"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 team focused on a small protein called Rap1, found in a specific part of the brain known as the ventromedial hypothalamus (VMH). The researchers discovered that metformin's ability to lower blood sugar at clinically relevant doses depends on turning off Rap1 in this brain region.

To test this, the Fukuda lab and his colleagues used genetically modified mice that lacked Rap1 in their VMH. These mice were fed a high-fat diet to mimic type 2 diabetes. When given low doses of metformin, the drug failed to lower their blood sugar. However, other diabetes medications like insulin and GLP-1 agonists still worked.

To further show that the brain is a key player, the researchers injected tiny amounts of metformin directly into the brains of diabetic mice. The result was a significant drop in blood sugar, even with doses thousands of times smaller than what's typically given by mouth.

"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."

Using brain slices, the scientists recorded the electrical activity of these neurons. Metformin made most of them more active, but only if Rap1 was present. In mice lacking Rap1 in these neurons, metformin had no effect, showing that Rap1 is essential for metformin to "switch on" these brain cells and lower 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."

Although few anti-diabetic drugs act on the brain, this study shows that widely used metformin has been doing so 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.