Scientists found that metformin acts in the brain through Rap1 to control blood sugar. This insight could lead to more precise diabetes treatments.
Metformin has been the standard treatment for type 2 diabetes for more than six decades, yet scientists still do not fully understand how it works. A team from Baylor College of Medicine, working with international collaborators, has now identified an unexpected factor in its effectiveness: the brain. Their findings reveal a brain pathway involved in metformin’s glucose-lowering action, pointing to new strategies for treating diabetes with greater precision. The study was 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,” explained Dr. Makoto Fukuda, associate professor of pediatrics – nutrition at Baylor and the study’s corresponding author. “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.”
The researchers concentrated on a small protein called Rap1, located in a region of the brain known as the ventromedial hypothalamus (VMH). They discovered that metformin’s ability to lower blood sugar at clinically relevant doses depends on suppressing Rap1 activity in this brain area.
Rap1 protein and experimental evidence
To explore this further, the Fukuda lab and collaborators studied genetically engineered mice that lacked Rap1 in their ventromedial hypothalamus (VMH). These mice were placed on a high-fat diet to simulate type 2 diabetes. When treated with low doses of metformin, their blood sugar levels did not decrease. In contrast, other diabetes drugs, including insulin and GLP-1 agonists, remained effective.
To strengthen the evidence that the brain plays a central role, the researchers administered extremely small amounts of metformin directly into the brains of diabetic mice. This approach produced a marked reduction in blood sugar, even when the doses were thousands of times lower than those typically given orally.
Neuronal activation in the hypothalamus
“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.”
Using brain slices, the scientists recorded the electrical activity of these neurons. Metformin made most of them more active, but only if Rap1 was present. In mice lacking Rap1 in these neurons, metformin had no effect, showing that Rap1 is essential for metformin to “switch on” these brain cells and lower 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.”
Although few anti-diabetic drugs act on the brain, this study shows that widely used metformin has been doing so 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.”
Reference: “Low-dose metformin requires brain Rap1 for its antidiabetic action” by 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 and Makoto Fukuda, 30 July 2025, Science Advances.
DOI: 10.1126/sciadv.adu3700
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.
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47 Comments
Very interesting. However in your review you said mice were fed a high fat diet which was confusing, as dietary fat produces no increase in blood sugar.
Review of the actual study shows this was incorrect as they actually gave the mice glucose intraperitoneally which made sense.
“These mice and their littermate controls were fed a high-fat diet (HFD) to induce moderate hyperglycemia.”
Quote directly from the original paper. Seems high fat produces high blood glucose. Three intraperitoneal glucose injection was for measuring the effectives of glucose clearing in the animal.
In the pathophysiology of Diabetes mellitus, Fats plays an important role in production of glucose termed gluconeogenesis also the deposits of fatty molecules can increase fatty liver as well as increased insulin insensitivity in the tissues leading to hyperglycaemia. That is one pathway out of the three pathways.
Yes, I noticed that non-sequitur too… thanks for confirming the correct method used.
Hi so metformin doesn’t work like it’s supposed to hmm interesting so why are we taking metformin is there no other drugs that we diabetics can take I’m getting tired of being a test dummy for the drugs
Metformin is cheap and well tolerated. It is well beyond the “test dummy” phase. It is one of the first drugs used because it has a long well documented history and is one of the cheapest diabetic drugs on the market with a good safety profile.
Safe apart from the vitamin B12 it prevents your body from absorbing.
Read the article again, you missed a lot.
Thats NOT what they said.
Dumbed down to your level?
It ALSO works on the brain, AS WELL AS the traditionally researched areas.
Cant you read?
No need to get aggressive 🤨
Metformin is cheap and well tolerated. It is well beyond the “test dummy” phase. It is one of the first drugs used because it has a long well documented history and is one of the cheapest diabetic drugs on the market with a good safety profile.
I HEARD THAT METFORMIN IS NO GOOD FOR PEOPLE WITH DIABETES. DOCTOR’S PRESCRIBE METFORMIN FOR EVERYONE.
Metformin isn’t the only medication for diabetics. When I was introduced to it, I was vomiting every morning for a week. Went back to the doctor and had my meds changed. It is unsuitable for anyone who has gastric or gastrointestinal issues. Makes it worse.
Enough of the treatments already. How about telling big pharma to give us a damn cure? You can’t tell me that after a 100 years of knowing about diabetes, there is no cure, we are sick and tired of lining big pharma pockets with useless treatments. ENOUGH!!!
There will never be a cure. There kind of is a cure and that is a pancreas transplant, but it has never been a good option due to most transplants are rejected within 10 years.
Carnivore…. Dr Ken Berry
My A1C was 6.8 and 8 months later is 5.1…. carnivore life style not diet… You’ll get off all your meds. 90% of doctors have no clue that diet is the key…. Research
Yes, I have done the same by eating a carnivore diet, reverse type two diabetes with no meds and diet alone.
So right. Me too. Taking it for over 20 year. My body don’t process protein well so carnivore diet is not good for me
Well, we do need to keep our funding. Give us another 50 years and a few hundred million.
There is a cure… it’s called eat clean and healthy and drink water. Vegetables, especially greens, greens, minimal amounts of fruits and go out and get exercise. Those are literally what reverses diabetes or will allow you to not ever develop diabetes in the first place.
There is a cure, but well people aren’t profitable.
EXACTLY!!!!
Article SHOULD READ: After 60 Years,Metformin can & should be avoided. Only prolongs the inevitable diabetes outcome – meanwhile creates other complications. Better off changing the causation- start here with this book. Glucose Revolution by Jessie Inchauspe from experience of AIC @11.2 to A1C @5.9 in less than a year.
No cure coming because $$$ takes / have more sleeping partners…
I went on Metformin and lost 50 lbs without even trying.
I have been prescribed Metformin for years now and yes my evening readings with just breakfast of two eggs or even with cereal (live grains no wheat) is very low and below 100. BUT taking before bed I still have high readings like 160. I have used Chia seeds for the passed 15 years one water bottle with one table spoon during the day. Recently drinking one bottle before bedtime it has gotten lower to 115 at times.
One very big mistake is doctors and people do not think about is a Blood Type diet – O and B can have Red Meat (B wild meat) where as A and AB no red meat and no one should have hog or pig! The proof of hog meat is recently it has been found eggs are great especially the yolk for it has the K2 vitamin that cleans the arteries. All the studies of egg and people did not take into awareness that ham/bacon and eggs are always together.
I am an O and love a good steak BUT I have also gout where beef and shell fish are bad for. But Again I am a hunter and deer, rabbit and squirrel have no effect so I say cows fed corn and grains is the cause.
I got off the insulin after 1 month of Chia seeds in 16 oz bottle of water and a jelly with Chia seeds made with juice good for my blood type. I guess it is all about hydration mainly!
The blood type diet doesn’t work for my multiple health conditions especially being diabetic. I have to eat meat because it has no carbs.
good for you for lowering it lowering it naturally with Chia seeds I disagree with the medical profession prescribing medication for peoples healthcare. When when you do that, you affect other parts of your body and it doesn’t solve the problem. Everybody should heal naturally with nutrition and not support pharmaceutical companies hurting peoples body, and the doctor profession acting like they are in charge of healthcare when all they do is push drugs for pharmaceutical companies they should be ashamed of themselves. They should be called pharmaceutical representatives and not doctors. Thank you for your post.
No work seems to have been done on reactivating the pancreas which seems to get deactivated by severe throat infections and other cold related ailments treated with antibiotics, other than to proceed to a transplant which is not a long – lasting solution. (Am not a physician, only a Type II inflicted male)
Secondly, has the Jamun Tree (a berry tree in India) for its sugar lowering fruit been examined ? Village people cut a six-inch piece of its branch, soak it in water overnight and drink it to lower blood sugar !! Works !
The blood type diet doesn’t work for my multiple health conditions especially being diabetic. I have to eat meat because it has no carbs.
Very good research. Kudos to the scientists. Continue to hold high the flame of knowledge.
I’m not sure. I read too many reports to the negative. I just don’t like the drug based on what I’ve seen. I don’t know who funded this study, but I find it skeptical.
Metformin caused me to develop gastroparesis, which led to DKA. I was inpatient for nine days, two in ICU. Metformin is not administered in hospitals. Process of elimination, it was metformin. I now take insulin. Metformin is cheap. Insulin isn’t.
May want to consider ivermectin and pickle juice…
I highly doubt doctors all over would be prescribing it on a regular basis as the default go-to #1 for the past 50+ years of it was really that bad for us!
I’ve seen far more beneficial stuff about metformin than I have negativity. The one or two you’ve seen/heard are most likely smear campaigns by other pharmaceutical companies trying to pimp out their new, similar drug.
My mother’s been diabetic for 30 plus years, she’s been taking metformin for years. Now she was only 58 whe She developed cerebellum atrophy. We did genetic testing it is not hereditary does not run in our family. I have been working in medical offices for 25 years. I have noticed majority of diabetic patients develop same symptoms as my mother. I know diabetes damage nerves. But to cause cerebellum atrophy. Just wanted to put this out there to see if someone would like to look into this.
Good safety profile my butt. That crap messes with your vision it can cause Alzheimer’s and a bunch more. My daddy took it and he had problems with his eyes and he had Alzheimer’s. And I have an aunt and uncle on it and their mind is slipping. So that crap is hurting you more than it helping you. I stopped taking it .
I often wondered about how metformin works because I’m taking it to lower my insulin levels. I don’t have diabetes but I have hyperinsulinemia. I thought it was odd that I’m taking the same medication as a person who has the opposite problem.
Turns out they don’t know why.
Dr put me on one tablet metforman per day and 0.5mg of centric once a week for my type 2 diabetes
So I am also interested in how Metformin works in people with asthma as well. I read that it is also prescribed to asthmatics. As I understand it asthma is an inflamatory disease so what is its mechanism of action in this role?
After 12 years on Metformin I had lost 85 pounds making me so thin I just quit it . I found I was mis-diagnosed when I’m actually Type 1. Now have diabetes under control but I wonder if I really had diabetes at all. No one in my family had diabetes, I was basically in good health, once diagnosed with type 2 and started on meds they increased significantly over the years and my health deteriorated every year. I’ve always believed I was led into diabetes and have been going downhill health wise ever since. Through the last 20 years this has wreaked havoc on my body. I’m 72 and have no strength, eyesight has been a problem, afraid to eat and afraid I won’t wake up. I’ve had to seek mental health all over Diabetes. Still fighting!
Metformin is an interesting drug. But unless I have missed it, this doesn’t hint at how BSL is lowered. There must be a messenger slowing Glucose production or (less likely) opening an exit for it.
Guys, what are you saying? Stop mertformin production and administer it to no patient?
What’s your alternative to metformin that was proved to work and clear diabetes?
i have used methformin for a few days an quit..it was prescribed by my phycisian..i consulted with my gp..strict diet..sips of water throughout the day & exercise along with monitoring..i began my own research..my gp was correct i further researched for a way to try an keep my levels under control..powered flaxeed which i add daily into my diet..grapefruit in moderation only if levels are high..skin of the grapefruit i oven dry on low heat an blend into powder an refrigerate..its hard work an frustrating but end results is worth the effort instead of harming our mind an body..best of luck to all thats going through a this..god bless..the F in my email is f not F
I have type 2 diabetes and suffer from constipational bloating irritable bowel syndrome, my doctor put me on 1 type of Metformin and I was feeling and nearly throwing up the Metformin for over a week and my doctor put me on slow release Metformin, which also makes me feel sick, so I think I might have to talk to my doctor again to see what else they can put me on.
I have type 2 diabetes. I agree with several others that exercise and proper diet are the keys to controlling it. I also take Metformin, which some research suggests slows aging, reduces cancer risk, and has some other benefits. It seems safe enough, too. And cheap. But no strong effect on my blood sugars, by my measurements — again, that was diet and exercise, mainly.