metformin, long used to control blood sugar in type 2 diabetes, has been shown to act directly in the brain, researchers at Baylor College of Medicine found in 2025 (ET). The team identified a brain pathway in the ventromedial hypothalamus (VMH) involving the protein Rap1 and specific SF1 neurons that is required for the drug’s blood-sugar–lowering effect in mice. The finding could open new avenues for targeted diabetes therapies and follow-up human studies at research centers.
Metformin’s brain pathway and Rap1
Researchers at Baylor College of Medicine identified a small protein called Rap1 in the VMH as a critical mediator of metformin’s action on glucose metabolism. In controlled tests on mice, the team observed metformin reaching the VMH and suppressing Rap1 activity; when Rap1 was genetically removed from that region, metformin no longer improved a diabetes-like condition even though other treatments still worked. The investigators delivered tiny doses of metformin directly into mouse brains and saw significant blood-sugar reductions at concentrations far lower than typical oral doses, reinforcing the brain pathway’s potency.
Dr. Makoto Fukuda, corresponding author and associate professor of pediatrics — nutrition at Baylor College of Medicine, 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. ” He framed the result as a shift in understanding from liver- and gut-centric models to one that includes a direct neural mechanism.
Neurons, experiments and comparative drug effects
The team examined which cells in the VMH mediate the response and identified SF1 neurons as being activated when metformin was introduced into the brain. “We also investigated which cells in the VMH were involved in mediating metformin’s effects, ” 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. ” Electrophysiological measures showed increased activity in most of these neurons when Rap1 was present; in mice lacking Rap1 in VMH neurons, metformin failed to change neuronal activity or blood glucose.
To test specificity, the researchers used genetically engineered mice placed on a high-fat diet to model type 2 diabetes. In those animals, low systemic doses of metformin depended on Rap1 for efficacy, whereas insulin and GLP-1 agonists remained effective even when Rap1 was absent. That contrast underscores a distinct mechanism for metformin tied to the brain pathway rather than a universal requirement for Rap1 across diabetes therapies.
Quick context and implications
Metformin has been prescribed for more than 60 years and has been widely understood to work largely by reducing hepatic glucose production and acting in the gut. The Baylor findings show the brain is an additional, previously underappreciated site of action and suggest the drug has been engaging central pathways all along.
“These findings open the door to developing new diabetes treatments that directly target this pathway in the brain, ” Fukuda said. He also noted metformin’s other observed effects on brain health and that the team plans to probe whether Rap1 signaling explains those benefits.
What’s next: the immediate priorities are replicating the VMH–Rap1–SF1 neuron findings in further preclinical models and designing human studies to test whether the same pathway operates in people. If confirmed, researchers expect work to follow on targeted strategies that boost metformin’s brain action or mimic it more precisely, and clinical teams will evaluate safety and dosing for central nervous system–directed approaches to diabetes care involving metformin.
