Ketogenic diet: origins, mechanisms and scientific evidence

In recent years the ketogenic diet (keto diet) has become one of the most discussed dietary models both in the clinical field and in mainstream communication. Unlike many diet 'fads', the keto diet boasts a solid biochemical foundation and a clinical history of over a century. Its fundamental principle consists of drastically reducing the intake of carbohydrates — generally below 50 grams per day, and in many clinical protocols under 20 g — thus inducing in the body a metabolic state known as nutritional ketosis: in this condition the liver produces ketone bodies (β-hydroxybutyrate, acetoacetate, acetone) from fatty acids, which become the main source of energy for the brain, muscles, and organs, replacing glucose.

Thescientific interest For this nutritional strategy, growth has been exponential: from the management of obesity to type 2 diabetes, from gut microbiota to neurological health, from cardiovascular diseases to applications in psychiatry, the number of randomized studies and systematic reviews published in peer-reviewed journals has increased exponentially. This article illustrates the basics of the ketogenic diet, traces its history, describes the criteria and stages of the protocol, and systematically presents the main evidencescientific evidence emerging in recent years.

History of the ketogenic diet

The roots of the keto diet lie in the ancient observation that the fasting can reduce the frequency of epileptic seizures. Already in the 5th century BC Hippocratic texts documented its beneficial effects. The modern breakthrough occurred in 1921, when endocrinologist Rollin Woodyatt described the production of ketone bodies following fasting or a high-fat, low-carb diet. In the same year Dr. Russell Wilder of the Mayo Clinic coined the term ‘ketogenic diet’ and systematically applied it to patients with epilepsy, publishing results on three clinical cases. Wilder's insight was brilliant: if fasting reduces seizures because it induces ketosis, a diet that mimics fasting metabolism — high in fat, low in carbohydrates, and moderate in protein — could sustainably produce the same effect.

In the following decades the protocol spread rapidly. Between the 1920s and 1930s of the 20th century more than ten studies were published on over 400 patients, with encouraging results in controlling seizures, especially in drug-resistant children. The discovery and spread of antiepileptic drugs starting from the 1950s marginalized the keto diet from the clinical arsenal for almost four decades.

The resurgence is partly due to the Abraham family: the child Charlie, suffering from refractory epilepsy, achieved extraordinary seizure control thanks to the ketogenic diet in 1994; the father, film producer Jim Abrahams, founded the Charlie Foundation, contributing to funding research and spreading the protocol. From that moment on, scientific interest regained momentum, progressively expanding far beyond the neurological field: ‘obesity medicine’, diabetology, cardiology, gastroenterology, psychiatry, and oncology began to examine the metabolic potential of ketone bodies as signaling molecules, anti-inflammatory agents, and microbiota modulators.

Ketogenic diet: criteria, variants and phases of the protocol

Definition and macronutrients

The ketogenic diet is defined as a dietary regimen with very low carbohydrate content (Very Low Carbohydrate Ketogenic Diet, VLCKD), typically structured with the following caloric distribution:

• fats: 60–75% of total calories (sometimes up to 80–90% in the classical antiepileptic protocol);
• proteins: 15–30%;
• carbohydrates: 5–10% (≤ 20–50 g/day, depending on the protocol).

There are different variants clinical and applicative:

• The Classic Keto (lipid:non-lipid ratio = 4:1) is used in pediatric neurology;
• The Very Low Calorie Ketogenic Diet (VLCKD or VLEKT, Very Low Energy Ketogenic Therapy) integrates high-protein meal replacements and is the most used format in obesity medicine in Italy and Europe;
• The Modified Atkins Diet and the Low Glycaemic Index Treatment (LGIT) are more permissive variants, with a slightly higher carbohydrate intake;
• the diet Mediterranean ketogenic (Whole-Food Mediterranean Ketogenic Diet) combines the principles of a low-carbohydrate regimen with the nutritional quality of the Mediterranean model, with promising results in terms of adherence and long-term sustainability (Masi et al., 2026).

Phases of the clinical protocol

In clinical practice — particularly in Italian and European protocols for obesity management — the ketogenic diet is structured into distinct and sequential phases:

• Phase 1 – Ketogenic induction (weeks 1–8/12): drastic reduction of carbohydrates to ≤ 30–50 g/day, with nutritional ketosis documented by capillary ketonemia (β-hydroxybutyrate ≥ 0.5 mmol/L) or ketonuria. This is the phase of maximum weight loss and induction of the target metabolic state. In many VLCKD protocols, caloric intake is 600–900 kcal/day, using protein meal replacements to ensure amino acid coverage;
• Phase 2 - Ketogenic maintenance (if applicable): ketosis is maintained with progressive customization of the diet, introducing foods with minimal carbohydrate content (non-starchy vegetables, aged cheeses, fatty fish, lean meats, extra virgin olive oil);
• Phase 3 - Exit from ketosis and progressive reintroduction of carbohydrates: this is the most delicate phase, following the active ketogenic phase. Carbohydrates are gradually reintroduced, starting with foods with the lowest glycemic index: fruits and dairy (phase 3a), then legumes (phase 3b), finally whole grains and pasta (phase 3c). Caloric intake during this phase usually varies between 800 and 1,500 kcal/day, alongside a parallel nutritional education program;
• Phase 4 - Long-term maintenance: balanced normo- or hypocaloric regimen, with periodic monitoring of anthropometric parameters, body composition and metabolic markers. In this phase, it is crucial to avoid the phenomenon of weight regain through continuous behavioral and nutritional support.

Supplementation with essential amino acids in the transition from the ketogenic phase has shown positive effects on the preservation of body cell mass, muscle strength, and inflammatory markers (Annunziata et al., 2025).

Scientific evidence

Weight loss and body composition

The reduction of body weight is the most studied clinical indication for the ketogenic diet. A systematic review with meta-analysis of randomized controlled trials (RCT) has documented significant reductions in fat mass and overall weight in overweight or obese adults, with effects superior to standard hypocaloric diets over a short- to medium-term timeframe (Leung et al., 2025). The meta-analysis by Feng et al. (2025), which analyzed various types of low-carbohydrate diets, confirmed the superiority of VLCKD on key metabolic indicators compared to low-fat replacement diets.

A Spanish randomized clinical trial (Martínez-Montoro et al., 2025) compared ketogenic diet, time-restricted feeding, and alternate-day fasting for weight loss in obese adults, finding that the ketogenic diet was associated with comparable or greater weight loss, with higher subjective adherence. In terms of personalized practice, the comparison between classic VLCKD and meal replacements and ketogenic Mediterranean diet with fresh foods it showed similar effectiveness on weight loss, with differences in body composition and adherence in favor of the Mediterranean approach (Masi et al., 2026). The review by Dyńka et al. (2025) systematically compared the keto diet with other dietary models, confirming its competitiveness in terms of weight loss, with an acceptable safety profile in subjects without contraindications.

The economic component It has also been considered: the study by Annunziata et al. (2025) analyzed the average costs of VLEKT with fresh foods versus meal replacements, finding that protocols based on fresh foods are not necessarily more expensive, paving the way for wider and more accessible clinical application.

Type 2 diabetes and glycemic control

The metabolic rationale for the use of the ketogenic diet in type 2 diabetes is strong: by reducing carbohydrate intake, the need for insulin is directly reduced and postprandial blood glucose is lowered. A meta-analysis of 29 clinical trials (Ghasemi et al., 2024) — conducted using the GRADE methodology on over 2,500 participants — documented significant reductions in fasting blood glucose and HbA1c (glycated hemoglobin, a blood test showing average blood glucose over the past 2–3 months) in patients with type 2 diabetes undergoing VLCKD compared to control diets.

These data align with the reviews by Teicholz et al. (2025), which debunk several common myths about low-carbohydrate diets and document their favorable glycemic profile. Du et al. (2025) tested a keto diet with digital support (via app) compared to a low-carb diet in an overweight Hispanic population, reporting improvements in cardio-renal-metabolic health in the ketogenic group.

A safety aspect was explored by Roberts et al. (2025), who analyzed the risk of diabetic ketoacidosis during VLCKD diets in diabetic patients: the risk exists — especially in subjects with type 1 diabetes or on SGLT-2 drugs — and requires medical supervision, underlining the importance of structured clinical protocols.

Cardiovascular health

The cardiovascular benefits of the ketogenic diet are documented on multiple fronts. Venturini et al. (2024) reviewed the cardioprotective mechanisms of nutritional ketosis, identifying anti-inflammatory effects, improvement of myocardial mitochondrial function, reduction of triglycerides and increase of HDL cholesterol.

The Keto-Salt pilot (Landolfo et al., 2025) compared a low-calorie high-protein ketogenic diet with a low-sodium high-potassium Mediterranean diet in patients with normal-high blood pressure or grade I hypertension: both regimens produced blood pressure reductions, while the keto diet was more effective on weight loss and body composition. Chen et al. (2026) showed synergistic effects between ketogenic diet and interval exercise on vascular function in obese female university students, with accelerated improvements compared to individual interventions.

The effects on plasma lipids remain however a matter of debate: in some subjects the keto diet can increase LDL, especially in variants very rich in saturated fats, a factor to consider in clinical personalization.

Intestinal microbiota

The relationship between ketogenic diet and Intestinal microbiota is one of the most dynamic and at the same time most controversial research areas. Mu et al. (2025), on Advanced Science, examined the bidirectional interaction between gut and keto diet in health and disease, documenting significant microbiome modifications in response to ketosis: reduction of saccharolytic bacteria (such as Bifidobacterium e Lactobacillus), increase of proteolytic species, with consequences not yet fully clear on the long-term intestinal ecosystem.

Bertuccioli et al. (2026) published a narrative review on Nutrition Reviews which summarizes the evidence on effects of keto and low-carb diets on the microbiota, concluding that the changes are real but reversible and strongly dependent on the quality of chosen foods (saturated vs. unsaturated fats, fiber, polyphenols). Palmas et al. (2025) conducted a 12-month pilot study on patients with diabesity drug-naive (i.e., not yet treated), comparing ketogenic diet and Mediterranean diet: microbiota profiles were significantly different between groups, with the Mediterranean diet more favorable to microbial diversity, but the keto diet more effective on glycemic control and weight loss.

Khazrai et al. (2026) analyzed the effects of VLEKT on body composition, microbiota, and metabolites in overweight subjects, documenting improvements in fat mass and related metabolites.

Inflammation

The modulation of inflammatory processes is one of the most interesting biochemical properties of ketone bodies. β-hydroxybutyrate (BHB) acts as an inhibitor of the NLRP3 inflammasome, one of the main sensors of low-grade chronic inflammation associated with obesity and diabetes. Rondanelli et al. (2024), in a systematic review and meta-analysis of RCTs, analyzed the effect of the keto diet on inflammatory markers in obese or overweight adults, documenting significant reductions in IL-6, TNF-α, and C-reactive protein, with more marked effects in longer protocolsprolonged. Alum et al. (2026) discussed the role of the ketogenic diet in obesity management, emphasizing the anti-inflammatory effects but also the potential long-term criticalities if the regimen is not qualitatively balanced.

Neurological and psychiatric applications

The neuroprotection of ketone bodies is today a flourishing field of research. A review published in Life (Nowak et al., 2025) documented how BHB reduces oxidative stress, modulates neuronal excitability, improves mitochondrial function and reduces neuroinflammation, with effects observed in experimental models and initial clinical studies on epilepsy, Alzheimer’s, Parkinson’s and multiple sclerosis.

Research on the latter indication has received renewed attention: Filippi et al. (2026) tested a ketogenic therapy onfatigue in patients with multiple sclerosis, reporting significant reductions in chronic fatigue compared to baseline, with a good tolerability profile. In psychiatry, the review by Boltri et al. (2025) systematically examined the potential of keto therapy in areas such as schizophrenia, mood disorders, and bipolar disorder, with promising preliminary results but requiring confirmation from larger randomized studies.

Regarding cognition, Khattak et al. (2026) analyzed the effect of a non-energy-restricted ketogenic diet on cognitive function in healthy sedentary young adults, documenting improvements in some measures of attention and working memory compared to baseline, albeit with methodological limitations related to study design. The AKMP protocol (Adaptive Ketogenic-Mediterranean Protocol) by García-Gorrita et al. (2025) proved effective in improving glucolipid markers in a real clinical setting, paving the way for integrated adaptive protocols.

Bone health

An emerging and still debated topic concerns the impact of the ketogenic diet on Bone health. Luo et al. (2025) reviewed in Frontiers in Nutrition the evidence on keto diet and β-hydroxybutyrate in osteoporosis: the data are contradictory, as some studies report a possible positive effect of BHB on bone formation, while others document reductions in bone mineral density following prolonged ketogenic diets, likely due to acidifying effects and reduced calcium availability. This aspect requires specific monitoring in long-term clinical protocols.

Preliminary conclusions

The ketogenic diet is a nutritional intervention with a century-long history, a well-defined biochemical mechanism, and a growing body of scientific evidence supporting its use in specific clinical contexts. The most solidly documented benefits concern weight loss in the short to medium term, improved glycemic control in type 2 diabetes, and reduction of chronic inflammation. Promising applications are emerging in neurology, psychiatry, and cardiology, although further long-term randomized trials are needed.

It is essential to emphasize that the ketogenic diet is not suitable for everyone nor should it be undertaken without medical and nutritional supervisionAbsolute contraindications include lipid metabolism disorders (acute porphyria, carnitine deficiency), advanced stage chronic renal failure, pregnancy, and breastfeeding. Periodic clinical monitoring — including blood count, renal and hepatic function, lipid profile, bone density — is essential in prolonged protocols. The quality of chosen foods — unsaturated fats, low glycemic index vegetables, high-quality protein sources, extra virgin olive oil — largely determines the sustainability and profile ofsafety of the intervention.

Dario Dongo

Credit cover Loren Castillo

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