- Ketogenic diets that provide most of the daily calorie intake from fats have gained considerable attention as a lifestyle intervention for managing obesity and diabetes.
- Despite its popularity and effectiveness in promoting short-term weight loss, some human and animal studies suggest an adverse impact of a keto diet on metabolic health.
- A new long-term study conducted in mice now shows that a keto diet causes an increase in blood lipid (fat) levels, excessive fat storage in the liver, and impaired glucose regulation.
- These results raise concerns about the use of a keto diet for the management of obesity and diabetes and underscore the need for a cautionary approach.
Ketogenic or keto diets are high-fat, low-carbohydrate diets that have been used to manage seizures and promote weight loss.
The keto diet was effective in inducing weight loss in mice with obesity but still had a negative impact on metabolic health.
One of the study authors, Amandine Chaix, PhD, an assistant professor of nutrition and integrative physiology at the University of Utah, noted that these effects of the keto diet on glucose regulation were reversible after its discontinuation.
Chaix told Medical News Today that the study “results suggest that more studies are warranted in humans to establish the cardiometabolic benefits and risks of prolonged [keto diet] feeding.”
These findings underscore the consideration of long-term risks of a keto diet in the clinic despite its potential to cause weight loss and the need for further research in animals and humans.
The
While the amount of calories obtained from fats in a keto diet can vary from 70% to 90%, a classic keto diet involves 90% of the daily energy intake in the form of fats. It works by forcing the body to use fats as a source of energy instead of glycogen.
The body breaks down ingested carbohydrates into glucose, which is then stored as glycogen in the liver and muscles. These glycogen stores are subsequently used to provide energy.
The depletion of glycogen stores after prolonged fasting or consuming a keto diet causes the body to break down fat into ketone bodies. These ketone bodies can then be used by the body as a source of energy.
Studies in rodent models have generally shown that a ketogenic diet is effective in inducing weight loss, but a few
Notably,
Moreover, the effects of a keto diet on the body’s ability to metabolize carbohydrates and maintain normal blood glucose levels are not well understood, with some studies showing improvements in glucose regulation and others showing
In the present study, the researchers aimed to further examine the long-term impact of a keto diet on the metabolic health of mice.
The present study looked at mouse models maintained on either a keto diet, a high-fat diet, a low-fat-moderate-protein diet, or a low-fat diet. The mice in the keto diet group were maintained on a classic keto diet that provided 90% of the daily calories from fat.
The high-fat diet provided 60% of the daily calories from fats and has been used to mimic the effects of obesity in rodent models. The two control groups consisted of mice maintained on a low-fat diet, with proteins providing either 10% or 20% of the daily calories.
The researchers measured long-term changes in the metabolic health of male and female mice after at least 27 and 15 weeks, respectively, from the start of the study.
While mice in both the keto diet and high-fat diet groups showed weight gain in comparison with the low-fat diet groups, the mice on the keto diet gained less weight than those in the high-fat diet group.
In addition, the mice in the keto diet group had higher levels of plasma lipids or fats, including triglycerides, than the high-fat diet and low-fat diet groups. Plasma cholesterol levels were also elevated in both the high-fat and keto groups.
This profile of elevated plasma lipids in the keto diet group suggested a decline in liver function. Further examination of the mice in the keto and high-fat diet groups revealed excessive storage of fats in the liver, or fatty liver disease, and liver inflammation. However, female mice in the keto diet group did not show signs of fatty liver disease.
The mice in the keto diet group also showed impaired glucose tolerance, which refers to the body’s ability to use and store glucose, a type of sugar. Glucose intolerance is characterized by the persistence of higher blood glucose levels after a meal.
Insulin is released after a meal and facilitates the uptake of glucose by the liver and muscles. Inadequate release of insulin or the lack of an adequate response of tissues to insulin can lead to elevated blood sugar levels or glucose intolerance.
Glucose intolerance was observed in mice in both the keto and high-fat diet groups but was more pronounced in the keto diet mice. The mice in the high-fat diet group showed insulin resistance due to a lack of sufficient response to insulin, whereas the mice in the keto group did not release sufficient insulin to normalize blood glucose levels.
To understand the mechanism underlying the inadequate insulin secretion in the mice on the keto diet, the researchers then examined changes in the islet cells of the pancreas that produce and secrete insulin.
The researchers found evidence suggesting a dysfunction of cellular structures that are involved in the transport and release of insulin.
At the same time, however, mice that were maintained on a keto diet for a long time showed improvements in glucose tolerance within 4 weeks after switching to a low-fat diet.
To understand the effects of a keto diet on individuals with preexisting conditions like obesity or diabetes, the researchers examined the impact of feeding a keto diet to mouse models of obesity.
While a keto diet was able to induce weight loss in these mice, they continued to exhibit high blood lipid levels and impaired glucose regulation. Notably, a low-fat diet was more effective in inducing weight loss in the mice with obesity while improving blood lipid levels and glucose regulation.
In other words, even though a keto diet may be effective in inducing weight loss in obese mice, it was associated with adverse effects on metabolic health. In contrast, a low-fat diet may be more effective than a keto diet in inducing weight loss while improving metabolic health.
A salient feature of this study was the maintenance of the animals on the keto diet for almost a year. Chaix told us:
“Our diet intervention was maintained for about a year, which represents approximately one third of a mouse’s lifespan, allowing us to assess long-term consequences of feeding a keto diet versus much faster than we could in humans.”
“[Furthermore], this is a very comprehensive study that carefully examined multiple biomarkers of cardiometabolic health, including a glucose challenge mimicking what may happen in people going off a keto diet,” the researcher added.
In their study, the researchers noted that the keto diet they used in the study had higher levels of fats than generally consumed by individuals following this dietary approach, namely: 4 grams (g) of fat to 1 g of carbohydrates and protein.
“To address this, we also put mice on a high protein, high-fat non-ketogenic diet which caused similar problems to a ketogenic diet and thereby suggesting that other high-fat, low-carbohydrate diets, like what many people consume, may also pose a risk to metabolic health if our mouse models recapitulate what happens in humans,” said the study’s first author, Molly Gallop, PhD.
Gallop further noted, however, that “[a] caveat to this study is that it was conducted in mice, so the results may not necessarily recapitulate what happens in humans.“
“While there is evidence that hyperlipidemia is a side effect of a ketogenic diet for epilepsy treatment in children, and other studies in humans suggest that a ketogenic diet impairs the body’s ability to respond to glucose, our study warrants more research in humans,” she added.
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