Scientists have only fully begun to understand how the medication works after six decades.
Metformin has been prescribed to type 2 diabetes patients to control blood sugar levels for over 60 years, yet scientists have only now begun to fully understand how it works. A new study, published in Science Advances, indicates that the drug works directly within the brain, potentially paving the way for innovative treatment approaches.
In 2025, researchers at the Baylor College of Medicine in the US pinpointed a brain pathway through which the drug appears to function, alongside its effects on biological processes elsewhere in the body. Makoto Fukuda, a pathophysiologist at Baylor, explained: “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.
“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.” Earlier research by some of the same scientists had identified a brain protein called Rap1 as influencing glucose metabolism, particularly within a region of the brain known as the ventromedial hypothalamus (VMH).
In their 2025 study, experiments on mice demonstrated that metformin travels to the VMH, where it combats type 2 diabetes by effectively deactivating Rap1.
When the team bred mice without Rap1, metformin had no effect on a diabetes-like condition – despite other medications proving effective. This provides compelling evidence that metformin operates within the brain through a mechanism different from other medications.
The research team was also able to examine closely the specific neurones that metformin was influencing. In future, this could pave the way for more precise treatments that specifically target these neurones.
Fukuda said: “We also investigated which cells in the VMH were involved in mediating metformin’s effects.
“We found that SF1 neurons are activated when metformin is introduced into the brain, suggesting they’re directly involved in the drug’s action.”
Metformin is both long-lasting and relatively inexpensive. It functions by decreasing the glucose produced by the liver and enhancing the body’s insulin efficiency, thereby helping to control type 2 diabetes symptoms.
We now understand it very likely operates through the brain, in addition to the liver and gut.
Obviously, this requires confirmation through human studies, but once that’s established, we may be able to identify methods to enhance metformin’s effects and increase its potency.
Fukuda added: “These findings open the door to developing new diabetes treatments that directly target this pathway in the brain.
“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.”
These findings also align with other compelling research suggesting the same drug can decelerate brain ageing and extend lifespan. As our knowledge of how metformin functions continues to grow, it could well be prescribed for a far wider range of conditions in the years ahead.
While metformin is generally considered safer than many other type 2 diabetes treatments, side effects aren’t uncommon with gastrointestinal issues such as nausea, diarrhoea, and stomach discomfort affecting as many as 75 per cent of patients.
Additional complications can arise in those with conditions such as kidney impairment, posing further risks to overall health.
Metformin is also classified as a gerotherapeutic: a drug capable of slowing various ageing processes within the body. Research has demonstrated, for instance, that it can limit DNA damage and encourage gene activity linked to longevity.
Earlier studies have indicated that metformin can reduce deterioration in the brain and even lower the risk of long COVID.
A 2025 study involving more than 400 postmenopausal women examined the comparative effects of metformin and another diabetes medication known as sulfonylurea.
Those taking metformin were found to have a 30 per cent lower risk of dying before the age of 90 compared to those on sulfonylurea, highlighting the drug’s promising role in combating the effects of ageing.
A deeper understanding of how metformin affects the body as a whole could guide medical professionals in prescribing it beyond diabetes treatment, and potentially enhance its safety profile even further.
Fukuda added: “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.”
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