"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."

The Brain's Role in Blood Sugar Control

The researchers focused on a protein called Rap1, located in a region of the brain known as the ventromedial hypothalamus (VMH). They found that metformin's ability to lower blood sugar at clinically relevant doses depends on suppressing Rap1 activity in this area.

To explore this further, the team used genetically engineered mice that lacked Rap1 in their VMH. These mice were placed on a high-fat diet to model type 2 diabetes. When given 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, suggesting a specific role for Rap1 in metformin's action.

Tiny Brain Doses, Big Effects

The scientists then tested whether the brain itself could drive these effects. They injected extremely small amounts of metformin directly into the brains of diabetic mice. Even at doses thousands of times lower than those taken orally, the treatment significantly reduced 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."

How Metformin Activates Brain Cells

Using brain tissue samples, the researchers measured the electrical activity of these neurons. Metformin increased the activity of most of these cells, but only when Rap1 was present. In mice lacking Rap1 in these neurons, the drug had no effect. This showed that Rap1 is necessary for metformin to activate these brain cells and reduce 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."

New Directions for Diabetes Treatment

Although only a few diabetes drugs are known to act on the brain, this research suggests that metformin has been doing so all along. The findings point to new opportunities for developing therapies that directly target this brain pathway.

"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."

Study Contributors and Funding

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.