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Low-dose metformin requires brain Rap1 for its antidiabetic action
Hsiao-Yun Lin1, Weisheng Lu1, Yanlin He1,2
1USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Science Advances
|July 30, 2025
Summary
Metformin
Area of Science:
- Neuroscience
- Endocrinology
- Pharmacology
Background:
- Metformin is a widely used antidiabetic drug with a controversial mechanism of action.
- Previous research suggested peripheral actions, such as reduced hepatic glucose output and altered gut function.
Purpose of the Study:
- To investigate a potential neural mechanism of metformin's antidiabetic effects.
- To explore the role of Ras-related protein 1 (Rap1) in the brain's response to metformin.
Main Methods:
- Utilized forebrain-specific Rap1 knockout mice to assess metformin's efficacy.
- Administered metformin centrally and manipulated brain Rap1 activity.
- Examined neuronal activation in the ventromedial hypothalamic nucleus (VMH).
Main Results:
- Forebrain-specific Rap1 knockout mice showed resistance to metformin's antidiabetic effects.
- Central metformin administration inhibited brain Rap1 and reduced hyperglycemia.
- VMH neurons requiring Rap1 were activated by metformin, and VMH Rap1 was essential for its action.
Conclusions:
- Metformin exerts its antidiabetic effects through a neural pathway involving Rap1 in the ventromedial hypothalamus.
- The VMH Rap1 pathway is a critical mediator of metformin's glucose-lowering action.
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