A study published in Science Advances by University of Utah Health researchers sheds light on the long-term effects of the ketogenic diet, raising important questions about its safety and efficacy for improving metabolic health. While the ketogenic diet was historically used to treat epilepsy, it has recently gained popularity for weight loss and management of conditions like obesity and type 2 diabetes. The new study, performed with mice, demonstrates that the diet can have potentially dangerous impacts on metabolic health, including how the body processes fats and carbohydrates.

A ketogenic diet is a very high-fat, very low-carbohydrate diet that was originally used to treat epilepsy. The idea is that the ketogenic diet induces ketosis, a metabolic state that produces ketone bodies, which act as an alternative brain fuel, stabilizing neuronal activity and reducing seizures. In this way, the diet mimics starvation, where reduced glucose availability also limits seizures, while ketones derived from fat provide the main energy source for the brain. Over time, the diet has also been promoted for weight loss and metabolic health, but most studies have focused on short-term outcomes.

“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 address this gap, Gallop and her colleagues conducted a long-term study in mice, placing male and female adults on one of four diets: a high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet where almost all calories come from fat, and a protein-matched low-fat diet. The mice were allowed to eat as much as they wanted for nine months or longer.

Throughout the study, the team monitored body weight, food intake, blood fat profiles, liver fat accumulation, and the levels of blood sugar and insulin. They also investigated which genes were active in the pancreatic cells that produce insulin. Finally. they used advanced microscopy to uncover the cellular mechanisms underlying observed 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, pancreas 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. 

###
The results are published in Science Advances as “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.”
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.