Type 2 diabetes patients on metformin, take note: After 60 years, scientists find this drug has hidden effects on the brain

Metformin, one of the world's most widely prescribed medicines for type 2 diabetes, has been used for more than six decades. While it has long been recognised for lowering blood sugar by acting on the liver and the gut, new research suggests the drug may also work in an unexpected place, the brain.

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The findings, published in the journal Science Advances in 2025, suggest that metformin activates a specific pathway in the brain that helps regulate blood glucose levels. Researchers say the discovery could reshape scientists' understanding of how the medicine works and potentially pave the way for new treatments for diabetes and other age-related conditions.

Metformin may work through the brain, not just the liver

For decades, scientists believed metformin primarily reduced blood glucose by suppressing glucose production in the liver, largely through activation of an enzyme known as AMP-activated protein kinase (AMPK). Later studies also showed the drug has important effects in the gut.

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However, researchers at Baylor College of Medicine wanted to investigate whether the brain also contributes to metformin's glucose-lowering effects.

"It has been widely accepted that metformin lowers blood glucose primarily by reducing glucose output in the liver," said Makoto Fukuda, a neurobiologist at Baylor College of Medicine, when the findings were published.

"Other studies have found that it acts through the gut. We looked into the brain as it is widely recognised as a key regulator of whole-body glucose metabolism. We investigated whether and how the brain contributes to the anti-diabetic effects of metformin."

How researchers uncovered metformin's hidden brain pathway

To explore the possibility, the research team used genetically modified mice that lacked a protein called Rap1 in a region of the brain known as the ventromedial nucleus of the hypothalamus (VMH).

Previous work by Fukuda's laboratory had shown that Rap1 in the VMH plays an important role in regulating blood glucose and energy balance.

The researchers wanted to determine whether this same pathway was essential for metformin to work.

Their experiments found that mice lacking the Rap1 protein did not experience the usual blood sugar-lowering effects of metformin after being fed a high-fat diet designed to mimic type 2 diabetes.

Interestingly, those same mice still responded to other diabetes treatments, including insulin and GLP-1 receptor agonists. This suggested that metformin relies specifically on the Rap1 signalling pathway within the brain to exert its effects.

Tiny brain dose dramatically lowered blood sugar in mice

In another experiment, scientists injected a very small amount of metformin directly into the brains of obese mice.

Even a dose as low as 1 microgram significantly reduced blood glucose levels.

According to the researchers, this amount was several thousand times lower than doses typically required when metformin is administered orally or elsewhere in the body in rodent studies.

"The effect was seen with as little as 1 µg of metformin, which is several thousand times lower than the doses required for oral or peripheral administration in rodent studies... suggesting that the brain is highly sensitive to metformin," the researchers wrote in the paper.

Which brain cells are involved?

The study found that metformin activates specialised brain cells known as SF1 neurons, which are involved in regulating:

• Blood glucose levels
• Appetite
• Energy balance
• Overall metabolism

By influencing these neurons through the Rap1 pathway, metformin appears to help control blood sugar in ways scientists had not previously recognised.

Could this discovery lead to new diabetes treatments?

Researchers believe understanding this newly identified brain pathway could eventually help scientists design diabetes medicines that target the brain more directly.

"These findings open the door to developing new diabetes treatments that directly target this pathway in the brain," Fukuda said.

The researchers also noted that metformin has previously been associated with several other health benefits beyond diabetes management.

What about metformin and brain ageing?

Earlier research has suggested metformin may have effects beyond blood sugar control.

Studies involving macaque monkeys have indicated that daily metformin treatment could slow certain markers of brain ageing. Other research has also linked the drug with potential anti-ageing benefits in humans, although more evidence is needed before any conclusions can be drawn.

Fukuda said the team now plans to investigate whether the same Rap1 brain signalling pathway could explain some of these previously observed effects.

"In addition, metformin is known for other health benefits, such as slowing brain ageing. We plan to investigate whether this same brain Rap1 signalling is responsible for other well-documented effects of the drug on the brain," he said.

What the findings mean

The study does not suggest that people should use metformin for brain health or anti-ageing purposes. The research was conducted in mice, and further studies are needed to determine whether the same mechanism operates in humans.

However, the findings add to growing evidence that metformin's effects extend far beyond the liver and gut. By revealing a previously unknown brain pathway involved in blood sugar regulation, the research offers fresh insight into one of the world's oldest and most widely used diabetes medicines.

The findings were published in Science Advances.





Disclaimer: This article is for informational purposes only and not a substitute for professional medical advice. Always seek the advice of your doctor with any questions about a medical condition.