Low-Dose Metformin Requires Brain Rap1 for Its Antidiabetic Action

Authors

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
Yong Xu
Makoto Fukuda

Language

English

Publication Date

8-1-2025

Journal

Science Advances

DOI

10.1126/sciadv.adu3700

PMID

40737402

PMCID

PMC12309675

PubMedCentral® Posted Date

7-30-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Metformin, Animals, Hypoglycemic Agents, Mice, Mice, Knockout, rap1 GTP-Binding Proteins, Brain, Ventromedial Hypothalamic Nucleus, Male, Neurons, Blood Glucose

Published Open-Access

yes

Recommended Citation

Lin, Hsiao-Yun; Lu, Weisheng; He, Yanlin; et al., "Low-Dose Metformin Requires Brain Rap1 for Its Antidiabetic Action" (2025). Faculty and Staff Publications. 4930.
https://digitalcommons.library.tmc.edu/baylor_docs/4930