Search Results (719)

Various neuromodulatory benefits of the ketogenic diet (KD) have been demonstrated, yet its influence on reward learning and underlying mechanisms remain poorly defined. This study combined proteomics and metabolomics to identify key molecular changes in the hippocampus of KD-fed mice. Our analysis revealed significant upregulation of the “dopaminergic synapse” pathway, with CAMK2A emerging as a central regulator. In vitro, treatment of the hippocampal neuronal cell line HT22 with β-hydroxybutyrate (BHB), a primary KD metabolite, increased the protein expression of CAMK2A and increased the phosphorylation of its downstream target, GluA1. Crucially, Camk2a knockdown completely blocked BHB-induced p-GluA1 enhancement. To determine the behavioral relevance, we stereotaxically delivered AAV-shCamk2a into the hippocampus of KD-fed mice. Knockdown of Camk2a reversed the pro-reward effects of KD, as measured by the sucrose preference test and conditioned place preference test, without impairing general locomotor activity in the open field test. Together, these results suggest a novel BHB–CAMK2A–dopaminergic signaling axis through which KD enhances reward learning, thus bridging systemic metabolism with cognitive function and expanding our understanding of KD-mediated neuromodulation. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Background/Objectives: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer’s disease, may be influenced by nutritional status and genetic susceptibility. This systematic review synthesised evidence on how nutritional biomarkers interact with genetic variants, particularly APOE ε4, to influence cognitive outcomes in individuals with MCI. Methods: Following PRISMA 2020 guidelines, seven studies were included (three longitudinal, two randomised controlled trials, and two cross-sectional) involving adults aged ≥55 years with MCI. Nutritional exposures comprised plasma or serum concentrations of vitamins A, D, E, the vitamin B group, lipids, selenium, and ketogenic medium-chain triglycerides. Genetic risk was assessed primarily through APOE ε4 status. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using GRADE. Due to heterogeneity in biomarkers, cognitive tools, and study designs, findings were synthesised narratively. Results: Across nutrient categories, higher concentrations of vitamin D, selenium, and antioxidants were associated with better cognitive outcomes. kMCT supplementation improved episodic memory and brain energy metabolism. Evidence for nutrient–gene interactions was mixed: APOE ε4 modified responses to vitamin B group and selenium but showed limited influence on vitamin D, lipids, or kMCT effects. Heterogeneity in biomarker assays, cognitive tools, and genetic stratification limited comparability across studies. Conclusions: Nutritional biomarkers appear to influence cognitive trajectories in MCI, and some associations may differ by APOE ε4 status. However, small samples and limited genetic stratification constrain interpretation. Future research should prioritise standardised biomarker measurement, genetically stratified cohorts, and individual participant data meta-analyses to clarify nutrient–gene interactions in MCI. Full article

Background: The ketogenic diet has gained substantial popularity in recent years, and an increasing number of caregivers of children with type 1 diabetes are considering it as a nutritional strategy to improve glycemic control. Reported benefits include fewer postprandial glucose fluctuations, lower insulin requirements, and reduced insulin-associated weight gain. However, the use of this diet in children with type 1 diabetes remains highly debated, and scientific evidence regarding its safety and long-term effects in the pediatric population is limited. This narrative review aims to explore the motivations that lead parents to initiate a ketogenic diet in their children with type 1 diabetes and to summarize current knowledge on its potential metabolic and developmental consequences. Methods: A narrative review of the literature was conducted, including original research articles, case reports, and existing reviews addressing the use of ketogenic diets in children with type 1 diabetes. Clinical observations and published accounts of family experiences were also examined to contextualize emerging concerns and motivations. Results: Parents most commonly adopt a ketogenic diet for their children due to the desire for tighter glucose control, concerns about insulin-related weight gain, and the influence of information shared on social media. Some observational data suggest improvements in glycemic stability and reduced insulin requirements under ketogenic dietary regimens, while available evidence also highlights several potential risks, including dyslipidemia, increased susceptibility to hypoglycemia, slowed linear growth, and possible neurocognitive and psychosocial effects. Long-term safety data remain scarce, and current findings are insufficient to establish clear clinical recommendations. Conclusions: Interest in ketogenic diets among families of children with type 1 diabetes is growing, yet existing evidence suggests that the diet may pose significant metabolic and developmental risks in this population. Further well-designed studies are needed to evaluate its safety and efficacy. This review may assist clinicians in counseling families and underscores the need for evidence-based guidelines regarding restrictive dietary patterns in youth with type 1 diabetes. Full article

Background/Objectives: Obesity is a chronic, relapsing disease in which lifestyle modification represents the cornerstone of treatment. Among dietary strategies, ketogenic diets can induce rapid weight loss, whereas the Mediterranean diet is associated with established cardiometabolic benefits but typically produces slower weight reduction. Very-low-calorie ketogenic diets (VLCKDs) are effective for weight loss but are often limited by cost, reliance on meal replacements, and reduced long-term feasibility. This study aimed to evaluate whether a whole-food Mediterranean ketogenic diet with moderate caloric restriction (MedKD) could represent a feasible and effective alternative to VLCKD for weight loss and metabolic improvement in adults with obesity. Methods: This 3-month prospective, real-world study compared VLCKD and MedKD in adults with obesity attending a clinical nutrition program. The primary outcome was percentage weight loss. Secondary outcomes included changes in waist circumference, waist-to-height ratio, insulin resistance (HOMA-IR), lipid profile, kidney function, and treatment tolerability. Clinical and biochemical parameters were assessed at baseline and after the intervention. Group differences and time-by-group interactions were analyzed to evaluate changes over the study period. Results: Sixty-two participants were enrolled, and 55 completed the study (27 VLCKD, 28 MedKD). Baseline characteristics were generally comparable, although the MedKD group had a higher prevalence of diabetes and higher baseline insulin resistance and triglyceride levels. Both dietary interventions resulted in substantial and comparable weight loss (approximately 15% of initial body weight), accompanied by significant reductions in waist circumference and waist-to-height ratio. Insulin resistance improved in both groups, with a greater reduction in HOMA-IR observed in the MedKD group (time × group p = 0.031). Serum creatinine decreased in the VLCKD group and slightly increased in the MedKD group (p = 0.025). Changes in lipid profile were not significantly different between groups. No severe adverse events were reported. Conclusions: A whole-food Mediterranean ketogenic diet with moderate caloric restriction achieved weight loss and metabolic improvements comparable to those observed with VLCKD over three months. These findings suggest that MedKD may represent a feasible alternative to formula-based ketogenic programs, supporting more flexible and personalized dietary strategies in the clinical management of obesity. Full article

Background/Objectives: Feeding with a ketogenic diet (KD), nutritionally devoid of carbohydrates, may be metabolically beneficial. The administration of a KD to mice after previous feeding with a high-fat, high-carbohydrate diet (HFD) induced weight loss, ketonemia, and glycemic normalization. Here, to compare organ-specific responses to KD, we analyzed lipogenic and gluconeogenic enzymes and genes in the liver and kidney of mice submitted to KD versus (i) HFD or (ii) a saccharose-enriched diet. Methods: Liver and kidney were from (i) mice fed a HFD followed by an 8-week switch to a chow diet (CD), KD continuation of HFD, and (ii) mice submitted to CD, KD, or a saccharose-enriched diet for 1 week. Protein expression levels were determined by Western blotting, and gene expression by qPCR. Hepatic lipid accumulation was visualized by red oil-O. Results: Switch to a KD led to a simultaneous decrease in lipogenic FASN (Fatty Acid Synthase), ACC (Acetyl-CoenzymeA Carboxylase), and its phosphorylated form (pACC-Ser79) in the liver and kidney. In parallel, we observed increased activating phosphorylation of AMPK, the kinase responsible for ACC phosphorylation. In the liver, but not in the kidney, the gluconeogenic rate-limiting enzyme G6Pase (Glucose 6-phosphatase) was repressed under a KD. The switch to a CD significantly reduced hepatic fat accumulation, while a switch to a KD did not allow a significant reversal of hepatic fat accumulation, suggesting resilience to hepatic fat loss under KD. Comparison of a KD versus saccharose-supplemented diet showed an opposite expression pattern of lipogenic enzymes. Conclusions: Administration of KD after previous HFD induced convergent repression of lipogenic enzymes in the liver and kidney, and specific repression of G6Pase in the liver, suggesting a role for kidney gluconeogenesis during KD. KD versus saccharose-supplemented diet had opposite effects on lipogenesis and glycemic control, but both induced loss of lean body mass. Full article

Background: Insulin resistance (IR) is a hallmark of metabolic disorders including type 2 diabetes mellitus (T2DM), metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), obesity, polycystic ovary syndrome (PCOS), and cardiovascular diseases. It arises from impaired insulin signaling in muscle, liver, and adipose tissue, driven by ectopic lipid accumulation, chronic inflammation, oxidative stress, and gut microbiota dysbiosis. Methods: This narrative review synthesizes IR mechanisms and the evidence on specific dietary patterns. A structured search of PubMed/MEDLINE and Embase (up to January 2026) prioritized RCTs, systematic reviews, meta-analyses, and clinical guidelines. Results: IR assessment relies on the hyperinsulinemic–euglycemic clamp as gold standard, with HOMA-IR and QUICKI as validated clinical surrogates. The Mediterranean diet is the most evidence-supported strategy, with consistent HOMA-IR reductions, a 31% decrease in T2DM incidence (PREDIMED-Plus), and demonstrated efficacy across T2DM, MASLD, and PCOS. Low-GI and DASH diets improve postprandial insulin dynamics and are particularly effective in PCOS. Low-carbohydrate and ketogenic diets produce the largest short-term reductions in fasting glucose and insulin secretion, though long-term sustainability requires further study. Plant-based diets and intermittent fasting improve IR primarily via weight loss and gut microbiota modulation. Most studies rely on surrogate IR indices and are short-term (≤26 weeks). Conclusions: Dietary pattern selection should be individualized according to metabolic phenotype, comorbidities, and adherence potential. Larger, longer, head-to-head trials measuring hard clinical outcomes are needed. Full article

Background/Objectives: Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, induces substantial weight loss in patients with obesity; however, pharmacologically induced weight reduction may be accompanied by losses in fat-free mass (FFM), muscle strength (MS), and resting metabolic rate (RMR), potentially influencing metabolic health. The metabolic implications of short-term preservation of metabolically active tissue during TZP therapy remain incompletely characterized. Methods: We performed a secondary, exploratory analysis of a previously published 12-week prospective, non-randomized comparative study including 60 patients with obesity treated with TZP (n = 30 TZP+Low Energy Ketogenic Therapy [LEKT]; n = 30 TZP+Low Calorie Diet [LCD]). Body weight (BW), fat mass (FM), FFM, MS, and RMR were assessed at baseline and week 12. Glycaemic parameters included fasting glucose, insulin, hemoglobin A1c (HbA1c), and HOMA-IR. All analyses were exploratory and hypothesis-generating. Results: Both groups achieved comparable reductions in BW after 12 weeks. FM decreased in both groups, while relative preservation of FFM, MS, and RMR was observed in one dietary context. Short-term changes in HbA1c, insulin, and HOMA-IR were statistically associated with concurrent changes in FFM, MS, and RMR, whereas no consistent associations were observed with changes in total BW or FM. Baseline glycaemic values were largely within the normoglycemic range. Conclusions: In this short-term secondary exploratory analysis, preservation of metabolically active tissue during TZP therapy was associated with concurrent glycaemic profiles, whereas no consistent associations were observed with total weight loss magnitude. These findings do not imply causality and should be interpreted as hypothesis-generating, warranting confirmation in larger, randomized, long-term studies. Full article

Background: Ketogenic dietary therapies (KDTs), characterized by substantial carbohydrate restriction and increased dietary fat intake, were originally developed for the treatment of drug-resistant epilepsy but have recently attracted broader scientific interest. In the context of population aging and the increasing prevalence of cognitive impairment and dementia, their potential relevance for brain health has received growing attention. Experimental and emerging clinical evidence suggests that ketogenic metabolism may influence biological processes involved in brain aging, including cerebrovascular regulation, neuroinflammatory signaling, and cerebral energy metabolism. Objective: This narrative review aims to synthesize current evidence on the relationship between ketogenic dietary therapies and brain health, with particular emphasis on cerebrovascular mechanisms, neuroinflammatory pathways, and neuroprotective processes relevant to aging. The review also briefly introduces the Semmelweis Study as an example of a translational research framework for evaluating nutrition-related interventions in real-world preventive settings. Methods: A narrative literature review was conducted using structured searches of major scientific databases to identify experimental and human studies investigating ketogenic dietary interventions, cerebrovascular mechanisms, and neuroprotective outcomes. Publications related to the Semmelweis Study were included solely to illustrate implementation-oriented research approaches and not as evidence supporting dietary efficacy. Results: Available evidence indicates that ketogenic dietary interventions may modulate several biological pathways relevant to brain health, including cerebral energy metabolism, mitochondrial function, oxidative stress regulation, and inflammatory signaling. However, the current evidence base is dominated by preclinical studies and short-term human investigations, and direct evidence linking ketogenic dietary therapies to long-term cerebrovascular or cognitive outcomes remains limited. Conclusions: Ketogenic dietary therapies represent metabolically distinct dietary strategies with potential relevance for cerebrovascular and neuroprotective mechanisms. Nevertheless, human evidence remains heterogeneous and insufficient to support broad clinical recommendations. Future research should prioritize well-designed long-term human studies with clearly defined metabolic, cerebrovascular, and cognitive endpoints. Translational research frameworks may facilitate the evaluation of feasibility, safety, and implementation of ketogenic interventions in aging populations. Full article

The ketogenic diet (KD) is a critical, evidence-based intervention within medical nutrition therapy for managing neurological disorders. In this article, we reviewed the published research on the efficacy of the ketogenic diet and its variations in treating epilepsy, particularly for patients unresponsive to anti-epileptic drugs. The literature review was performed on PubMed between 2022 and 2025. The review of clinical studies across various age groups reveals that, while the KD is effective for both focal and generalized seizures, infants often achieve higher rates of seizure freedom compared to adults, potentially due to better dietary compliance. Despite its success, the restrictive nature of the diet presents significant challenges for individuals suffering from epilepsy. The key challenges that reduce compliance over time include side effects, such as gastrointestinal issues, potential for malnutrition, and a high risk of micronutrient deficiencies. The role of the registered dietitian is paramount in this interdisciplinary approach, ensuring personalized education by monitoring growth and adjusting nutritional plans to optimize health outcomes for children unresponsive to anti-epileptic drugs. Ultimately, integrating MNT with traditional pharmacological or surgical treatments offers the most promising path for significant seizure reduction and improved quality of life for epileptic patients. Full article

Medium-chain triglycerides (MCTs, C6–C12 fatty acids) exhibit rapid absorption, preferential portal transport, efficient mitochondrial β-oxidation, promoting acetyl-CoA formation and ketogenesis. Under high lipid flux or impaired β-oxidation, MCTs undergo ω-oxidation, producing dicarboxylic acids further metabolized peroxisomally, preventing fatty acid accumulation. Industrially, MCTs are synthesized via chemical or enzymatic esterification of caprylic (C8) and capric (C10) acids, yielding high-purity triglycerides used in food and medical nutrition. In Germany and across the European Union, they are primarily used in Foods for Special Medical Purposes (FSMPs) for conditions such as fat malabsorption, ketogenic dietary therapy for refractory epilepsy, and inherited disorders of long-chain fatty-acid oxidation. In Japan, MCTs are additionally incorporated into functional food systems, including Foods for Specified Health Uses (FOSHU) and Foods with Function Claims (FFC), targeting generally healthy adults and older populations. In the United States, MCTs are widely marketed as food ingredients, dietary supplements, clinical nutrition products, and medical foods, reflecting their status as generally recognized as safe (GRAS). This review integrates knowledge on MCT metabolism, industrial production, clinical applications, and regulatory frameworks in Germany, Japan, and the United States, highlighting how regulatory environments influence the translation of MCTs from clinical nutrition toward broader preventive health strategies. Full article

The increasing popularity of carnivore and animal-based diets among athletes has generated substantial interest, despite limited direct scientific evidence supporting their efficacy and safety in sport-specific contexts. This narrative review critically evaluates the current evidence and examines the physiological, performance, and health-related implications of these dietary models in athletic populations. These dietary models, characterized by the partial or complete exclusion of plant-derived foods, are often promoted on the basis of mechanistic arguments, anecdotal reports, and extrapolations from research on ketogenic and very low-carbohydrate diets. However, their physiological relevance, long-term health implications, and compatibility with the demands of athletic training remain poorly defined. This narrative review provides a critical perspective on the current evidence related to carnivore and animal-based diets in sport, integrating findings from studies on low-carbohydrate, ketogenic, high-protein, and elimination-based dietary patterns. The analysis focuses on metabolic adaptations, body composition, exercise performance, gastrointestinal function, micronutrient adequacy, hormonal responses, and potential long-term health risks. Particular attention is given to the distinction between metabolic adaptations and functional performance outcomes, as well as to the high interindividual variability in dietary responses. The available evidence suggests that while carbohydrate restriction may induce specific metabolic adaptations, such as increased fat oxidation, these changes do not consistently translate into improved performance, particularly in high-intensity or high-volume training contexts. Moreover, the highly restrictive nature of carnivore and animal-based diets raises concerns about micronutrient deficiencies, alterations in the gut microbiota, changes in the lipid profile, and potential effects on eating behaviours, particularly in competitive athletic populations. Given the absence of well-controlled, long-term intervention studies in athletes, carnivore and animal-based diets cannot currently be recommended as safe or optimal nutritional strategies for sports performance. Rather than representing viable alternatives to established sports nutrition guidelines, these dietary models may be better understood as experimental or short-term tools within highly controlled research or diagnostic frameworks. Future research should prioritize rigorous, sport-specific study designs, long-term safety outcomes, and personalized approaches that account for individual metabolic and physiological variability. Full article

Pyruvate dehydrogenase complex deficiency (PDCD) is a heterogenous mitochondrial inborn error in carbohydrate oxidation manifesting as congenital lactic acidosis. PDCD presents diagnostic and therapeutic challenges. While no curative treatment exists for PDCD, certain therapeutic modalities may improve prognosis and ameliorate symptom severity. This article examines the effectiveness of treatments for PDCD and presents a case series of three patients with PDCD. A scoping literature review was conducted for treatments of PDCD. Patient data for case reports was extracted retrospectively from electronic medical records from a large tertiary hospital. We reviewed and summarized findings from seven preclinical studies and ten human studies, which showed that dichloroacetate and the ketogenic diet were the most frequently studied treatments. Therapeutic approaches observed select positive outcomes such as reduced lactate levels, improved neuropathological manifestations, and increased longevity. However, most interventions have yet to be rigorously investigated. Early diagnosis of PDCD is integral, as treatment methods may offer improved clinical and biochemical outcomes. Clinical trials of existing and novel treatments are necessary to improve management and further understand the prognostic potential of this metabolic disorder. Full article

Background: For decades, the ketogenic diet has been successfully used for the treatment of obesity, metabolic syndrome, and type 2 diabetes. The mechanisms through which it affects metabolism are not fully understood, but the hormonal changes that occur during ketogenic nutrition are likely to play an important role. Objectives: To investigate the effect of the ketogenic diet on various hormones associated with obesity and the accompanying metabolic disorders in childhood. Methods: One hundred children aged 8–18 years with obesity were enrolled. After baseline anthropometric, biochemical, and hormonal testing, they followed a 4-month “well-formulated ketogenic diet.” Fifty-eight of them successfully completed the study with follow-up assessments. Among them, 8 girls had polycystic ovary syndrome (PCOS) and 7 children had Hashimoto’s autoimmune thyroiditis. Results: At the end of the 4-month period, there was a significant decrease in basal insulinemia (p < 0.0001) and in mean morning cortisol levels (p = 0.04), as well as an increase in adiponectin levels (p = 0.04). All girls with PCOS experienced spontaneous menstrual cycles, accompanied by a reduction in testosterone levels. TSH levels showed no change for the whole group (p = 0.13), but there was a significant decrease in T3 (p < 0.0001) and a mild increase in T4 (p = 0.05). Among patients with Hashimoto’s thyroiditis, TSH levels were significantly higher at the end of the study. Conclusions: A short-term, well-formulated ketogenic diet in children with obesity is associated with hormonal changes that support weight loss and improve insulin sensitivity. The diet shows particularly beneficial effects in girls with PCOS and may be considered as part of a comprehensive therapeutic approach in these patients. Monitoring thyroid function during ketogenic nutrition is advisable in patients with hypothyroidism and thyroid disorders. Full article

Background: Sudden unexpected death in epilepsy (SUDEP) causes significant mortality, affecting approximately 1 in 1000 people with epilepsy. Clinical and preclinical studies have identified severe seizures, bradycardia, apnea, severe postictal hypoxia, and sleep deficiency that emerge prior to SUDEP and thus may represent temporal biomarkers. The metabolic ketogenic diet (KD) therapy increases longevity in preclinical SUDEP models. Here, the hypothesis that KD therapy would determine whether the emergent sleep deficiency, bradycardia, apnea and/or hypoxemia persist as temporal biomarkers in preclinical SUDEP was tested. Methods: Kv1.1 knockout (KO) mice, a preclinical SUDEP model, and wild-type littermates were weaned onto a standard diet (SD) or treated with KD. In separate cohorts, approximately every 10 days, seizures and sleep architecture were recorded with electroencephalography–electromyography (EEG-EMG), heart rate was measured with noninvasive ECGenie, apnea was assessed with noninvasive airway mechanics, and blood O₂ saturation was measured with pulse oximetry. Data were aligned from the day of sudden death and analyzed retrospectively. Results: KD treatment significantly increased longevity and reduced seizures, reproducing previous studies. Using retrospective analyses from the day of death, KD treatment attenuated the emergence of (i) interictal intermittent bradycardia in the last 20 days of life, (ii) apnea, and (iii) intermittent hypoxemia in the last 10 days of life. In contrast, (iv) KD treatment did not rescue REM and NREM sleep deficiencies during the last 10 days of life. Conclusions: Our findings provide novel preclinical support for KD as a candidate therapy to attenuate seizure frequency and burden, bradycardia, apnea, and hypoxemia in SUDEP. In addition, sleep deficiency persisted as a potential temporal biomarker of preclinical SUDEP; however, causality will need to be tested in future studies. Full article