New Insights into Metformin’s Action on Blood Sugar

Recent research has revealed that metformin, a widely used medication for type 2 diabetes, operates by influencing the brain to regulate blood sugar levels. This discovery, made by a team at Baylor College of Medicine in collaboration with international partners, highlights the potential for more targeted diabetes treatments.

Despite being the go-to drug for over sixty years, the precise mechanisms of how metformin works remain unclear. The latest findings suggest a significant brain pathway might be involved in its glucose-lowering effect, with results published in Science Advances.

Dr. Makoto Fukuda from Baylor explained, “Traditionally, it’s been thought that metformin reduces blood glucose mainly by decreasing glucose production in the liver or acting through the gut. We turned our attention to the brain, recognizing it as a vital regulator of glucose metabolism across the body.”

The focus of the study was on a small protein called Rap1, found in the ventromedial hypothalamus (VMH) of the brain. The team discovered that metformin’s effectiveness at lowering blood sugar is linked to its ability to suppress Rap1 activity in this specific region.

Examining Rap1 and Experimental Findings

To further investigate, researchers looked at genetically modified mice that lacked Rap1 in the VMH. When these mice were given a high-fat diet to mimic type 2 diabetes, low doses of metformin didn’t lower their blood sugar. However, other diabetes medications like insulin and GLP-1 agonists continued to work.

To provide stronger evidence of the brain’s involvement, the team injected tiny amounts of metformin directly into the brains of diabetic mice. This approach resulted in significant reductions in blood sugar levels, even with doses that were much lower than what’s typically administered orally.

Neuronal Activity in the Hypothalamus

“We also looked at which specific cells in the VMH were responsible for mediating the effects of metformin,” Fukuda noted. “Our findings indicate that SF1 neurons become active when metformin is introduced into the brain, implying their direct involvement in the drug’s mechanism.”

Through recordings of brain slices, researchers noted that most of these neurons became more active after metformin exposure, but only if Rap1 was present. Conversely, in mice lacking Rap1 in those neurons, metformin had no impact, emphasizing Rap1’s crucial role in activating these brain cells for blood sugar reduction.

“This changes our understanding of metformin,” Fukuda said. “It’s not confined to the liver or gut; it works in the brain as well. While both the liver and intestines require higher doses of the drug, the brain can respond to much lower levels.”

While most anti-diabetic medications don’t target the brain, this study suggests that metformin has always played a role there. “These results pave the way for developing new diabetes treatments that could directly target brain pathways,” Fukuda added. “Additionally, metformin is noted for various other health benefits, such as its potential to slow brain aging. We’re interested in exploring whether this same brain Rap1 signaling pathway contributes to those effects.”

Reference: “Low-dose metformin requires brain Rap1 for its antidiabetic action” by Hsiao-Yun Lin et al., July 30, 2025, Science Advances.