Animal study indicates ketogenic diet may impair blood sugar control and liver health — Evidence Review

A new study from the University of Utah Health finds that long-term ketogenic dieting in mice leads to fatty liver disease and impaired blood sugar regulation, raising concerns about its safety for metabolic health. While many previous studies report short-term benefits of ketogenic diets, these new results contrast with much existing research on liver fat and glucose control.

• Most clinical and short-term studies in humans report that ketogenic diets reduce liver fat and improve glycemic control, often alongside significant weight loss 1 2 4 6 7 9 10. However, the new mouse study observed fatty liver development and glucose intolerance with prolonged ketogenic feeding, especially in male mice.
• Some mechanistic animal studies support the idea that effective ketogenesis is protective against fatty liver; disruptions in ketone body production can promote hepatic fat accumulation 3 5. Yet, the new study suggests that even with ongoing ketogenesis, excessive dietary fat may overwhelm protective mechanisms over time.
• Short-term improvements in blood lipids and glucose control are well-documented, but the long-term impact remains uncertain. The current findings underscore the need for extended studies in humans to clarify potential risks of chronic ketogenic diets 6 7 9 10.

Study Overview and Key Findings

While the ketogenic diet is widely promoted for weight loss and metabolic disorders, most research has focused on short-term effects. The new study addresses the lack of long-term data by examining how months of ketogenic feeding affect metabolic health in both male and female mice. Notably, the research uncovers sex-specific differences in liver fat accumulation and provides mechanistic insights into how chronic high-fat intake may impair insulin secretion, highlighting risks not previously seen in short-duration studies.

Property	Value
Organization	University of Utah Health, Earlham College
Journal Name	Science Advances
Authors	Molly Gallop, Amandine Chaix
Population	Adult male and female mice
Methods	Animal Study
Outcome	Body weight, blood lipid levels, liver fat, blood sugar, insulin levels
Results	Ketogenic diet led to fatty liver disease and disrupted blood sugar control

Literature Review: Related Studies

To place these findings in context, we searched the Consensus database, which contains over 200 million research papers. The following search queries were used to identify relevant studies:

1. keto diet fatty liver disease
2. ketogenic diet blood sugar control
3. weight loss side effects ketogenic diet

Topic	Key Findings
Does the ketogenic diet reduce or promote fatty liver disease?	- Short-term ketogenic diets in humans generally reduce liver fat and improve NAFLD markers 1 2 4. - Animal studies suggest that intact ketogenesis protects against fatty liver, but disruption of ketone body production increases risk 3 5.
How does the ketogenic diet impact blood sugar control and diabetes?	- Ketogenic diets consistently improve glycemic control and reduce HbA1c and fasting glucose in type 2 diabetes over short and medium terms 6 7 9 10. - In type 1 diabetes, improved glycemia is sometimes offset by increased hypoglycemia and dyslipidemia 8.
What are the long-term metabolic effects and risks of ketogenic diets?	- Most human studies are short-term (≤6-12 months), showing benefits for weight and metabolic markers 6 7 9 10. - Evidence for long-term safety is limited; some studies note concerns about adherence, potential side effects, and possible liver and lipid abnormalities 8 9.
What mechanisms underlie the effects of ketogenic diets on the liver and glucose metabolism?	- Enhanced ketogenesis via HMGCS2 appears to protect against hepatic fat accumulation in mice, and overexpression improves steatosis and glucose homeostasis 3 5. - Ketogenic diets shift hepatic metabolism toward fat oxidation and ketone production, reducing triglyceride synthesis 2 3 5.

Does the ketogenic diet reduce or promote fatty liver disease?

Most clinical studies in humans report that ketogenic or very low-carbohydrate diets reduce liver fat and improve nonalcoholic fatty liver disease (NAFLD) markers, often alongside notable weight loss 1 2 4. Mechanistic mouse studies indicate that intact ketone body production is protective against hepatic steatosis, while loss of ketogenesis increases fatty liver risk 3 5. The new mouse study diverges from these findings, showing that long-term ketogenic feeding can promote fatty liver, at least in male mice.

• Human pilot and controlled trials show liver fat reduction and improved liver histology after short-term ketogenic dieting 1 2 4.
• Animal studies emphasize the importance of ketogenesis in safely disposing of hepatic fat; impaired ketone production worsens fatty liver 3 5.
• The new study found the opposite effect in mice over longer durations, with fatty liver developing even with ongoing ketogenesis.
• Sex differences were observed: male mice developed fatty liver while female mice did not, a distinction not commonly addressed in human trials.

How does the ketogenic diet impact blood sugar control and diabetes?

Short and medium-term human studies consistently find that ketogenic diets improve glycemic control in type 2 diabetes, lowering HbA1c, fasting glucose, and sometimes reducing medication needs 6 7 9 10. In type 1 diabetes, glycemic benefits are tempered by increased hypoglycemia and dyslipidemia risk 8. The new mouse study observed initial improvements in blood glucose and insulin, but longer-term ketogenic feeding led to impaired glucose tolerance and pancreatic dysfunction.

• Meta-analyses show significant reductions in blood glucose and HbA1c for type 2 diabetes patients on ketogenic diets 6 7 9 10.
• Improvements are generally maintained for up to 6-12 months, but long-term data are scarce 9 10.
• In type 1 diabetes, glycemic variability and dyslipidemia can offset benefits 8.
• The new study found that prolonged high-fat intake can eventually impair insulin secretion and glucose regulation in mice, effects which reversed after stopping the diet.

What are the long-term metabolic effects and risks of ketogenic diets?

Most clinical evidence for ketogenic diets comes from studies lasting 6-12 months, during which benefits are seen for weight, glucose, and lipid profiles 6 7 9 10. However, adherence often declines over time and data on long-term safety are limited. Some reports point to possible negative effects on lipid profiles and liver health, particularly with extended use or in the context of underlying metabolic risk 8 9. The new study provides direct evidence of adverse metabolic effects after nine months or more on a ketogenic diet in mice.

• Human studies show initial metabolic improvements, but the effects beyond one year are not well established 9 10.
• Concerns exist regarding sustainability, adverse lipid changes, and hepatic function with long-term use 8 9.
• The new mouse study uniquely documents the emergence of fatty liver disease and glucose intolerance with long-term exposure, especially in males.
• Reversibility of some metabolic changes after stopping the diet provides a potential avenue for further research.

What mechanisms underlie the effects of ketogenic diets on the liver and glucose metabolism?

Mechanistic studies in animals show that robust ketogenesis (via HMGCS2) allows efficient disposal of hepatic fat and supports glucose homeostasis 3 5. Ketogenic diets drive hepatic metabolism toward fat oxidation and ketone production rather than triglyceride synthesis, rapidly reducing liver fat in humans 2. The new study suggests that prolonged exposure to high dietary fat, even with active ketogenesis, can induce cellular stress in the pancreas and disrupt insulin secretion, indicating that protective mechanisms may be overwhelmed over time.

• Ketogenic diets promote ketone body production, which typically reduces liver triglyceride content 2 3 5.
• Loss of ketogenesis in mice results in spontaneous fatty liver and impaired glucose regulation 3 5.
• The new study found that sustained high-fat intake stresses pancreatic cells, leading to impaired insulin release and glucose intolerance.
• The interplay between dietary fat load, ketogenesis, and organ-specific effects requires further investigation to clarify long-term outcomes.

Future Research Questions

Despite extensive research on short-term effects, many questions remain about the long-term safety and mechanisms of ketogenic diets, especially in diverse populations. The new findings highlight the need for further studies in humans, a better understanding of sex differences, and exploration of the underlying biological mechanisms.

Research Question	Relevance
What are the long-term metabolic effects of the ketogenic diet in humans?	Most clinical studies are short-term; long-term impacts on liver health, glucose control, and lipid profiles remain unclear and need direct human evidence 6 7 9 10.
Are there sex-specific differences in metabolic responses to the ketogenic diet?	The new mouse study found male-female differences in liver fat accumulation, but these differences have not been systematically explored in human studies [current study].
What mechanisms drive fatty liver disease on prolonged ketogenic diets?	While ketogenesis is generally protective, this study suggests that high dietary fat may overwhelm hepatic and pancreatic adaptation, leading to steatosis and insulin dysfunction 3 5.
Can the metabolic effects of chronic ketogenic dieting be reversed in humans?	The mouse study found reversibility after discontinuing the ketogenic diet; understanding reversibility in humans could inform dietary recommendations and risk mitigation [current study].
How does dietary fat quantity and quality influence long-term outcomes of ketogenic diets?	The balance and type of fats in ketogenic diets may impact liver and metabolic health differently; most studies have not disentangled these effects 2 3 5.