After 60 Years, a Diabetes Drug Reveals an Unexpected Effect on the Brain
Metformin has been prescribed for over sixty years to people with type 2 diabetes to regulate their blood sugar levels, but scientists have never fully understood how it works. An article published on Science Alert on November 23, 2025, reports a new study suggesting that it acts directly on the brain—an unexpected discovery that could pave the way for new treatments.
Researchers from Baylor College of Medicine in the United States identified a brain pathway through which the drug seems to operate, in addition to its effects on other biological processes in the body.
"It has long been accepted that metformin lowers glucose primarily by reducing sugar production in the liver. Other studies have shown an action through the intestine," explains Makoto Fukuda, a pathophysiologist at Baylor.
"We focused on the brain because it is recognized as a central regulator of glucose metabolism. We wanted to understand if it contributes to the anti-diabetic effects of metformin, and how."
Previous research had already shown that a brain protein called Rap1 plays a role in glucose metabolism, particularly in a part of the brain known as the ventromedial hypothalamus (VMH).
In their 2025 study, tests on mice revealed that metformin reaches the VMH, where it helps combat type 2 diabetes by 'deactivating' the Rap1 protein.
In genetically modified mice that lacked Rap1, metformin had no effect on a diabetes-like condition, while other medications still worked.
This provides solid evidence that metformin indeed acts in the brain through a different mechanism.
The researchers were also able to identify the specific neurons affected by the drug. This could eventually lead to the development of more targeted treatments.
"We analyzed which cells in the VMH were involved in the effects of metformin," Fukuda continues.
"We found that SF1 neurons were activated when metformin was introduced into the brain, indicating that they play a direct role in its action."
Metformin is a sustainable, low-cost medication that reduces glucose production by the liver and improves insulin efficiency, helping to control type 2 diabetes symptoms.
It is now understood that it likely also acts through the brain, not just the liver and intestines.
These results need to be confirmed in humans, but if validated, they could enhance or optimize the effects of metformin.
"These discoveries pave the way for new diabetes treatments that would directly target this brain pathway," Fukuda claims.
"Additionally, metformin is known for other benefits, including its effects on brain aging. We will study whether the same mechanism involving Rap1 explains these effects."
These findings add to other studies showing that metformin can slow brain aging and increase lifespan. A better understanding of its mechanisms could thus broaden its use in other areas.
While generally safe, metformin can cause side effects, including gastrointestinal issues (nausea, diarrhea, abdominal pain), affecting up to 75% of those treated. Complications can also arise in patients with kidney failure.
Metformin is also considered a gerotherapeutic: a drug that can slow down certain aging processes, such as by limiting DNA damage or stimulating genes associated with longevity.
Previous studies have shown that it can reduce brain damage and even lower the risk of developing long COVID.
In 2025, a study involving more than 400 postmenopausal women compared metformin to another diabetes medication, sulfonylureas.
The result: women on metformin had a 30% reduced risk of dying before the age of 90.
Better understanding its effects on the entire body could help specialists prescribe it beyond diabetes, while also improving its safety profile.
"This discovery changes our perception of metformin," concludes Fukuda.
"It doesn't just act on the liver or intestines, but also on the brain. We found that the brain responds to much lower doses than those required for other organs."
The study was published in Science Advances.