A recent groundbreaking study from University of Utah Health, published in Science Advances, offers compelling insights into the long-term metabolic impacts of the ketogenic diet, challenging prevailing assumptions about its safety and therapeutic value. While the ketogenic diet has long held esteem as an effective intervention for epilepsy and, more recently, as a popular regimen for weight loss and metabolic disease management, this new research elucidates critical metabolic disturbances that arise with extended adherence to the diet, revealed through rigorous experimental inquiry using murine models.
The ketogenic diet, characterized by its extreme macronutrient composition—high fat, minimal carbohydrates, and moderate protein—induces a metabolic state known as ketosis. In ketosis, the body shifts from utilizing glucose as the primary energy substrate to deriving energy from ketone bodies synthesized from fat. This metabolic rewiring has been historically harnessed to stabilize neuronal excitability in epileptic patients, reducing seizures by replicating a starvation-like physiological condition where glucose scarcity limits neuronal overactivity. However, while short-term benefits on weight and glucose regulation have been demonstrated, long-term data remain scarce, a gap this study robustly addresses.
Under the leadership of Dr. Molly Gallop and senior author Dr. Amandine Chaix, researchers subjected adult male and female mice to four distinct diet regimens over an extensive period exceeding nine months: a standard high-fat Western diet, a low-fat high-carbohydrate diet, a classic ketogenic diet constituting nearly all calories from fat, and a protein-matched low-fat diet. The mice’s spontaneous feeding behaviors were unrestricted, mimicking ad libitum human consumption patterns, allowing the team to capture authentic metabolic responses devoid of caloric restriction artifacts.
During this longitudinal assessment, body composition was meticulously tracked alongside a comprehensive metabolic profiling regime. Blood lipid concentrations, hepatic fat infiltration, glycemic indices, insulin plasma levels, and pancreatic islet gene expression patterns were systematically evaluated. Moreover, advanced microscopic analyses unraveled subcellular alterations in pancreatic beta cells, key regulators of insulin secretion, thus providing mechanistic context to observed physiological perturbations.
Initial findings confirmed the ketogenic diet’s robust efficacy in preventing weight gain relative to the Western diet. Both male and female subjects exhibited significantly lower body weights, predominantly attributed to a reduced fat mass accrual rather than changes in lean mass. Such results reinforce the ketogenic diet’s reputation as a weight management strategy; however, these benefits came at a substantial metabolic cost.
Foremost among these adverse effects was the progressive development of severe hepatic steatosis, commonly known as fatty liver disease, predominantly pronounced in male mice. This pathological fat accumulation within the liver is a hallmark of metabolic syndrome and a precursor to more severe conditions such as non-alcoholic steatohepatitis (NASH) and cirrhosis. Intriguingly, female mice displayed resistance to this phenotype, a sex-specific differential that signals complex biological interactions and hormonal modulatory effects that warrant future exploration.
The mechanistic underpinnings of this hepatic lipid overload appear to stem from the sheer abundance of dietary lipids that overwhelm conventional metabolic clearance pathways. Dr. Chaix explains that the excessive fatty acid influx necessitates ectopic storage in blood and hepatic tissues, exacerbating lipotoxicity and compromising liver function. This finding starkly contrasts with the common perception that ketogenic diets universally confer protective metabolic effects.
Further complicating the metabolic landscape was the dysregulation of glucose homeostasis observed in long-term ketogenic diet-fed mice. After sustained exposure exceeding two months, subjects exhibited hypoglycemia and hypoinsulinemia at baseline. Paradoxically, when challenged with carbohydrate intake, these mice demonstrated exaggerated and prolonged hyperglycemic excursions due to impaired pancreatic insulin secretion. This glucose intolerance is indicative of beta-cell dysfunction precipitated by chronic lipid exposure.
Delving into cellular phenomena, pancreatic beta cells displayed signs of endoplasmic reticulum stress and disrupted intracellular protein trafficking—processes critical for appropriate insulin synthesis and exocytosis. These molecular disturbances likely impair the cells’ capacity to mount an adequate insulin response to glycemic loads. The study highlights a novel pathological axis linking dietary fat overload to beta-cell secretory failure, a phenomenon that may underpin the observed glycemic dysregulation.
Notably, the metabolic impairments were partially reversible. Upon cessation of the ketogenic diet, the mice showed restoration of normal blood glucose regulation, signifying that these diet-induced abnormalities are at least transient. This reversibility underscores the importance of dietary modulation and raises questions regarding the long-term cannabinoid safety should such diets be followed indefinitely.
While extrapolation from mice to humans requires caution, these findings compel a reevaluation of extended ketogenic diet deployment, especially given its increasing popularity for managing obesity and type 2 diabetes. The study’s revelation of significant risks—including fatty liver and impaired insulin secretion—mandates close collaboration with healthcare providers before embarking on sustained ketogenic regimens.
The research received robust support from multiple NIH institutes, including the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, as well as foundations such as the Damon Runyon Cancer Research Foundation and the American Cancer Society, reflecting its critical relevance to public health domains.
In sum, this long-term examination of ketogenic dieting presents a nuanced portrait of metabolic health—a promise of weight control shadowed by potential hepatic and pancreatic dysfunction. It accentuates the complex biochemical interplay underpinning diet-induced metabolic states and highlights the indispensable role of rigorous, longitudinal research in informing evidence-based nutritional guidance.
Subject of Research: Animals
Article Title: A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice
News Publication Date: 19-Sep-2025
Web References: http://dx.doi.org/10.1126/sciadv.adx2752
References:
Chaix, A. et al. (2025). A long-term ketogenic diet causes hyperlipidemia, liver dysfunction, and glucose intolerance from impaired insulin secretion in mice. Science Advances. DOI: 10.1126/sciadv.adx2752
Image Credits: Charlie Ehlert / University of Utah Health
Keywords: High fat diets, Diets, Metabolism, Insulin secretion, Lipid metabolism, Metabolic health, Diabetes, Fatty liver disease, Metabolic disorders
