After 60 Years, Scientists Uncover Metformin's Hidden Brain Effects Through Rap1 Signaling

Metformin查看药品详情, a cornerstone of type 2 diabetes (搜索)搜索该疾病 treatment for more than six decades, may owe part of its glucose-lowering power to an unexpected organ: the brain. A study published in Science Advances in 2025 by researchers at Baylor College of Medicine查看公司主页 has identified a neural pathway through which metformin influences blood sugar regulation, challenging the long-held assumption that the drug works exclusively through the liver and digestive system.

"It's been widely accepted that metformin查看药品详情 lowers blood glucose primarily by reducing glucose output in the liver. Other studies have found that it acts through the gut," said corresponding author Dr. Makoto Fukuda, associate professor of pediatrics—nutrition at Baylor. "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."

The Rap1 (搜索)搜索该靶点 Connection in the Ventromedial Hypothalamus

The research team focused on a protein called Rap1 (搜索)搜索该靶点, located in a region of the brain known as the ventromedial hypothalamus (VMH), an area critically involved in metabolic control. Earlier work from the group had already identified Rap1 as an important regulator of glucose metabolism in this region. The new findings suggest that metformin查看药品详情's ability to lower blood sugar at clinically relevant doses depends on suppressing Rap1 activity in the VMH.

To test this hypothesis, the scientists used genetically engineered mice that lacked Rap1 (搜索)搜索该靶点 in their VMH. These mice were placed on a high-fat diet to model type 2 diabetes (搜索)搜索该疾病. When given low doses of metformin查看药品详情, their blood sugar levels did not improve. In contrast, other diabetes treatments such as insulin and GLP-1 agonists remained effective in these animals, suggesting a specific and essential role for Rap1 in mediating metformin's therapeutic action.

Brain Responds to Remarkably Low Doses

In one of the study's most striking experiments, the researchers injected extremely small amounts of metformin查看药品详情 directly into the brains of diabetic mice. Even at doses thousands of times lower than those typically administered orally, the treatment significantly reduced blood sugar levels. This finding points toward a previously underappreciated sensitivity of neural circuits to the drug.

"We also investigated which cells in the VMH were involved in mediating metformin查看药品详情'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."

Using brain tissue samples, the team measured the electrical activity of these neurons. Metformin查看药品详情 increased the activity of most SF1 neurons, but only when Rap1 (搜索)搜索该靶点 was present. In mice lacking Rap1 in these neurons, the drug had no effect—demonstrating that Rap1 is necessary for metformin to activate these brain cells and reduce blood sugar.

A More Nuanced Mechanism Than AMPK (搜索)搜索该靶点 Alone

The findings also add complexity to the understanding of metformin查看药品详情's molecular targets. The drug has traditionally been associated with AMP-activated protein kinase (AMPK (搜索)搜索该靶点), a cellular energy-sensing enzyme. Over time, however, research has shown that metformin's biological effects are more complicated than a single pathway can explain. The new brain-focused research adds another potential mechanism to that evolving picture.

"This discovery changes how we think about metformin查看药品详情," Fukuda said. "It's not just working in the liver or the gut, it's also acting in the brain. We found that while the liver and intestines need high concentrations of the drug to respond, the brain reacts to much lower levels."

Implications for Future Diabetes Therapies

Although only a few diabetes drugs are known to act on the brain, this research suggests that metformin查看药品详情 has been doing so all along. The findings point to new opportunities for developing therapies that directly target this brain pathway, potentially enabling more selective interventions with fewer peripheral side effects.

"These findings open the door to developing new diabetes treatments that directly target this pathway in the brain," Fukuda said. "In addition, metformin查看药品详情 is known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 (搜索)搜索该靶点 signaling is responsible for other well-documented effects of the drug on the brain."

The researchers caution that the key experiments were conducted in mice, and more research is needed to establish how directly these findings translate to people taking metformin查看药品详情 for type 2 diabetes (搜索)搜索该疾病. Importantly, the study should not be interpreted as evidence that metformin damages the brain. The research investigated a potentially beneficial mechanism for lowering blood glucose, and patients should not stop or alter prescribed treatment based on these preliminary findings.

The study was supported by grants from the National Institutes of Health (R01DK136627, R01DK121970, R01DK093587, R01DK101379, P30-DK079638, R01DK104901, R01DK126655), USDA/ARS, the American Heart Association, the American Diabetes Association, the Uehara Memorial Foundation, the Takeda Science Foundation, and the Japan Foundation for Applied Enzymology. Contributors to the work include researchers from Baylor College of Medicine查看公司主页, Louisiana State University, Nagoya University in Japan, and Meiji University in Japan.