For over 60 years, metformin has been a first-line treatment for type 2 diabetes, yet scientists have not fully understood how it works. Researchers at Baylor College of Medicine, along with international collaborators, have now identified an unexpected factor behind the drug’s effects: the brain. By uncovering a brain-based pathway involved in metformin’s ability to lower blood sugar, the team has opened the door to more targeted and effective diabetes therapies. The findings were published in Science Advances.
“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,” 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.”
Rap1 Protein and the Hypothalamus
The researchers focused on a small protein called Rap1, located in a brain region known as the ventromedial hypothalamus (VMH). They found that metformin’s ability to reduce blood sugar at clinically relevant doses relies on suppressing Rap1 activity in this specific area of the brain.
To test this idea, the Fukuda lab used genetically engineered mice that lacked Rap1 in the VMH. These mice were placed on a high-fat diet to model type 2 diabetes. When treated with low doses of metformin, their blood sugar levels did not improve. In contrast, other diabetes treatments such as insulin and GLP-1 agonists remained effective.
Direct Brain Effects of Metformin
To further confirm the brain’s role, researchers delivered very small amounts of metformin directly into the brains of diabetic mice. Even at doses thousands of times lower than those typically taken orally, the treatment led to a marked reduction in blood sugar levels.
“We also investigated which cells in the VMH were involved in mediating metformin’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.”
Neuron Activation and Blood Sugar Control
Using brain tissue samples, the team measured the electrical activity of these neurons. Metformin increased activity in most of them, but only when Rap1 was present. In mice that lacked Rap1 in these neurons, the drug had no effect, demonstrating that Rap1 is required for metformin to activate these brain cells and regulate blood sugar.
“This discovery changes how we think about metformin,” 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 Diabetes Treatment and Brain Health
Although most diabetes medications do not target the brain, this research shows that metformin has been influencing brain pathways all along. “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. We plan to investigate whether this same brain Rap1 signaling is responsible for other well-documented effects of the drug on the brain.”
Other contributors to this work include Hsiao-Yun Lin, Weisheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peimeng Huang, Ana B De la Puente-Gomez, Chunmei Wang, Yongjie Yang, Feng Li and Yong Xu. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Louisiana State University, Nagoya University — Japan and Meiji University — Japan.
This work was supported by grants from: National Institutes of Health (R01DK136627, R01DK121970, R01DK093587, R01DK101379, P30-DK079638, R01DK104901, R01DK126655), USDA/ARS (6250-51000-055), American Heart Association (14BGIA20460080, 15POST22500012) and American Diabetes Association (1-17-PDF-138). Further support was provided by the Uehara Memorial Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology and the NMR and Drug Metabolism Core at Baylor College of Medicine.