A study finds that long-term keto dieting may come with hidden metabolic costs.
A recent study from the University of Utah Health, published in Science Advances, explores how the ketogenic diet affects the body over long periods and raises new concerns about its overall safety and effectiveness for metabolic health. Once used primarily to treat epilepsy, this high-fat, low-carbohydrate eating plan has become a popular method for weight loss and managing conditions such as obesity and type 2 diabetes. The researchers found that, in mice, long-term adherence to the diet may disrupt normal metabolic function and change how the body processes fats and sugars in ways that could be harmful.
The ketogenic diet works by sharply reducing carbohydrate intake so the body shifts into a state called ketosis. During ketosis, the liver produces molecules known as ketone bodies, which serve as an alternative fuel for the brain and help stabilize nerve activity, reducing the frequency of seizures. This process mirrors what happens during periods of starvation, when limited glucose forces the body to rely on fat for energy. Although keto has gained attention for its potential benefits in weight management and metabolic health, most studies until now have focused mainly on short-term effects rather than the long-term biological consequences.
“We’ve seen short-term studies and those just looking at weight, but not really any studies looking at what happens over the longer term or with other facets of metabolic health,” said Molly Gallop, PhD, now assistant professor of anatomy and physiology at Earlham College, who led the study as a postdoctoral fellow in nutrition and integrative physiology at U of U Health.
The keto diet prevents weight gain
To fill this research gap, Gallop and her team carried out an extended experiment using mice, assigning both males and females to one of four dietary plans: a high-fat Western diet, a low-fat and high-carbohydrate diet, a traditional ketogenic diet in which nearly all calories came from fat, and a protein-matched low-fat diet. The animals were allowed to eat freely for at least nine months.
During this period, the researchers tracked changes in body weight, eating behavior, blood fat composition, liver fat buildup, and levels of blood sugar and insulin. They also analyzed which genes were active in pancreatic cells responsible for insulin production and used high-resolution microscopy to observe the cellular processes linked to these metabolic changes.
The ketogenic diet successfully prevented weight gain in both sexes compared to the high-fat Western diet. Mice on the ketogenic diet maintained significantly lower body weights, with weight gain primarily attributed to increased fat mass rather than lean mass.
Keto is linked to fatty liver disease
Despite this apparent benefit, mice fed the ketogenic diet developed severe metabolic complications, with some changes starting within days.
“One thing that’s very clear is that if you have a really high-fat diet, the lipids have to go somewhere, and they usually end up in the blood and the liver,” said Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at U of U Health and senior author on the study.
The accumulation of fat in the liver, known as fatty liver disease, is a hallmark of metabolic disease associated with obesity. “The ketogenic diet was definitely not protective in the sense of fatty liver disease,” Chaix added.
The researchers observed notable differences in how male and female mice responded to the ketogenic diet: males developed severe fatty liver and had worse liver function, a key marker of metabolic disease, while females had no significant buildup of fat in the liver. The scientists plan to explore why female mice didn’t get fatty liver disease in future research.
Keto diet may harm blood sugar regulation
The study also revealed a paradox in blood sugar regulation. After two to three months on the ketogenic diet, mice had low levels of blood sugar and insulin.
“The problem is that when you then give these mice a little bit of carbs, their carb response is completely skewed,” Chaix said. “Their blood glucose goes really high for really long, and that’s quite dangerous.”
Mice couldn’t regulate their blood sugar properly because cells in the pancreas weren’t secreting enough insulin, the researchers discovered. Probably due to chronically high levels of fat in their environment, pancreatic cells showed signs of stress, unable to move proteins around like they should. The researchers think that the impaired blood sugar regulation is caused by this cellular stress, but identifying the exact mechanism is a future research direction.
Importantly, problems with blood sugar regulation reversed when mice went off the ketogenic diet, suggesting that at least some metabolic issues may not be permanent if the diet is stopped.
While mice and humans differ, the findings reveal previously unexplored long-term negative metabolic health risks that individuals considering the ketogenic diet should take into account. “I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop cautioned.
Reference: “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice” by Molly R. Gallop, Renan F.L. Vieira, Peyton D. Mower, Elijah T. Matsuzaki, Willisa Liou, Faith E. Smart, Seth Roberts, Kimberley J. Evason, William L. Holland and Amandine Chaix, 19 September 2025, Science Advances.
DOI: 10.1126/sciadv.adx2752
This work was supported by the National Institutes of Health, including the National Institute on Aging (grant number R01AG065993), the National Institute of Diabetes and Digestive and Kidney Diseases (grant numbers P30DK020579, F32DK137475, T32DK110966, DK108833, and DK112826), the National Heart, Lung, and Blood Institute (grant number HL170575), and the National Cancer Institute (grant number R01CA222570). Work was also supported by the Damon Runyon-Rachleff Innovation Award (DR 61-20) and the American Cancer Society (RSG-22-014-01-CCB). Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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37 Comments
😂 Total propaganda nonsense, funded by the NIH.
Exactly. Utter nonsense. Study used inappropriate model (mice) without verifying ketosis.
Misinterpreted adaptive physiological responses as pathology.
Contradicts abundant clinical evidence from humans.
Ignores massive real-world clinical success.
Funded by historically biased sources.
Essentially fear-mongering without mechanistic support.
HUMANS ARE NOT MICE. Any study not done on humans is not reliable in terms of the effects on humans.
Exactly
9 months isn’t long term. Mice are not humans. Keto fights fatty liver.
Dr Gerald Shulman and Dr Neal Barnard have unequivocally shown that saturated fat in high fat “keto” diets is THE cause of insulin resistance as measured definitively by the Oral Glucose Tolerance Test ( and not HbA1c , glucose or insulin levels which give artificial or false measures of glucose tolerance ). We have known this for more than two decades! Yet physicians get essentially zero training in nutrition! The only diet that will totally prevent AND reverse Type 2 Diabetes, as well as heart disease ( see the work of Dr Caldwell Esselstyn) and many other chronic diseases is a very low fat whole plant based no oil diet as shown for over 40 years by Dr John Mcdougall.
If anyone takes the time to read the study, at no time are the study subjects (mice) measured for ketosis. Additionally, the nice are fed and libitum ..meaning they are able to eat as many carbs as they want, even under the keto feed type.
This is INCOMPLETE science, at best and this paper needs to be withdrawn.
Even you article states it “MAY” before every statement. How about some actual facts. I’ve been on Keto for 7 years and am down 72lbs. My blood work is perfect at 60y/o. When I turned 50 I was overweight and bloodwork was a mess.
Everytime I see my MD he says “ good job” , and yes,, he knows what I’m doing.
Thanks for sharing, but that perspective is outdated and doesn’t hold up to current clinical experience or metabolic science.
1. Saturated fat doesn’t cause insulin resistance — excess carbohydrates and seed oils do. (Dr. Ken Berry, Dr. Georgia Ede)
2. OGTT is unreliable on low-carb diets — it reflects glucose adaptation, not pathology. (Dr. Georgia Ede)
3. Carnivore and ketogenic diets routinely reverse Type 2 Diabetes — often within weeks — without the nutrient deficiencies of plant-based diets. (Dr. Shawn Baker, Dr. Paul Saladino)
The vegan model is one theory. The carnivore approach is a proven clinical reality.
Ken “Dirty Needles” Berry get his license back?
Joker.
A poorly constructed study. Many studies in Humans show the metabolic health benefits of keto. The Nutrition establishment strikes again. They grow rich on your suffering.
Yes, yes agree!
If I had read at the beginning, that the NIH was in on the study, I would’ve not went any further. This is nonsense. Since going on the Keto diet (several years ago), I have lost over 50lbs., glucose and A1C are normal, and I’ve gotten off BP meds, PPI meds, (acid reflux), statens. I also exercise 5 days a week. I’m 70 years old.
Oh really? Oh no! Anyway. (Munches on ribeye steak)
LOLOLOLOLOL. This is utter propaganda.
Absolute nonsense. Mice are not supposed to normally eat high fat ketogenic diet. Long term ketogenic diet reverses type 2 diabetes, lowers triglycerides, preventing heart attacks, improve kidney health and increases insulin sensitivity. Pancreatic beta cells needs time to synthesize and secrete insulin after prolonged periods of insulin suppression and that is why glucose will rise after reintroducing carbohydrate. There is nothing pathological or concerning about that. Dr Ben Bikman explained all of these mechanisms years ago. There’s nothing new here. Stop scamming naive people.
The only types of fats that will lead to insulin resistance are polyunsaturated fats, NOT saturated fats.
The balance of O3 and O6 are thrown off by the consumption of said polyunsaturated fats, leading to a body’s cell membranes containing more O6 and less glucose transporters (GLUT-4), with said transporters being less efficient at ferrying glucose inside the cell as well.
That’s a bunch of bs. Fat doesn’t cause fatty liver, it’s carbs, like sugar.
If anyone takes the time to read the study, at no time are the study subjects (mice) measured for ketosis. Additionally, the nice are fed and libitum ..meaning they are able to eat as many carbs as they want, even under the keto feed type.
This is INCOMPLETE science, at best and this paper needs to be withdrawn.
I just don’t know how these scientists can take the liberty to draw conclusions about something they never measure (ketosis) among their animals.
The problem here is that many people will only read the title and maybe one paragragh, and then totally miss out on the real benefits of a keto lifestyle. This is pure trash, in my opinion.
How would this “science” explain the exceptional health of:
Dr. Anthony Chaffee
• Carnivore Duration: Over 12 years (with prior experience over 20 years ago)
• Details:
Dr. Chaffee began experimenting with the carnivore diet in the 1990s as a university athlete, eating only meat for 5 years, then returned to it more seriously later in life.
He describes himself as having eaten a strict carnivore diet for over a decade, with his views rooted in both medical research and personal experience.
Dr. Shawn Baker
• Carnivore Duration: Over 7 years (since ~2016)
• Details:
Dr. Baker is one of the earliest and most vocal pioneers of the modern carnivore movement.
He began his strict carnivore diet around 2016, documenting his journey openly.
He remains fully committed to this way of eating and regularly discusses his long-term experience with the diet’s effects on athletic performance and health.
I mean, come on…not mice, Drs and human ones.
Saturated fats do not cause fatty liver in humans… Insulin is the problem! It is highly inflammatory when it’s in excess and sending signals to the liver to package energy as glucose. If you’re eating too often and eating to excess, your pancreas’s is overworking itself and causing visceral and ectopic fat to build up in and around your organs. The problem is we eat too often. Even if your sugar is coming back down, the insulin stays in your system and is glycating your cells and mitochondria, causing inflammation and metabolic dysfunction. Time restricted eating keeps insulin low for the majority of each day. Don’t snack… Eat a couple meals a day in a 6-8 hour window and eat until you’re full, then don’t eat. Your body will get used to it very quickly and you’ll have less hunger during fasting times and more energy. You are not a rat, and these studies do not outweigh the evidence of 100,000s of people who are reversing insulin resistance and fatty liver through these methods I mentioned. Don’t listen to studies funded by Pharma or that look at rats. Watch what successful people are doing and copy them.
THANKS
Mice and humans can’t be compared when it comes to diet.
Both evolved very differently in that regard.
This is nonsense. My 16 year old son was diagnosed with fatty liver disease couple years ago. We tried everything and this year we decided on the keto diet. He’s lost over 30 lbs and no longer has fatty liver disease. His liver enzymes started at 98 and now they’re normal! He even has cheat days from time to time because he misses bread but he keeps between 30-50 carbs maximum a day. Keto has literally saved his life!
Clown propaganda. Gaslighting from who the heck knows, but this is not genuine. Follow the money most likely. Jump off a bridge sciencenow.
Everybody knows cavemen were vegan> Wink, wink wink wink.
In the interest of science , please list who the grants were funded by to rule out social or financial bias and link the peer reviews for each grantee number referenced. Science shouldn’t leave room for yellow journalism.
We both know they won’t be doing that John, lol.
I thought we were already clear that a ketogenic diet worsens glucose tolerance due to the phenomenon of “glucose sparing:” insulin is low and is kept low in order to save as much glucose as possible for tissues and organs (brain, kidneys, red blood cells) that have an absolute requirement for it. As the article calls out, this condition usually reverses a while after returning to a high carb diet. The insulin resistance while on the ketogenic diet isn’t a bug; it’s a feature.
…this is trolling, right? Nobody can actually believe something so untrue, right?
The woman who oversaw this study is pure evil
They need to do this study on actual humans. There results will be very different. Also most individuals doing keto are not doing it with a western diet flare. They are eating healthy fats and vegetables. Contrary to what this study claims I’ve had a different experience. I did keto strictly for two years. When I stopped I didn’t gain my weight back. My liver actually improved its function likewise my body metabolizes through sugar faster now.
It doesn’t stay high for very long at all. I’m actually more sensitive to it now and can’t physically handle eating what everyone else eats, sugar wise. Most people consume a ton of sugar and don’t even think about it.
Likewise my average blood sugar is below 100, even when I do eat highly sugary items like others. It’s actually improved my overall digestive system and even helped eliminate flares of IBS.
I’m not buying this for a second. It’s keto for life for me!
just ran this article through Proplexity AI by having it research the actual study and asking for criticism against it. Sounds familiar.
The actual study, published in Science Advances by University of Utah Health, was a controlled experiment on mice fed a long-term, very high-fat ketogenic diet (about 90% fat) and compared to other diets. It found that, while the keto diet limited weight gain and led to lower body weights, the mice—especially males—developed severe metabolic problems: fatty liver disease, hyperlipidemia (high blood fat), and glucose intolerance due to impaired insulin secretion. Some of these problems reversed when the diet was stopped.
Key criticisms and limits of this study:
Animal Model Only: The study was conducted exclusively on mice, not humans. Experts caution that mouse biology does not always translate to human outcomes. Many interventions found effective or harmful in mice frequently fail when replicated in people.
Extreme Diet Composition: The mouse “keto” diet used in the study was about 90% fat, far higher and unrepresentative of most human ketogenic diets, which are usually less extreme and often medically supervised.
Duration Relativity: The feeding period (~9 months–1 year for mice) is equivalent to decades in human terms, making direct translation to shorter human use uncertain.
Conflicting Rodent Research: Previous rodent studies on ketogenic diets have shown mixed results, with some reporting improved metabolic health and longevity. This raises questions about the consistency and reproducibility across models and diet formulations.
Sex-Specific Effects: The study found that harmful effects (like fatty liver) were mainly in male mice, with female mice less affected, suggesting complex biological interactions not addressed by the authors.
Critique from Experts: Some researchers, including those with experience in human clinical trials, warned about the risk of overinterpreting animal data, as the vast majority of promising rodent findings do not pan out in human RCTs, which remain the gold standard for guidance.
Summary:
The study raises theoretical concerns about long-term ketogenic diets but is limited by its use of an extreme mouse diet, species differences, and lack of human data. Criticism focuses on the limited relevance to typical human diets and the caution not to generalize mouse findings to people. RCTs in humans are needed to confirm these effects.