What Happens To Your Brain When You Take Metformin?

Before GLP-1 drugs came onto the market, metformin was the go-to prescription for people with type 2 diabetes. It is still one of the most widely used medications, with an estimated 200 million people worldwide relying on it to help control their blood sugar (via UC Health). While it is considered safe and effective, metformin can cause side effects such as reduced appetite, diarrhea, or muscle cramps.

For decades, scientists have worked to understand exactly how metformin works. Much of the focus has been on its ability to activate the AMPK enzyme, which plays a key role in regulating liver metabolism. Metformin also acts in the gut, where it can shift the balance of the microbiome, increase glucose absorption, and boost hormones such as GLP-1 that promote fullness and slow digestion.

Now research is revealing another site of action: the brain. A 2025 study in Science Advances found that metformin blocks Rap1, a signaling protein that works like a metabolic switch in the hypothalamus. When Rap1 is active, blood sugar rises. When metformin blocks it, even at very low doses, blood sugar drops. 

"This discovery changes how we think about metformin," Associate Professor and study author Dr. Makoto Fukuda said in a news release. "We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels."

Although this study was done in mice, it gives more insight into the different ways metformin helps control blood sugar. When researchers removed the Rap1 protein from the brain, metformin no longer lowered blood sugar. Insulin and GLP-1 drugs, however, still worked as expected.

Next, the researchers artificially kept the Rap1 signaling protein switched on, which caused blood sugar levels to rise. In this case, metformin was ineffective, suggesting that the drug lowers blood sugar by turning Rap1 off. Interestingly, even though metformin is normally taken by mouth, a small dose injected directly into the brain also brought blood sugar down.

"These findings open the door to developing new diabetes treatments that directly target this pathway in the brain," Fukuda said. "In addition, metformin is known for other health benefits, such as slowing brain aging."

While GLP-1 drugs are now widely used for weight loss, a 2020 review in Frontiers in Endocrinology outlined these additional health benefits of metformin, including weight loss. For example, metformin may enhance the effectiveness of certain cancer treatments in people with type 2 diabetes. It may also help reduce inflammation and oxidative stress, which could slow the growth of some cancers and improve heart health. In addition, taking metformin may lower the risk of liver and kidney diseases.