Six Decades On, Diabetes Medication Found to Have Surprising Effects on the Brain
A finding in medical research shows that a common diabetes drug, metformin, used for over 60 years, may act in a more complex way than previously thought, including actions in the brain. The study, published in Science Advances in 2025, challenges current ideas about how metformin works and may affect approaches to diabetes treatment. The work comes from a team at the Baylor College of Medicine in the United States, led by pathophysiologist Makoto Fukuda.
Metformin is well known for reducing glucose production in the liver and for effects on the gut. Recent work shows it also acts directly in the brain via a specific pathway in the ventromedial hypothalamus (VMH), targeting a molecular component called Rap1. In mice studies carried out in 2025, the drug appeared to act at much lower concentrations in the brain than in the liver and intestines. As Fukuda puts it, “it’s not just working in the liver or the gut, it’s also acting in the brain,” which suggests a wider range of action than previously recognised.
New insights from the lab
Experiments on mice showed that metformin can deactivate Rap1 in the VMH, which then affects diabetes-related measures. Genetically modified mice that lack Rap1 did not show any improvement in diabetes-like conditions when given metformin, whereas other diabetes drugs still worked in those animals. That points to a mechanism that seems unique to metformin. As Fukuda explains, “these findings open the door to developing new diabetes treatments that directly target this pathway in the brain.”
The team also found that SF1 neurons in the VMH (a type of neuron in that region) were activated by metformin introduced into the brain. These neurons could be useful targets for more tailored treatment approaches. Figuring out how they contribute to metformin’s effects might lead to therapies that boost its benefits while reducing side effects.
What this could mean for health and lifespan
Metformin’s effects may extend beyond diabetes. A 2025 study on more than 400 postmenopausal women found that those taking metformin had a 30% lower risk of dying before the age of 90 compared with those on sulfonylurea, another class of diabetes drug. That is consistent with past findings suggesting metformin has gerotherapeutic properties, including slowing brain ageing, promoting gene activity linked to longevity, and reducing some risks associated with long COVID.
Metformin can cause gastrointestinal side effects, such as nausea, diarrhoea and abdominal discomfort, in up to 75% of users. It is also important to take kidney function into account when prescribing metformin, as problems can arise if renal impairment is present.
Where research could go next
The connections between brain and body functions mean more study is needed into how metformin works in the brain. Makoto Fukuda highlights the brain’s role as a regulator of whole-body glucose metabolism and calls for follow-up studies in humans to confirm these animal findings. Researchers say that understanding how metformin acts through brain pathways could improve diabetes outcomes and make the drug safer for patients.
Ongoing work is focused on brain Rap1 signalling, both for glucose control and for potential neurological effects. These insights could inform development of treatments that target the brain more precisely, potentially improving diabetes management and other aspects of health. Further research may clarify metformin’s range of effects and guide clinical care.