Researchers at University of Utah Health have raised fresh concerns about the long-term safety of the ketogenic diet, one of the most popular dietary approaches for weight loss and metabolic health. Published in Science Advances, the study examined how prolonged adherence to the high-fat, low-carbohydrate diet affects metabolism, revealing potential risks that extend beyond short-term weight management.
Originally developed as a treatment for epilepsy, the ketogenic diet shifts the body into a state of ketosis, where fat is converted into ketone bodies to fuel the brain. While this metabolic state can stabilize neural activity and reduce seizures, the diet has gained widespread popularity for its effects on weight loss, obesity management, and type 2 diabetes. However, most research to date has focused on short-term outcomes, leaving questions about long-term effects largely unanswered.
“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, assistant professor at Earlham College, who led the study while at University of Utah Health.
Study Design and Methodology
To fill this knowledge gap, Gallop and her team conducted a long-term experiment using adult male and female mice. The animals were assigned to one of four diets: a high-fat Western diet, a low-fat high-carbohydrate diet, a traditional ketogenic diet, and a protein-matched low-fat diet. Mice were allowed to eat freely for nine months or longer, with researchers tracking body weight, food consumption, blood lipid levels, liver fat accumulation, and insulin and blood sugar responses. Advanced microscopy and genetic analysis of insulin-producing pancreatic cells provided further insights into cellular changes underlying these metabolic effects.
Weight Control Masked by Changes in Body Composition
Mice on the ketogenic diet gained significantly less weight than those on a high-fat Western diet, a trend observed in both sexes. However, weight gain that did occur was primarily from increased fat rather than lean muscle mass, indicating altered body composition despite overall weight control.
Fatty Liver and Metabolic Dysfunction Emerged
The study also revealed that the ketogenic diet can trigger serious metabolic issues, some developing within days. Excess fat accumulated in the liver, a hallmark of fatty liver disease and metabolic dysfunction. “The ketogenic diet was definitely not protective in the sense of fatty liver disease,” noted Amandine Chaix, PhD, assistant professor at University of Utah Health and senior author of the study.
Male mice were particularly affected, developing severe fatty liver disease and impaired liver function, while female mice showed minimal liver fat accumulation. Researchers plan to investigate the biological factors behind these sex-specific differences.
Blood Sugar Regulation Disrupted
Unexpectedly, the ketogenic diet also altered blood sugar control. After two to three months, mice had lower blood sugar and insulin levels. However, when carbohydrates were reintroduced, their glucose response was abnormal, with blood sugar rising sharply and remaining elevated for extended periods. Analysis suggested that prolonged high-fat intake stressed pancreatic cells, impairing their ability to secrete insulin effectively. Encouragingly, these effects were partially reversible once the diet ended.
Implications for Humans
Although mouse studies do not directly translate to humans, these findings highlight potential long-term risks of ketogenic diets, especially for metabolic health. “I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop advised.
The study, titled “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice,” underscores the need for caution and further research into the extended effects of this increasingly popular diet.
