Study Finds Ketogenic Diet Alters Long-Term Metabolic Health

A study from University of Utah Health published in Science Advances examined the lasting metabolic consequences of the ketogenic diet, revealing complex effects that extend beyond short-term weight loss. Once developed as a treatment for epilepsy, the ketogenic diet is characterized by very high fat and extremely low carbohydrate intake that triggers ketosis—a state in which the liver produces ketone bodies to fuel the brain. Over time, the diet has gained popularity for weight management and addressing metabolic disorders such as type 2 diabetes. Yet, most research has focused on short-term impacts rather than its sustained effects on metabolism.

According to study leader Molly Gallop, few investigations had looked comprehensively at long-term metabolic outcomes. To address this gap, Gallop and colleagues placed adult male and female mice on one of four diets for nine months or more: a high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet, or a protein-matched low-fat diet. The mice ate freely while researchers tracked their body weight, food intake, blood lipids, liver fat, glucose, and insulin levels, alongside gene activity in pancreatic insulin-producing cells and structural changes observed via microscopy.

The ketogenic diet prevented weight gain compared to the high-fat Western diet, as mice maintained lower body weights despite increased fat mass. However, these apparent benefits were accompanied by severe metabolic complications. “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 senior author Amandine Chaix. The team found that mice on the ketogenic diet developed fatty liver disease—a key marker of metabolic dysfunction—particularly in males, while females appeared protected from this effect.

After two to three months on the ketogenic diet, mice also exhibited impaired blood sugar regulation and reduced insulin secretion. When exposed to carbohydrates, their blood glucose rose sharply and remained elevated. The pancreatic cells showed stress and difficulty managing proteins, likely due to chronic exposure to dietary fat. Encouragingly, glucose control improved after mice returned to a regular diet. The study highlights potentially harmful consequences of long-term ketogenic dieting and urges individuals to seek medical advice before adopting it.