The ketogenic diet has surged in popularity for its promises of weight loss and blood sugar control, but new research from University of Utah Health suggests the long-term effects may not be so simple.
In a study published in Science Advances, researchers found that extended adherence to a high-fat, low-carbohydrate diet caused serious metabolic problems in mice, including fatty liver disease and impaired insulin secretion.
“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, who led the study while at U of U Health.
The team placed male and female mice on one of four diets for nine months: a high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet and a protein-matched low-fat diet. The ketogenic group maintained lower body weights and avoided the obesity typical of the Western diet. But despite these apparent benefits, the keto-fed mice developed severe fat accumulation in the liver, a condition known as fatty liver disease, along with hormonal and metabolic disruptions.
“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, senior author and assistant professor of nutrition and integrative physiology at U of U Health. “The ketogenic diet was definitely not protective in the sense of fatty liver disease.”
The study also revealed a paradox in blood sugar regulation. After several months on the ketogenic diet, mice had low blood glucose and insulin levels, but when given carbohydrates, their blood sugar spiked dramatically and stayed high for longer than normal. The researchers traced the problem to stressed pancreatic cells that struggled to produce insulin, likely due to prolonged fat exposure.
“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.”
Interestingly, these effects disappeared once the mice were switched off the ketogenic diet, suggesting that some of the metabolic damage could be reversible.
While the study was conducted in mice, the findings raise important questions about the long-term safety of ketogenic diets for humans. The researchers note that sex differences were also observed: male mice were more prone to fatty liver, while females were relatively protected. Future studies will explore why.
“I would urge anyone to talk to a health care provider if they’re thinking about going on a ketogenic diet,” Gallop said.
This research was supported by the National Institutes of Health, including 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, as well as the Damon Runyon-Rachleff Innovation Award and the American Cancer Society.