Diabetes drug metformin does more than control blood sugar, study finds it also affects the brain

Metformin has been used for more than 60 years as a standard treatment for type 2 diabetes. It is widely known for being reliable, affordable and safe. For a long time, its primary role has been understood in a fairly straightforward way, helping control blood sugar levels by acting on the liver and improving insulin use.

But recent research is adding another layer to that understanding. A study published in Science Advances by researchers at Baylor College of Medicine and international collaborators suggests that metformin may also work directly in the brain. The findings, also reported by Science Alert, point to a new way of looking at how the drug functions in the body.

Metformin helps manage type 2 diabetes mainly by reducing the amount of glucose produced by the liver and improving how the body uses insulin. This mechanism has been widely accepted for years.

“It’s been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver,” said Dr Makoto Fukuda, associate professor of pediatrics and nutrition at Baylor and the study’s corresponding author. He added, “Other studies have found that it acts through the gut. We looked into the brain as it is widely recognized as a key regulator of whole-body glucose metabolism.”

The study identified a specific brain pathway linked to how metformin works. Researchers found that the drug shuts down a protein called Rap1 in a part of the brain that helps regulate energy and glucose.

They also observed that SF1 neurons were activated when metformin was introduced into the brain. “We investigated whether and how the brain



contributes to the anti-diabetic effects of metformin,” Dr Fukuda said. “We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they're directly involved in the drug's action.”

Another key finding was related to how the drug behaves across different parts of the body. “This discovery changes how we think about metformin. It’s not just working in the liver or the gut, it’s also acting in the brain,” he said. “We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels.”

The findings could help guide the development of new treatments that target this brain pathway more directly. “These findings open the door to developing new diabetes treatments that directly target this pathway in the brain,” Dr Fukuda said.

Metformin has also been linked to other health benefits in previous research. It is regarded as a gerotherapeutic, meaning it may help slow certain ageing processes. Studies suggest it can limit DNA damage and support gene activity linked to longevity.

“In addition, metformin is known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain,” Dr Fukuda said.

Earlier studies have also suggested that metformin may reduce wear and tear in the brain and could lower the risk of Long COVID. A 2025 study involving over 400 postmenopausal women compared metformin with another diabetes drug, sulfonylurea, to better understand its broader effects.