For more than 60 years, metformin has been used as a first-line treatment for type 2 diabetes, but scientists don’t fully understand how it works. Baylor College of Medicine researchers, along with international collaborators, have identified an unexpected factor behind the drug’s effects: the brain. By elucidating the brain-based pathways involved in metformin’s ability to lower blood sugar, the researchers opened the door to more targeted and effective diabetes treatments. The results of this study were published in Science Advances.
“It is widely accepted that metformin lowers blood sugar levels primarily by reducing glucose excretion in the liver. Other studies have shown that metformin acts through the intestine,” said corresponding author Dr. Makoto Fukuda, associate professor of pediatric nutrition at Baylor University. “We investigated the brain because it is widely recognized as an important regulator of systemic glucose metabolism. We investigated whether and how the brain contributes to metformin’s antidiabetic effects.”
Rap1 protein and 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 lower blood sugar at clinically relevant doses was dependent on suppressing Rap1 activity in this particular region of the brain.
To test this idea, the Fukuda lab used genetically engineered mice lacking Rap1 in the VMH. These mice were fed a high-fat diet as a model for type 2 diabetes. Treatment with low-dose metformin did not improve blood sugar levels. In contrast, other antidiabetic drugs, such as insulin and GLP-1 agonists, remained effective.
Direct effects of metformin on the brain
To further confirm the brain’s role, the researchers administered very small doses of metformin directly into the brains of diabetic mice. The treatment significantly lowered blood sugar levels, even at doses thousands of times lower than those typically taken orally.
“We also investigated which cells in the VMH are involved in mediating the effects of metformin,” said Professor Fukuda. “We found that SF1 neurons were activated when metformin was introduced into the brain, suggesting that SF1 neurons are directly involved in the drug’s effects.”
Activation of neurons and control of blood sugar levels
The research team used brain tissue samples to measure the electrical activity of these neurons. Metformin increased activity in most of them, but only when Rap1 was present. In mice lacking Rap1 in these neurons, the drug had no effect, indicating that Rap1 is required for metformin to activate these brain cells and regulate blood sugar.
“This discovery has changed the way we think about metformin,” said Professor Fukuda. “It’s not just acting on the liver and intestines, it’s also acting on the brain. It takes high concentrations of the drug for the liver and intestines to respond, but we found that the brain responds at much lower levels.”
Diabetes treatment and its impact on brain health
Although most diabetes drugs do not target the brain, this study shows that metformin has been affecting brain pathways all along. “These findings open the door to the development of new diabetes treatments that directly target this pathway in the brain,” Professor Fukuda said. “Additionally, metformin is also known for other health benefits, such as slowing brain aging. We plan to investigate whether this same brain Rap1 signaling is also involved in the drug’s other well-documented effects on the brain.”
Other contributors to this work include Hsiao-Yun Lin, Wesheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peimen 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 study was supported by the National Institutes of Health (R01DK136627, R01DK121970, R01DK093587, R01DK101379, P30-DK079638, R01DK104901, R01DK126655), USDA/ARS (6250-51000-055), American Supported by a grant from Heart. Association (14BGIA20460080, 15POST22500012) and American Diabetes Association (1-17-PDF-138). Additional support was provided by the Uehara Memorial Foundation, the Takeda Science Foundation, the Foundation for Applied Enzymology, and the NMR and Drug Metabolism Core at Baylor College of Medicine.
