Low-dose metformin requires brain Rap1 for its antidiabetic action

Authors: LIN, HSIAO - Children'S Nutrition Research Center (CNRC); LU, WEISHENG - Children'S Nutrition Research Center (CNRC); HE, YANLIN - Children'S Nutrition Research Center (CNRC); FU, YUKIKO - Children'S Nutrition Research Center (CNRC); KANEKO, KENTARO - Children'S Nutrition Research Center (CNRC); DE LA PUENTE-GOMEZ, ANA - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); LI, FENG - Baylor College Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); FUKUDA, MAKOTO - Children'S Nutrition Research Center (CNRC)

Submitted to: Science Advances
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2025
Publication Date: 7/30/2025
Citation: Lin, H.Y., Lu, W., He, Y., Fu, Y., Kaneko, K., De La Puente-Gomez, A.B., Wang, C., Yang, Y., Li, F., Xu, Y., Fukuda, M. 2025. Low-dose metformin requires brain Rap1 for its antidiabetic action. Science Advances. 11(31). Article eadu3700. https://doi.org/10.1126/sciadv.adu3700.
DOI: https://doi.org/10.1126/sciadv.adu3700

Interpretive Summary: Metformin is the most common drug used to treat type 2 diabetes. People have been using it to lower their blood sugar for over half a century. Quite surprisingly, however, no one really understood how it worked. For a long time, experts believed that metformin worked mainly in the liver and the gut to help control diabetes. Our research has now shown for the first time that metformin actually works through the brain. In experiments with mice, we removed a certain molecule in their brains called Rap1 and found that the mutant mice didn't respond to metformin, even though other diabetes drugs still worked for them. When metformin was given directly into the brain, it lowered high blood sugar. However, when we turned on Rap1 in the brain, it raised blood sugar and blocked metformin's effects. Our study also found a specific part of the brain, called the VMH, where metformin seems to work. This discovery changes what we know about metformin and the brain's role in diabetes. This could mean new treatments for diabetes that target the brain instead of just the body.

Technical Abstract: Metformin is the most commonly prescribed antidiabetes drug, yet its precise mechanism of action remains controversial. Previous studies have suggested that metformin acts peripherally by reducing hepatic glucose output and altering gut functions. Here, we report a neural mechanism via the small guanosine triphosphatase Ras-related protein 1 (Rap1). Mice with forebrain-specific Rap1 knockout exhibited resistance to the antidiabetic effects of low-dose metformin while remaining sensitive to other antidiabetic agents. Centrally administered metformin inhibited brain Rap1 and reduced hyperglycemia. Conversely, forced activation of brain Rap1 increased glycemia and abolished the glycemic effect of metformin. Metformin activated a specific subset of neurons in the ventromedial hypothalamic nucleus (VMH) that requires Rap1. Both loss-of-function and gain-of-function studies suggest that VMH Rap1 is indispensable for the antidiabetic effects of metformin. These findings highlight the VMH Rap1 pathway as a critical mediator of metformin action.