Researchers at University of Utah Health have published published findings in Science Advances that examine the long-term effects of the ketogenic diet. Their results raise new questions about whether the ketogenic diet is safe or beneficial for metabolic health when followed for extended periods. Although the ketogenic diet was originally developed to help treat epilepsy, it has become popular for weight loss and for managing conditions such as obesity and type 2 diabetes. In this study, scientists used mice to explore how the diet alters metabolism over time, and they observed potentially harmful shifts in how the body handles fats and carbohydrates.
The ketogenic diet is built on very high fat intake and very low carbohydrate intake. By sharply reducing carbs, the body enters ketosis, a state in which fat is broken down into ketone bodies that serve as an alternative energy source for the brain. This metabolic switch can help reduce seizures, and it resembles some of the effects seen during fasting. However, while keto is often promoted for weight loss and improved metabolic health, much of the existing research has focused on short-term outcomes rather than long-term 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 an assistant professor at Earlham College, who led the work while a postdoctoral fellow at University of Utah Health.
How the long-term study was carried out
To address the lack of long-term data, the researchers ran an extended experiment in adult male and female mice. Animals were assigned to one of four diets: a high-fat Western-style diet, a low-fat high-carbohydrate diet, a classic ketogenic diet in which nearly all calories came from fat, and a protein-matched low-fat diet. The mice ate freely for nine months or longer.
Throughout the study, the team tracked body weight and food intake, tested blood lipid levels, measured fat accumulation in the liver, and assessed blood glucose and insulin. They also analyzed gene activity in insulin-producing pancreatic cells and used advanced microscopy to better understand the cellular changes underlying the metabolic effects they observed.
Keto limited weight gain but shifted body composition
Compared with mice eating a high-fat Western diet, mice on the ketogenic diet gained much less weight, in both males and females. But the pattern of weight change differed: when keto-fed mice did gain weight, it was mostly in fat mass rather than lean tissue.
Fatty liver disease appeared despite weight control
Even though the ketogenic diet helped prevent weight gain, it was associated with serious metabolic issues, some emerging within only a few 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, an assistant professor at University of Utah Health and senior author of the study.
The buildup of excess fat in the liver—fatty liver disease—is a major marker of metabolic dysfunction and is often linked to obesity. The researchers found that keto did not protect against fatty liver disease.
The effects also differed by sex. Male mice developed severe fatty liver disease and signs of impaired liver function, which the researchers described as an important indicator of metabolic illness. Female mice did not show significant liver fat accumulation. The team plans further work to understand why females appeared resistant in this experiment.
Blood sugar control worsened when carbs returned
The ketogenic diet also produced unexpected changes in blood sugar regulation. After two to three months on keto, mice showed low blood glucose and low insulin. However, the researchers found this came with a significant 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.”
Further testing suggested that the mice struggled to control blood sugar because pancreatic cells released too little insulin. The team believes prolonged exposure to very high fat levels may stress these cells and disrupt normal protein handling inside them. While the exact biological pathway is still being investigated, the researchers suspect this type of cellular stress contributes to impaired glucose control.
Notably, blood sugar regulation improved after the mice were taken off the ketogenic diet, indicating that at least part of the metabolic disruption may be reversible.
What this could mean for people
Animal results do not always translate directly to humans, but the study underscores potential long-term metabolic risks that remain poorly understood. The researchers say the findings suggest anyone considering keto should weigh possible benefits against possible harms.
“I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop said.
The study was published in Science Advances with the title “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.”
The research received funding from multiple institutes and organizations, including the National Institutes of Health and additional biomedical research foundations.
