SALT LAKE CITY, January 27, 2026
Ketogenic Diet’s Long-Term Effects Questioned in New Mouse Study
Research suggests the popular diet may disrupt metabolism and blood sugar control despite aiding weight loss.
- A long-term ketogenic diet in mice led to fatty liver disease and impaired insulin secretion.
- While the diet prevented weight gain, increases in fat mass were observed rather than lean tissue.
- Male mice experienced more severe liver problems than females, prompting further research into sex-specific effects.
- Blood sugar control worsened after prolonged keto, with a dangerous spike when carbohydrates were reintroduced.
- Experts urge anyone considering the diet to consult a healthcare provider.
The ketogenic diet, a high-fat, very-low-carbohydrate regimen, has exploded in popularity as a weight-loss tool and potential treatment for conditions like obesity and type 2 diabetes. But a new study from University of Utah Health raises concerns about its long-term metabolic consequences. Researchers found that while the diet curbed weight gain in mice, it also triggered a cascade of problems, including fatty liver disease and disrupted blood sugar control. The study highlights that the ketogenic diet, while effective for short-term weight loss, may not be a sustainable or healthy approach to metabolic health in the long run.
From Epilepsy Treatment to Diet Fad
Originally developed in the 1920s to manage epilepsy, the ketogenic diet forces the body into a metabolic state called ketosis. By drastically reducing carbohydrate intake, the body begins to break down fat into ketone bodies, which the brain can use for fuel. This process mimics the effects of fasting and can stabilize brain activity, reducing seizures. “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.
How the Study Was Conducted
To investigate the long-term effects, Gallop and her team conducted a nine-month experiment with adult male and female mice. The animals were divided into four diet groups: a high-fat Western diet, a low-fat high-carbohydrate diet, a traditional ketogenic diet consisting almost entirely of fat, and a protein-matched low-fat diet. Researchers meticulously tracked body weight, food consumption, blood lipid levels, fat accumulation in the liver, and blood sugar and insulin levels. They also analyzed gene activity in pancreatic cells and used advanced microscopy to examine cellular changes.
Weight Control Came at a Cost
Mice on the ketogenic diet gained significantly less weight compared to those consuming a high-fat Western diet. However, the weight loss wasn’t entirely positive. Any weight gain that *did* occur on the keto diet was primarily due to increased fat mass, not the development of lean muscle.
Fatty Liver Disease Emerged
Despite preventing weight gain, the ketogenic diet led to serious metabolic issues, some appearing 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,” explained Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at U of U Health and senior author on the study. Excess fat in the liver, known as fatty liver disease, is a key indicator of metabolic dysfunction and is often linked to obesity. “The ketogenic diet was definitely not protective in the sense of fatty liver disease,” Chaix added.
The study also revealed striking sex differences. Male mice developed severe fatty liver disease and impaired liver function, a significant sign of metabolic illness. Female mice, however, showed no substantial fat buildup in the liver, prompting the team to investigate this disparity further.
Blood Sugar Regulation Disrupted
The ketogenic diet also unexpectedly affected blood sugar regulation. After two to three months, mice exhibited low blood sugar and insulin levels. But this apparent benefit was overshadowed by a dangerous downside. “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.”
Researchers found that the mice struggled to regulate blood sugar because their pancreatic cells weren’t releasing enough insulin. They believe prolonged exposure to high fat levels stressed the pancreatic cells, interfering with their ability to process proteins. While the exact mechanism is still under investigation, the team suspects this cellular stress plays a crucial role in the impaired glucose response. Importantly, blood sugar regulation improved when the mice were taken off the ketogenic diet, suggesting some of the damage may be reversible.
What This Means for Humans
While results from mice don’t always directly translate to humans, the study underscores potential long-term metabolic risks that haven’t been fully explored. These findings suggest individuals considering the ketogenic diet should carefully weigh the potential benefits against the possible harms. “I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop cautioned.
The study, titled “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice,” appeared in Science Advances.
The research was funded 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). Additional support came from 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.
