Opening new doors for diabetes treatment
Baylor College of Medicine
For over 60 years, metformin has been a first-line treatment for type 2 diabetes, yet scientists have not fully understood how it works. Researchers at Baylor College of Medicine, along with international collaborators, have now identified an unexpected factor behind the drug's effects: the brain.
By uncovering a brain-based pathway involved in metformin's
ability to lower blood sugar, the team has opened the door to more targeted and
effective diabetes therapies. The findings were published in Science Advances.
"It's been widely accepted that metformin lowers blood
glucose primarily by reducing glucose output in the liver. Other studies have
found that it acts through the gut," said corresponding author Dr. Makoto
Fukuda, associate professor of pediatrics -- nutrition at Baylor. "We
looked into the brain as it is widely recognized as a key regulator of
whole-body glucose metabolism. We investigated whether and how the brain
contributes to the anti-diabetic effects of metformin."
Rap1 Protein and the 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 reduce blood sugar at clinically relevant
doses relies on suppressing Rap1 activity in this specific area of the brain.
To test this idea, the Fukuda lab used genetically
engineered mice that lacked Rap1 in the VMH. These mice were placed on a
high-fat diet to model type 2 diabetes. When treated with low doses of
metformin, their blood sugar levels did not improve. In contrast, other
diabetes treatments such as insulin and GLP-1 agonists remained effective.
Direct Brain Effects of Metformin
To further confirm the brain's role, researchers delivered
very small amounts of metformin directly into the brains of diabetic mice. Even
at doses thousands of times lower than those typically taken orally, the
treatment led to a marked reduction in blood sugar levels.
"We also investigated which cells in the VMH were
involved in mediating metformin's effects," Fukuda said. "We found
that SF1 neurons are activated when metformin is introduced into the brain,
suggesting they're directly involved in the drug's action."
Neuron Activation and Blood Sugar Control
Using brain tissue samples, the team measured the electrical
activity of these neurons. Metformin increased activity in most of them, but
only when Rap1 was present. In mice that lacked Rap1 in these neurons, the drug
had no effect, demonstrating that Rap1 is required for metformin to activate
these brain cells and regulate blood sugar.
"This discovery changes how we think about
metformin," Fukuda said. "It's not just working in the liver or the
gut, it's also acting in the brain. We found that while the liver and
intestines need high concentrations of the drug to respond, the brain reacts to
much lower levels."
Implications for Diabetes Treatment and Brain Health
Although most diabetes medications do not target the brain,
this research shows that metformin has been influencing brain pathways all
along. "These findings open the door to developing new diabetes treatments
that directly target this pathway in the brain," Fukuda said. "In
addition, metformin is known for other health benefits, such as slowing brain
aging. We plan to investigate whether this same brain Rap1 signaling is
responsible for other well-documented effects of the drug on the brain."
Other contributors to this work include 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 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 work was supported by grants from: National Institutes
of Health (R01DK136627, R01DK121970, R01DK093587, R01DK101379, P30-DK079638,
R01DK104901, R01DK126655), USDA/ARS (6250-51000-055), American Heart
Association (14BGIA20460080, 15POST22500012) and American Diabetes Association
(1-17-PDF-138). Further support was provided by the Uehara Memorial Foundation,
Takeda Science Foundation, Japan Foundation for Applied Enzymology and the NMR
and Drug Metabolism Core at Baylor College of Medicine.
Story Source:
Materials provided by Baylor College of Medicine. Note:
Content may be edited for style and length.
Journal Reference:
- 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. Low-dose metformin requires brain Rap1 for its
antidiabetic action. Science Advances, 2025; 11 (31)
DOI: 10.1126/sciadv.adu3700
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