformin has been used for decades but was long believed to work primarily in the liver and gut. New research from Baylor College of Medicine shows that the brain is a key player in its effectiveness. The drug works by suppressing a protein called Rap1 located in the ventromedial hypothalamus (VMH), a region that regulates metabolism. Metformin activates specific brain cells called SF1 neurons; The researchers found that if Rap1 is missing, metformin cannot activate these neurons, and its ability to lower blood sugar fails. Interestingly, the brain responded to much lower doses of metformin than the liver or gut, suggesting that the brain is highly sensitive to drug signals.
experimental evidence
When scientists injected small amounts of metformin directly into the brains of diabetic mice, their blood sugar dropped significantly – even though the dose was thousands of times less 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 necessary for the drug to act.
In this regard, corresponding author Dr. Makoto Fukuda, associate professor of pediatric-nutrition at Baylor, said: “We focused on the brain because it is widely recognized as a key regulator of glucose metabolism throughout the body. We investigated whether and how the brain contributes to the anti-diabetes effects of metformin.”
This discovery could lead to the development of new diabetes drugs that specifically target brain pathways for better outcomes with fewer side effects. Beyond diabetes, researchers believe this same Rap1 signaling may explain why metformin helps slow brain aging and provides other neuroprotective benefits.
