Researchers at Baylor College of Medicine, along with international collaborators, have identified a new mechanism by which metformin lowers blood sugar. The study, published in Science Advances, points to the brain as a key site of action for the commonly used diabetes medication.
“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 Dr. Makoto Fukuda, associate professor of pediatrics – nutrition at Baylor and corresponding author on the study. “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 research team focused on Rap1, a protein located in the ventromedial hypothalamus (VMH) region of the brain. Their experiments showed that when Rap1 was absent from this area in genetically modified mice, low doses of metformin did not reduce blood sugar levels. However, other diabetes medications such as insulin and GLP-1 agonists remained effective in these mice.
To further test their findings, scientists administered small amounts of metformin directly into the brains of diabetic mice and observed significant reductions in blood sugar with doses much lower than those typically given orally.
“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.”
By recording electrical activity from these neurons using brain slices, researchers observed increased activity only if Rap1 was present. In its absence, metformin had no effect on neuronal activation or blood sugar lowering.
“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.”
The findings suggest potential for developing future diabetes treatments targeting this newly discovered pathway within the brain. “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 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 from institutions including Baylor College of Medicine; Louisiana State University; Nagoya University – Japan; and Meiji University – Japan.
The research received funding from organizations such as National Institutes of Health (NIH), USDA/ARS (United States Department of Agriculture/Agricultural Research Service), American Heart Association (AHA), American Diabetes Association (ADA), Uehara Memorial Foundation (Japan), Takeda Science Foundation (Japan), Japan Foundation for Applied Enzymology and resources from Baylor College of Medicine's NMR and Drug Metabolism Core Facility.
