metformin brain is now at the center of a major shift in how scientists explain a drug prescribed for type 2 diabetes for more than 60 years. In a 2025 study led by researchers at Baylor College of Medicine in the United States, the team identified a brain pathway that the drug appears to work through, in addition to effects in other parts of the body. The finding matters because it could open a route to new, more targeted diabetes treatments, but the researchers stress the need for confirmation in human studies.
What the researchers say they found inside the brain
For decades, metformin’s blood-sugar impact has been widely tied to reduced glucose output in the liver, with other studies pointing to action through the gut. Makoto Fukuda, a pathophysiologist at Baylor College of Medicine, said the team focused on the brain because it is widely recognized as a key regulator of whole-body glucose metabolism.
The researchers zeroed in on a small protein called Rap1 in a brain region known as the ventromedial hypothalamus (VMH). In tests on mice, metformin traveled to the VMH and appeared to help address a diabetes-like condition by suppressing—essentially turning off—Rap1 activity in that specific region. The study also indicates metformin’s ability to reduce blood sugar at clinically relevant doses relies on suppressing Rap1 activity in the VMH.
To test the importance of Rap1, the lab used genetically engineered mice that lacked Rap1 in the VMH. Those mice were placed on a high-fat diet to model type 2 diabetes. When treated with low doses of metformin, their blood sugar levels did not improve. In contrast, other diabetes treatments such as insulin and GLP-1 agonists remained effective—evidence the team points to in arguing Rap1 is central to metformin’s effect in this model.
The researchers also delivered very small amounts of metformin directly into the brains of diabetic mice. Even at doses described as thousands of times lower than those typically taken orally, the treatment led to a marked reduction in blood sugar levels, reinforcing the idea that the brain pathway is highly sensitive to the drug.
Immediate reactions from the lab: Rap1 and SF1 neurons in focus
“It’s been 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, ” said Dr. Makoto Fukuda, associate professor of pediatrics—nutrition at Baylor College of Medicine. “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. ”
Fukuda said the team also examined which cells in the VMH were involved. “We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action, ” he said.
Using brain tissue samples, the researchers measured electrical activity in these neurons. Metformin increased activity in most of them, but only when Rap1 was present. In mice lacking Rap1 in these neurons, metformin had no effect, which the team describes as demonstrating that Rap1 is required for metformin to activate these brain cells and regulate blood sugar.
“This discovery changes how we think about metformin, ” Fukuda said. “It’s not just working in the liver or the gut, it’s also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels. ”
Quick context: why this matters after 60 years of use
Metformin has been prescribed for type 2 diabetes for more than 60 years, yet scientists have not been exactly sure how it works. The Baylor team’s work reframes part of that long-standing question by placing a key mechanism inside the brain’s VMH, rather than only in peripheral organs.
What’s next for metformin brain research
The researchers say these findings open the door to developing diabetes treatments that directly target this brain pathway, potentially aiming at specific VMH neurons implicated in the drug’s action. Still, the work described here is based on mouse experiments, and the team notes it needs to be shown in human studies as well.
Fukuda also pointed to broader questions the team plans to pursue, including whether the same brain Rap1 signaling could help explain other documented effects of the drug on the brain, including slowing brain aging. For now, the key takeaway is clear: the metformin brain pathway identified in 2025 is reshaping how scientists describe a familiar drug—and setting up the next phase of research into targeted therapies and confirmation in people.
