Recent research from University of Utah Health, published in Science Advances, investigates the long-term implications of the ketogenic diet. These findings raise significant questions about the safety and effectiveness of the diet for enhancing metabolic health over prolonged periods. Initially developed as a treatment for epilepsy, the ketogenic diet has gained popularity in recent years for weight loss and managing conditions like obesity and type 2 diabetes. This study utilized mice to assess how the diet affects metabolism over time, with results indicating potentially unfavorable changes in the body’s management of fats and carbohydrates.
The foundation of the ketogenic diet lies in its very high fat content and minimal carbohydrates. It was originally designed to control seizures in epilepsy patients. By drastically lowering carbohydrate intake, the diet induces a state known as ketosis, in which fat is converted into ketone bodies that provide an alternative energy source for the brain. This metabolic shift stabilizes brain activity and reduces seizure frequency, similar to fasting impacts. Although the diet has been promoted for weight loss and improving metabolic health, existing research has largely focused on short-term effects rather than long-term consequences.
“While short-term studies and those concentrating on weight loss have been conducted, there has been a lack of investigations into the long-term effects or additional aspects of metabolic health,” remarked Molly Gallop, PhD, who led the study as a postdoctoral fellow in nutrition and integrative physiology at U of U Health and is now an assistant professor of anatomy and physiology at Earlham College.
How the Long-Term Study Was Conducted
To fill this research gap, Gallop and her team implemented a long-term experiment involving adult male and female mice. The mice were divided into four dietary groups: a high-fat Western diet, a low-fat high-carbohydrate diet, a traditional ketogenic diet that derived nearly all calories from fat, and a protein-matched low-fat diet. They were allowed free access to food for nine months or longer.
Throughout the experiment, researchers monitored changes in body weight, food consumption, blood lipid levels, fat accumulation in the liver, as well as blood sugar and insulin levels. Additionally, the team investigated active genes in insulin-producing pancreatic cells and employed advanced microscopy techniques to deepen their understanding of the cellular changes related to the observed metabolic effects.
Keto Prevented Weight Gain but Changed Body Composition
When comparing the ketogenic diet to a high-fat Western diet, mice on the ketogenic diet experienced significantly less weight gain, a trend evident in both male and female subjects. Notably, however, the weight changes were not uniformly distributed. Any weight gain observed in the ketogenic cohort primarily resulted from increased fat mass rather than lean muscle.
Fatty Liver Disease Emerged Despite Weight Control
While the ketogenic diet helped mitigate weight gain, it also triggered serious metabolic complications, some appearing within just days of the dietary change.
“It’s evident that a high-fat diet forces lipids to accumulate somewhere, typically in the bloodstream and liver,” said Amandine Chaix, PhD, assistant professor of nutrition and integrative physiology at U of U Health and the study’s senior author.
The buildup of excess fat in the liver, known as fatty liver disease, serves as a key indicator of metabolic dysfunction and is frequently associated with obesity. “The ketogenic diet did not provide protection against fatty liver disease,” Chaix added.
The researchers observed notable gender differences; male mice developed severe fatty liver disease and impaired liver function, significant indicators of metabolic issues. In contrast, female mice showed no considerable fat accumulation in the liver. Future studies aim to explore why female mice appear to exhibit resistance to this condition.
Blood Sugar Control Was Disrupted on Keto
The ketogenic diet also caused unexpected disruptions in blood sugar regulation. After two to three months on the diet, mice exhibited low blood sugar and insulin levels. However, this apparent advantage came with a concerning drawback.
“The issue arises when these mice are exposed to even a small amount of carbohydrates; their response is severely impaired,” Chaix explained. “Their blood glucose levels spike significantly and persist for an extended duration, posing a significant risk.”
Further analysis revealed that the mice struggled to maintain blood sugar levels because their pancreatic cells were insufficiently secreting insulin. The researchers suspect that prolonged exposure to high fat may stress the pancreatic cells and hinder their protein transportation capabilities. Although the exact biological mechanisms await further study, the team believes this cellular stress is central to the observed glucose regulation problems.
Encouragingly, the blood sugar regulation improved once the mice were removed from the ketogenic diet, indicating that some of the metabolic damage may be reversible.
What the Findings Mean for People
While findings from mice do not always directly translate to human physiology, this research highlights potential long-term metabolic risks that have not previously been explored in depth. Individuals contemplating the ketogenic diet should carefully consider the possible benefits alongside the potential health risks.
“I strongly recommend that anyone thinking about adopting a ketogenic diet consult with a healthcare provider,” Gallop advised.
The study is available in Science Advances under the title “A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice.”
This research received funding from various entities, including the National Institutes of Health, which provided grants associated with multiple institutes. Additional support came from the Damon Runyon-Rachleff Innovation Award and the American Cancer Society. The content reflects the views of the authors and does not necessarily represent the official positions of the National Institutes of Health.
