Over half a century ago, metformin became one of the most consistent drugs for treating type 2 diabetes. Doctors all over the world prescribe it as a first-line medication, and millions of people use it to regulate their blood glucose. But despite its background and tradition, scientists never fully understood how the medication actually works in the human body.
And now, after 60 years, scientists have made a startling breakthrough — metformin does not just target the intestines and liver, as everyone had assumed. It also works in the brain by inhibiting the protein Rap1 in the hypothalamus. This breakthrough upturns our knowledge of the drug and suggests new avenues for creating more effective anti-diabetic medications.
The discovery, published in the journal Science Advances by Baylor College of Medicine scientists and global collaborators, could revolutionize therapy for type 2 diabetes and even prolong the proven health benefits of metformin.
A Familiar Drug with a Mysterious Key
Metformin was available more than five decades ago and is the most commonly prescribed type 2 diabetes drug. Doctors recommend it because it lowers blood glucose, avoids complications, and has less side effect compared to other drugs.
Traditional insight led scientists to believe that metformin worked its way in the way described below:
- Decreasing liver glucose production
- Increasing insulin sensitivity in the body
- Receiving the gut to limit glucose uptake
Despite these reports, however, there were gaps in scientific understanding. Some results of patient treatments could not be explained fully by gut and liver processes. That’s where the new study comes in with new discoveries.
The Brain’s Role in Controlling Blood Sugar
The brain has also been found to be a skilled metabolite regulator, but its function in the mechanism of metformin had never before been investigated in earnest.
Baylor’s Dr. Makoto Fukuda, associate professor of pediatrics-nutrition and corresponding author, had this to say:
“It has long been recognized that metformin decreases blood glucose primarily by inhibiting glucose production in the liver. Other studies have shown that it also acts in the intestine. We looked to the brain because it’s recognized to be a significant regulator of body glucose metabolism as a whole.”
The researchers zeroed in on a small protein, Rap1, present in one specific area of the brain known as the ventromedial hypothalamus (VMH). VMH regulates hunger, metabolism, and energy balance.
Turning off Rap1: The Master Switch
The researchers discovered from their experiment that metformin’s therapeutic efficacy to lower blood glucose is dependent on turning off Rap1 within the VMH.
To confirm, the researchers:
- Used genetically altered mice that contained no Rap1 in the VMH.
- fed mice on a high-fat diet to mimic type 2 diabetes conditions.
- treated mice with low levels of metformin.
And the results were stunning: in the Rap1-free mice, metformin couldn’t lower blood sugar. However, other drugs for diabetes like insulin and GLP-1 agonists were completely normal.
This revealed Rap1’s involvement in the action mechanism of metformin.
Direct Evidence through Brain Injections
The researchers further supported their findings by injecting tiny amounts of metformin directly into diabetic mouse brains. At concentrations thousands of times less than the usual dose taken orally, the drug led to a drastic reduction in blood sugar.
This, of course, firmly established that the brain is far more than a secondary character but is a master switch in the metformin mechanism.
SF1 Neurons: The Brain Cells Behind It
Scientists were also keen on knowing exactly which brain cells were behind it. They discovered that SF1 neurons of the VMH were essential. With metformin present in the brain, these types of neurons were stimulated.
- This activation was only seen when Rap1 was present.
- In Rap1-deficient mice within SF1 neurons, metformin had no impact on blood glucose levels.
This research supported the fact that Rap1 plays a central role in enabling metformin “to turn on” the brain cells that control glucose metabolism.
Rethinking Metformin’s Action
This discovery flips the scientific and medical community’s conventional wisdom on metformin on its head. Instead of analyzing the gut and liver separately, scientists now understand that:
- Brain is extremely sensitive to metformin
- Lower doses are adequate to stimulate brain activity
- Liver and gut require higher doses but brain can function with extremely small doses
As per Dr. Fukuda:
“It is not just playing in the liver or the intestine, it’s playing in the brain. We found that while the liver and intestines need high doses of the drug to become activated, the brain is activated with many, many lower doses.”
Why This Discovery Matters
The importance of this study is gigantic, not only diabetes treatment but other areas of medicine in which metformin has been shown to work.
Implications:
- Better Diabetes Treatment: Having a clue about the brain pathway could ultimately lead to better targeted medications that mimic metformin’s effect, improving blood sugar control.
- Less Side Effect: Since less is required in the brain, medications in the future could be more effective with fewer doses of the medicine.
- Increased Health Advantages: Metformin has also been linked to slowing brain aging, reducing the threat of cancer, and improving cardiovascular function. This new mechanism could provide the basis for some of these broader benefits.
- Precision Medicine: Doctors may one day make treatments based on whether a patient’s brain circuit is normal or not, providing more customized diabetes care.
Metformin’s Increased Health Benefits
Beyond diabetes, metformin is studied for a variety of other effects:
- Anti-aging effects: It has a few studies to indicate that it retards the aging of cells and increases lifespan.
- Neuroprotection: It is also believed to safeguard brain function and reduce cognitive impairment risk.
- Cancer research: Metformin has been promising to reduce the risk of developing certain cancers.
- Cardiovascular health: It improves heart and blood vessel function in some patients.
The finding of the novel pathway of Rap1 signaling in the brain could also be attributed to such long-range impacts, which researchers are now eager to explore.
The Future of Diabetes Research
The study has unveiled a whole new field in diabetes treatment. Though not many anti-diabetic medicines are aiming for the brain, metformin has been doing it all along without our knowledge.
Future studies will thus be aiming:
- Creating drugs that act on Rap1 specifically within the brain.
- Examining how SF1 neurons can be more efficiently activated to control glucose.
Establishing whether other therapeutic actions of metformin, such as slowing brain aging, are being mediated via this brain mechanism.
Conclusion
After 60 years of widespread use, metformin has finally shed one of its biggest secrets. By acting on the brain, specifically the Rap1 protein of the hypothalamus, the drug regulates blood glucose through mechanisms scientists never really understood before.
It is not only a scientific achievement but also a new hope for the millions of type 2 diabetes patients. It is more intelligent, more efficient, and more powerful than what metformin alone can offer.
While scientists continue to unravel the secrets of this widely prescribed drug, one thing is for sure: the brain is at the forefront of diabetes treatment debate, and metformin’s place in it has only recently gone unheard.