Type 2 diabetes mellitus (T2DM) and obesity represent a growing global public health challenge, strongly associated with excess body weight, unhealthy dietary habits, and a sedentary lifestyle. The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein intake, and high fat consumption, induces a metabolic state known as ketosis, in which the body switches from glucose to fat as its primary energy source. KD has gained increasing interest as a strategy to improve glycemic control, reduce body weight, and improve lipid profiles in individuals with obesity and T2DM. The purpose of this narrative review is to summarize the current scientific evidence on the effects of KD on key metabolic parameters, including blood glucose levels, glycated hemoglobin (HbA1c), body weight, and body composition. The analysis is based on peer-reviewed articles retrieved from PubMed, Embase, and Scopus with particular emphasis on clinical studies that provide robust evidence on the efficacy and safety of KD in the treatment of metabolic disorders. Conventional therapeutic interventions often have limited efficacy, and the incidence of metabolic disorders continues to rise. Therefore, there is growing interest in novel dietary strategies that can help manage disease and prevent disease progression [ 4 , 5 ]. The ketogenic diet (KD), defined as a nutritional approach characterized by very low carbohydrate intake and high fat consumption, has garnered increasing scientific attention due to its potential to improve various metabolic parameters [ 6 , 7 ]. Four main types of KD can be identified: the classic ketogenic diet, based on long-chain triglycerides used clinically, is characterized by a 4:1 (g/g) ratio of fat to protein and carbohydrates. It is effective but difficult to prepare and is often poorly accepted in terms of taste [ 18 ]. The MCT diet, developed in 1971, uses MCT oil as the main source of fat, allowing greater flexibility in the selection of macronutrients and stronger ketogenesis, although it might cause gastrointestinal discomfort [ 18 ]. The modified Atkins diet (MAD) is actually a milder and less strict version of KD—it does not require strict food weighing or calorie restriction. Biochemical and Metabolic Basis of the Ketogenic Diet Implementing KD requires a marked reduction in carbohydrate intake, typically below 50 g/day, and during the initial adaptation phase, even to approximately 20 g/day [ 20 ]. Reduced glucose availability lowers insulin levels and increases adrenaline secretion, thus activating hormone-sensitive lipase and promoting lipolysis. This process leads to the release of free fatty acids, which undergo β-oxidation in hepatocyte mitochondria. A key non-pharmacological strategy capable of reducing glycemic variability and improving metabolic control is lifestyle modification, with particular emphasis on dietary interventions. The American Diabetes Association (ADA) report recommends a low-carbohydrate diet as an appropriate dietary intervention for patients with diabetes or prediabetes. One variant of low-carbohydrate diets is the ketogenic diet. The KD can be risky for patients with type 1 diabetes (T1DM), especially when using SGLT-2 inhibitors, and requires Ketogenic Diet as an Effective Approach to Treating Obesity and Reducing Body Weight A major motivation for following a ketogenic diet is its proven effectiveness in promoting weight loss. Accomplishing weight loss requires an effective metabolic change toward nutritional ketosis. The initial weight loss is mainly due to water loss, which occurs as a result of glycogen depletion. This water was then restored with the reintroduction of carbohydrates and the replenishment of glycogen [ 13 ]. Supplementation with ω-3 fatty acids is particularly important for patients with obesity, as it supports reductions in visceral fat and total fat mass while preserving lean body mass [ 41 ]. 3.6. Mechanisms of Weight Reduction Associated with the Ketogenic Diet The ketogenic diet can effectively support weight loss in the short and medium term, particularly in real-life conditions. Although the mechanisms underlying this effect have not yet been fully elucidated, evidence from the literature [ 7 , 11 , 42 ] indicates several likely physiological processes. VLEKT also increases adiponectin levels, an adipose-derived protein with anti-inflammatory properties [ 52 ]. A study [ 8 ] evaluated insulin sensitivity in adipose tissue by measuring lipolysis suppression during a hyperinsulinemic–euglycemic clamp (HEC) using a free fatty acid (FFA) tracer. The ketogenic diet was associated with reduced insulin-mediated suppression of lipolysis compared to a standard diet. This finding initially raised concerns about a possible adverse effect of KD on insulin sensitivity, as elevated circulating FFAs can induce insulin resistance through lipotoxic mechanisms. VLEKT offers short-term benefits in reducing visceral adipose tissue, associated inflammation, and oxidative stress. This diet intervention effectively improves adiposity profiles and may help prevent obesity-related diseases [ 10 ]. 3.8. The Impact of the Ketogenic Diet on Liver Function in Obesity Ketogenic diets can exert beneficial effects on hepatic function by increasing fatty acid oxidation and reducing circulating insulin levels [ 10 ]. Current evidence indicates that KD represents a promising therapeutic strategy for metabolic liver disorders. Many studies do not define obesity or T2DM-related endpoints as primary outcomes, which limits generalizability [ 23 , 31 ]. Long-term safety, tolerability, and adherence, particularly for very-low-energy ketogenic therapy, remain insufficiently studied and require careful monitoring of nutrient intake, renal and thyroid function, and organ-specific results [ 31 , 43 ]. The long-term impact of KD on gut health, hepatic function, cardiovascular risk, and preservation of lean body mass remains unclear.

Abstract Background: Glioblastoma (GBM) remains the most common and lethal primary central nervous system tumor, with a median survival of only 14.6 months under standard care. The tumor’s characteristic "Warburg effect"—a dependency on aerobic glycolysis for energy—creates a metabolic vulnerability. This review evaluates the efficacy and safety of the ketogenic diet (KD) as an adjunctive metabolic therapy aimed at exploiting this glucose dependency. Methods: This PRISMA-compliant systematic review updates clinical evidence by synthesizing data from database inception through September 2025. We searched PubMed, Embase, Cochrane, and Web of science for human studies assessingthe ketogenic diet in glioblastoma and high-grade gliomas. Primary outcomes included overall survival (OS), progression-free survival (PFS), feasibility, and adverse events. Results: Forty-one studies were included, ranging from randomized trials to case series and abstracts, utilizing interventions such as the classic 4:1 ketogenic diet, Modified Atkins Diet, and calorie restriction. Adherence was high, with over 75% of patients maintaining nutritional ketosis. Recent data indicate significant survival benefits; adherent cohorts achieved a median OS of 29.4 months compared to historical controls, with some studies reporting a 66.7% 3-year survival rate. The diet was well-tolerated, with adverse events limited to mild gastrointestinal symptoms and fatigue, and no Grade 3/4 diet-related toxicities reported. Conclusion: Current evidence supports the ketogenic diet as a safe, feasible, and biologically rational adjunct to standard glioblastoma treatment. It demonstrates potential to prolong survival and maintain quality of life without severe toxicity, highlighting the need for standardized Phase III trials to establish clinical guidelines. This metabolic vulnerability-glucoseaddiction and defective oxidative phosphorylation-creates a therapeutic opportunity for ketogenic diets (KD), which mimic metabolic state of fasting bylowering glucose availability to tumor cells while providing ketones as alternative fuel for healthy neurons that they can readily utilize(6). However, KD’s clinical role in GBM remains uncertain. Variations in diet formulation, targets for ketosis, duration of the intervention, macronutrient ratios, andtiming relating to surgery, radiotherapy, or chemotherapy make study comparison dicult. Patient selection and disease stage further complicateinterpretation. Thus, ketogenic diets are not integrated into standard GBM guidelines, and clinicians lack evidence-based recommendations on optimalprotocols, patient eligibility, or meaningful clinical endpoints. These gaps highlight the need for a comprehensive synthesis of current clinical data. Evidenceis limited by small cohorts ranging from 6 to 29 patients, heterogeneous designs, and the absence of any phase III trials(6, 7). The classical ketogenic diet (KD) that uses a 4:1 ratio of fat to combined carbohydrate and protein, induces a state of systemic ketosis. It is dened by bloodlevels of β -hydroxybutyrate greater than 0.5 mmol/L. Adverse events were mostly mild, with gastrointestinal symptoms,weight loss, and fatigue being the most common. No grade 3/4 toxicities directly related to the ketogenic diet were reported. Full details of study design,population, intervention type, outcomes, and adverse events are presented in (Table 1). For an extended period of 24 months, thepatient adhered to a rigorously calorie-restricted ketogenic diet while undergoing concurrent clinical monitoring. The report did not indicate whetherchemotherapy or radiation was given concurrently with the diet, but it was implemented in conjunction with standard care measures. The patient continuedto follow the dietary plan during the 24-month follow-up period.(22) Research began to While the classical 4:1 fat-to-carbohydrate-plus-protein ratio diet remains the gold standard, newer regimens such as the modied Atkins diet,calorie-restricted ketogenic diet, and intermittent fasting variants exhibited equal metabolic ecacy (30, 38). A randomized trial ERGO2 by Voss et al. (2020)(38) established a calorie-restricted KD in conjunction with reirradiation in recurrent glioma patients to be safe and associated with improved metabolicproles and survival trends compared to controls. Equally, Martin-McGill et al. (2018)(34) showed the deliverability and tolerability ofKD within a nationalhealth service. van der Louw E, Reddingius RE, Olieman JF, Neuteboom RF, Catsman-Berrevoets CE (2019) Ketogenic diet treatment in recurrent diffuse intrinsic pontineglioma in children: A safety and feasibility study. Pediatr Blood Cancer 66(3):e27561 22. Elsakka AMA, Bary MA, Abdelzaher E, Elnaggar M, Kalamian M, Mukherjee P et al (2018) Management of Glioblastoma Multiforme in a Patient TreatedWith Ketogenic Metabolic Therapy and Modied Standard of Care: A 24-Month Follow-Up. Front Nutr 5:20 23. Perez A, van der Louw E, Nathan J, El-Ayadi M, Golay H, Korff C et al (2021) Ketogenic diet treatment in diffuse intrinsic pontine glioma in children:Retrospective analysis of feasibility, safety, and survival data. Cancer Rep (Hoboken NJ) 4(5):e1383 35. Seyfried TN, Shivane AG, Kalamian M, Maroon JC, Mukherjee P, Zuccoli G (2021) Ketogenic Metabolic Therapy, Without Chemo or Radiation, for theLong-Term Management of IDH1-Mutant Glioblastoma: An 80-Month Follow-Up Case Report. Front Nutr 8:682243 3. Martin-McGill KJ, Marson AG, Tudur Smith C, Jenkinson MD (2018) The Modied Ketogenic Diet in Adults with Glioblastoma: An Evaluation of Feasibilityand Deliverability within the National Health Service. Nutr Cancer 70(4):643–649 53. Dong Z, Cui H (2019) Epigenetic modulation of metabolism in glioblastoma. Sem Cancer Biol 57:45–51 54. Talib WH, Mahmod AI, Kamal A, Rashid HM, Alashqar AMD, Khater S et al (2021) Ketogenic Diet in Cancer Prevention and Therapy: Molecular Targetsand Therapeutic Opportunities.

(MCTs)—made from fatty acids with shorter carbon chains than LCTs—are more ketogenic. A variant of the classic diet known as the MCT ketogenic diet uses a form The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than carbohydrates. Carbohydrates in food are converted into glucose, which is then transported around the body and is important in fueling brain function. However, The ketogenic diet is a high-fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than carbohydrates. Carbohydrates in food are converted into glucose, which is then transported around the body and is important in fueling brain function. However, if only a little carbohydrate remains in the diet, the liver converts fat into fatty acids and ketone bodies, the latter passing into the brain and replacing glucose as an energy source. An elevated level of ketone bodies in the blood (a state called ketosis) eventually lowers the frequency of epileptic seizures. Around half of children and young people with epilepsy who have tried some form of this diet saw the number of seizures drop by at least half, and the effect persists after discontinuing the diet. Some evidence shows that adults with epilepsy may benefit from the diet and that a less strict regimen, such as a modified Atkins diet, is similarly effective. Side effects may include constipation, high cholesterol, growth slowing, acidosis, and kidney stones. The original therapeutic diet for paediatric epilepsy provides just enough protein for body growth and repair, and sufficient calories to maintain the correct weight for age and height. The classic therapeutic ketogenic diet was developed for treatment of paediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective anticonvulsant medications. This classic ketogenic diet contains a 4:1 ketogenic ratio or ratio by weight of fat to combined protein and carbohydrate. This is achieved by excluding high-carbohydrate foods such as starchy fruits and vegetables, bread, pasta, grains, and sugar, while increasing the consumption of foods high in fat such as nuts, cream, and butter. Most dietary fat is made of molecules called long-chain triglycerides (LCTs). However, medium-chain triglycerides (MCTs)—made from fatty acids with shorter carbon chains than LCTs—are more ketogenic. A variant of the classic diet known as the MCT ketogenic diet uses a… In…