Summary: A new long-term study in mice finds that while the ketogenic diet prevents weight gain, it can provoke serious metabolic problems. Researchers report that prolonged adherence to a high-fat, very-low-carbohydrate ketogenic regimen led to fatty liver, elevated blood lipids, and impaired blood sugar control driven by stressed insulin-producing cells in the pancreas.

These adverse effects were more pronounced in male mice; female mice showed partial protection against liver fat accumulation. The results call for caution and medical supervision for anyone considering long-term ketogenic dieting, and suggest some harmful changes may reverse after the diet is discontinued.

Key Facts:

• Metabolic strain: Long-term ketogenic feeding increased blood lipids and promoted fat deposition in the liver while disrupting normal insulin secretion.
• Sex differences: Male mice developed more severe fatty liver and liver dysfunction than females, who showed relative resistance to hepatic fat buildup.
• Reversibility: Several measures of impaired blood sugar regulation improved after mice returned to a standard diet, indicating some effects may not be permanent.

Source: University of Utah

Overview: A study published in Science Advances by University of Utah Health researchers examined the long-term metabolic consequences of a classic ketogenic diet. While short-term trials have emphasized weight loss and improvements in some metabolic markers, this controlled long-term mouse study reveals significant risks to liver function and glucose regulation when the diet is maintained for months.

The ketogenic diet is a very-high-fat, very-low-carbohydrate eating plan originally developed to reduce seizures in epilepsy. By restricting carbohydrates, the body shifts to burning fat and producing ketone bodies, which serve as an alternative fuel for the brain. In recent years, many people have adopted keto approaches to lose weight or try to improve metabolic conditions such as obesity and type 2 diabetes. However, most human and animal studies have focused on short-term effects, leaving long-term outcomes underexplored.

“Many studies look only at weight or short-term outcomes,” said Molly Gallop, PhD, who led the research as a postdoctoral fellow at University of Utah Health and is now an assistant professor of anatomy and physiology at Earlham College. “We wanted to understand what happens with prolonged exposure to a ketogenic diet across multiple aspects of metabolic health.”

The ketogenic diet prevented weight gain but produced other harms

To evaluate chronic effects, researchers placed adult male and female mice on one of four diets for nine months or longer: a high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet in which nearly all calories come from fat, and a protein-matched low-fat diet. Mice had unrestricted access to food, and investigators tracked body weight, calorie intake, blood lipid profiles, liver fat, glucose and insulin levels, and gene activity in pancreatic islet cells. High-resolution microscopy was used to examine cellular changes underlying metabolic dysfunction.

The ketogenic diet did prevent weight gain: mice on the keto regimen maintained significantly lower body weights than those on the high-fat Western diet. Weight differences were mainly due to changes in fat mass rather than lean mass. Despite this apparent benefit, important metabolic harms emerged with prolonged ketogenic feeding.

Long-term keto feeding led to fatty liver and altered liver function

Researchers observed that the high-fat composition of the ketogenic diet caused lipids to accumulate in the bloodstream and the liver. This hepatic steatosis, or fatty liver disease, is a key marker of metabolic illness and can impair liver function.

“When you consume a very high-fat diet for an extended period, the excess lipids have to be processed somewhere — and they often end up in the liver and blood,” said Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at University of Utah Health and senior author of the study. In this experiment, male mice developed significant fatty liver and showed worse liver function; female mice had less liver fat, a sex difference the team plans to investigate further.

Keto impaired insulin secretion and glucose regulation

A paradox emerged in measures of blood sugar control. After two to three months on the ketogenic diet, mice exhibited low fasting blood glucose and low circulating insulin. However, when given carbohydrate challenges, these same mice mounted exaggerated and prolonged spikes in blood glucose, indicating poor glucose tolerance.

The investigators traced this defect to the pancreatic islets: insulin-producing beta cells showed molecular and structural signs of stress. Transcriptomic profiling indicated activation of endoplasmic reticulum (ER) and Golgi stress pathways, and electron microscopy revealed dilated Golgi structures consistent with impaired processing and trafficking of insulin granules. Functionally, both whole-animal clamp studies and ex vivo glucose-stimulated insulin secretion assays demonstrated reduced insulin release.

The team interprets these findings to mean that chronic exposure to a high-lipid environment compromises the ability of beta cells to synthesize, traffic, and secrete insulin appropriately, which in turn undermines blood sugar control. Importantly, when mice were taken off the ketogenic diet and returned to a standard diet, several measures of glucose regulation improved, suggesting partial reversibility of the dysfunction.

While mouse models do not perfectly replicate human physiology, the results highlight previously underappreciated long-term metabolic risks associated with sustained ketogenic dieting, especially for liver health and insulin secretion. “People considering a long-term ketogenic diet should consult health care providers and weigh potential benefits against these risks,” Gallop advised.

Funding: This research was supported by multiple grants from the National Institutes of Health, including awards from the National Institute on Aging, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung, and Blood Institute, and the National Cancer Institute. Additional support came from the Damon Runyon-Rachleff Innovation Award and the American Cancer Society. The content is the responsibility of the authors.

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About this research and reporting

Author: Sophia Friesen
Source: University of Utah
Contact: Sophia Friesen, University of Utah
Image credit: Neuroscience News

Original research (open access): “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice” by Molly Gallop et al., Science Advances. The study reports transcriptomic and ultrastructural evidence that chronic ketogenic feeding causes ER/Golgi stress and defective insulin granule trafficking in pancreatic islets.

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Abstract

A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice

Ketogenic diets (very-low-carbohydrate, very-high-fat) are increasingly used to address obesity and type 2 diabetes, but their extended effects on metabolic health are not well understood. In male and female mice, long-term ketogenic feeding prevented weight gain and induced weight loss but eventually caused hyperlipidemia, hepatic steatosis, and marked glucose intolerance. Unlike conventional high-fat diet–fed mice, ketogenic-fed mice remained insulin sensitive while exhibiting low circulating insulin. Physiological and ex vivo assays showed systemic and cell-intrinsic defects in insulin secretion. Islet transcriptomics revealed ER and Golgi stress and impaired ER–Golgi protein trafficking; electron microscopy confirmed a dilated Golgi network consistent with defective insulin granule processing. These results indicate that prolonged ketogenic dietary exposure produces multiple adverse metabolic changes and advise caution in its sustained use as a health intervention.