Search Results (55)

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is), initially developed as antihyperglycemic agents, have emerged as multifunctional therapeutics with profound cardiorenal and metabolic benefits. Their unique insulin-independent mechanism, targeting renal glucose reabsorption, distinguishes them from conventional antidiabetic drugs. Mechanisms and Clinical Evidence: SGLT2is induce glycosuria, reduce hyperglycemia, and promote weight loss through increased caloric excretion. Beyond glycemic control, they modulate tubuloglomerular feedback, attenuate glomerular hyperfiltration, and exert systemic effects via natriuresis, ketone utilization, and anti-inflammatory pathways. Landmark trials (DAPA-HF, EMPEROR-Reduced, CREDENCE, DAPA-CKD) demonstrate robust reductions in heart failure (HF) hospitalizations, cardiovascular mortality, and chronic kidney disease (CKD) progression, irrespective of diabetes status. Adipose Tissue and Metabolic Effects: SGLT2is mitigate obesity-associated adiposopathy by shifting macrophage polarization (M1 to M2), reducing proinflammatory cytokines (TNF-α, IL-6), and enhancing adipose tissue browning (UCP1 upregulation) and mitochondrial biogenesis (via PGC-1α/PPARα). Modest weight loss (~2–4 kg) occurs, though compensatory hyperphagia may limit long-term effects. Emerging Applications: Potential roles in non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and neurodegenerative disorders are under investigation, driven by pleiotropic effects on metabolism and inflammation. Conclusions: SGLT2is represent a paradigm shift in managing T2DM, HF, and CKD, with expanding implications for metabolic syndrome. Future research should address interindividual variability, combination therapies, and non-glycemic indications to optimize their therapeutic potential. Full article

Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by progressive neuronal loss and share key pathological features such as oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation. Recent research has highlighted the potential of ketogenic metabolism, particularly the use of ketone bodies like β-hydroxybutyrate, as a therapeutic approach targeting these shared mechanisms. This review provides a comprehensive synthesis of current knowledge on the neuroprotective effects of ketogenic interventions, including both dietary strategies and exogenous ketone supplementation. We discuss how ketone bodies improve mitochondrial function, reduce reactive oxygen species, modulate inflammatory pathways, and influence neurotransmission and synaptic plasticity. Additionally, we examine experimental and clinical evidence supporting the application of ketogenic therapies in neurodegenerative diseases, highlighting disease-specific findings, benefits, and limitations. While preclinical data are robust and suggest meaningful therapeutic potential, clinical studies remain limited and heterogeneous, with challenges related to adherence, safety, and patient selection. The review also addresses the translational relevance of ketogenic strategies, considering their feasibility, combination with other therapies, and the need for personalized approaches based on genetic and metabolic profiles. By critically evaluating existing data, this article aims to clarify the mechanisms through which ketogenic metabolism may exert neuroprotective effects and to outline future directions for research and clinical application in the context of neurodegenerative disorders. Full article

Background/Objectives: In diabetic ketoacidosis (DKA), absolute insulin deficiency and elevation of counter-regulatory hormones may cause osmotic diuresis and water and electrolyte loss, which may lead to dehydration and renal failure. Fluids with high Na content are preferred in the DKA fluid therapy algorithm due to the association of Na with β-Hydroxybutyrate (β-HB) and the renal excretion of Na-β-HB. However, these fluids may cause hyperchloremic metabolic acidosis due to their high chloride concentration. In the literature, base-excess chloride (BE_Cl) has been suggested as a better approach for assessing the effect of chloride on acid–base status. Our aim in this study was to investigate the effect of fluids with BE_Cl values less than zero versus those with values equal to or greater than zero on the metabolic acid–base status in the first 6 h of DKA. Methods: This retrospective study included DKA cases managed in the tertiary intensive care units of five hospitals in the last 10 years. Patients were divided into two groups according to the Na-Cl difference of the administered fluids during the first 6 h of treatment: Group I [GI, fluids with Na-Cl difference = 0, chloride-rich group] and Group II [GII, fluids with Na-Cl difference > 32 mmol, chloride non-rich group]. Demographic data, blood gas analysis results, types and amounts of administered fluids, urea–creatinine values, and urine ketone levels were recorded. Results: Thirty-five patients with DKA in the ICU were included in the study (GI; 22 patients, GII; 13 patients). There was no difference between the patients in the two groups in terms of age, gender, and LOS-ICU. According to the distribution of the administered fluids, the main fluid administered in GI was 0.9% NaCl, whereas in the GII, it was bicarbonate, Isolyte-S, and 0.9% NaCl. In GI, the chloride load administered was higher; the BE_Cl level of the fluids was lower than in GII. At the end of the first 6 h, although sodium and strong ion gap values were similar, patients in GI were more acidotic due to iatrogenic hyperchloremia and, as a result, were more hypocapnic than GII. Conclusions: In conclusion, administering chloride-rich fluids in DKA may help reduce unmeasured anion acidosis. Still, risks cause iatrogenic hyperchloremic acidosis, which can hinder the expected resolution of acidosis and increase respiratory workload. Therefore, it is suggested that DKA guidelines be revised to recommend an individualized approach that avoids chloride-rich fluids and includes monitoring of metabolic parameters like Cl and BE_Cl. Full article

The mortality risk in systemic sclerosis (SSc) is primarily determined by pulmonary involvement (interstitial lung disease (ILD), pulmonary fibrosis), pulmonary arterial hypertension (PAH), and cardiac involvement. With timely and intensive treatment, the disease can be halted or even improved. Therefore, early diagnosis remains crucial. Unfortunately, biomarkers currently available cannot meet this requirement. SSc is characterized by autoimmune inflammation, vasculopathy, and fibrosis. The immunometabolic characterization of autoimmune diseases contributes to a better understanding of the underlying inflammatory processes. In this narrative review, we included 13 studies on metabolomic patterns in SSc in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA). Current studies indicate an altered metabolome in SSc. All documented significant differences between patients with SSc and healthy controls, although the observed metabolomic patterns in SSc were inconsistent between studies. Metabolome alterations include, in particular, energy-related metabolic pathways such as glycolysis/gluconeogenesis, including the synthesis and degradation of ketones, fatty acid oxidation, amino acid-related metabolic pathways, lipid metabolism, and the tricarboxylic acid (TCA) cycle, including pyruvate metabolism. The most frequently examined organ complications with reported significant aberrations of the metabolome were skin involvement, ILD, and PAH. Conclusion: The detailed characterization of the SSc-specific metabolome promises a more comprehensive understanding of the pathogenic mechanisms of the disease. Furthermore, the detection of associations between specific metabolic aberrations and disease phenotypes bears hope for new biomarkers and an improved personalized approach to diagnostics, therapy, and follow-up in the management of SSc. Full article

Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article

Drug-resistant epilepsy (DRE) affects 20–30% of patients with epilepsy who fail to achieve seizure control with antiseizure medications, posing a significant therapeutic challenge. In this narrative review, we examine the clinical efficacy and safety of the classic ketogenic diet (cKD) and its variants, including the modified Atkins diet (MAD), medium-chain triglyceride diet (MCTD), and low glycemic index treatment (LGIT), in patients with genetically confirmed drug-resistant epilepsy. These diets induce a metabolic shift from glucose to ketones, enhance mitochondrial function, modulate neurotransmitter balance, and exert anti-inflammatory effects. However, genetic factors strongly influence the efficacy and safety of the cKD, with absolute indications including glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase complex deficiency (PDCD). Preferred adjunctive applications of the KD include genetic epilepsies, such as SCN1A-related Dravet syndrome, TSC1/TSC2-related tuberous sclerosis complex, and UBE3A-related Angelman syndrome. However, because of the risk of metabolic decompensation, the cKD is contraindicated in patients with pathogenic variants of pyruvate carboxylase and SLC22A5. Recent advancements in precision medicine suggest that genetic and microbiome profiling may refine patient selection and optimize KD-based dietary interventions. Genome-wide association studies and multiomics approaches have identified key metabolic pathways influencing the response to the cKD, and these pave the way for individualized treatment strategies. Future research should integrate genomic, metabolomic, and microbiome data to develop biomarker-driven dietary protocols with improved efficacy and safety. As dietary therapies continue to evolve, a personalized medical approach is essential to maximize their clinical utility for genetic epilepsy and refractory epilepsy syndromes. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial disorder characterized by excessive lipid accumulation in the liver which dysregulates the organ’s function. The key contributor to MASLD development is insulin resistance (IR) which affects many organs (including adipose tissue, skeletal muscles, and the liver), whereas the molecular background is associated with oxidative, nitrosative, and carbonyl stress. Among molecules responsible for carbonyl stress effects, methylglyoxal (MGO) seems to play a major pathological function. MGO—a by-product of glycolysis, fructolysis, and lipolysis (from glycerol and fatty acids-derived ketone bodies)—is implicated in hyperglycemia, hyperlipidemia, obesity, type 2 diabetes, hypertension, and cardiovascular diseases. Its causative effect in the stimulation of prooxidative and proinflammatory pathways has been well documented. Since metabolic dysregulation leading to these pathologies promotes MASLD, the role of MGO in MASLD is addressed in this review. Potential MGO participation in the mechanism of MASLD development is discussed in regard to its role in different signaling routes leading to pathological events accelerating the disorder. Moreover, treatment strategies including approved and potential therapies in MASLD are overviewed and discussed in this review. Among them, medications aimed at attenuating MGO-induced pathological processes are addressed. Full article

The key fatty acid β-oxidation protein acetyl-CoA acyltransferase 2 (ACAA2) plays a significant role in myocardial lipid peroxidation and cardiac dysfunction induced by renal insufficiency. However, the mechanisms of lipid metabolism related to renal insufficiency-associated cardiac dysfunction remain poorly understood, and current clinical treatments have been largely ineffective. Through analysis of the Gene Expression Omnibus (GEO) database, we identified that the cardiac functional changes caused by renal insufficiency were primarily centered around the fatty acid β-oxidation signaling pathway, where ACAA2 plays a pivotal role in fatty acid β-oxidation, the tricarboxylic acid cycle, and ketone body metabolism. In an adenine-induced renal insufficiency mouse model, further examination with hematoxylin-eosin staining, Masson staining, and Oil Red O staining revealed alterations in the heart and kidney as well as the accumulation of lipid. Non-invasive blood pressure measurements and ultrasound images demonstrated improvements of peripheral vascular and right ventricular hemodynamic parameters with S-nitroso-L-cysteine (CSNO) inhalation therapy. In cell experiments, knocking down ACAA2 led to accumulation of lipid droplets and exacerbation of oxidative stress in cardiomyocytes, while overexpression of ACAA2 reversed these effects. The transcription factor FOXO4 was found to regulate lipid peroxidation by modulating ACAA2, and knocking down FOXO4 partially restored the expression of ACAA2, reducing oxidative stress in cardiomyocytes. Furthermore, exogenous CSNO effectively restored the expression of ACAA2 and reduced the level of FOXO4, thereby mitigating lipid peroxidation and improving cardiac function. Therefore, in the context of renal insufficiency, regulating the FOXO4–ACAA2 axis through CSNO inhalation therapy may provide a novel therapeutic strategy for alleviating myocardial lipid peroxidation and improving cardiac function. Full article

Reprogramming energy metabolism is pivotal to tumor development. Ketone bodies (KBs), which are generated during lipid metabolism, are fundamental bioactive molecules that can be modulated to satisfy the escalating metabolic needs of cancer cells. At present, a burgeoning body of research is concentrating on the metabolism of KBs within tumors, investigating their roles as signaling mediators, drivers of post-translational modifications, and regulators of inflammation and oxidative stress. The ketogenic diet (KD) may enhance the sensitivity of various cancers to standard therapies, such as chemotherapy and radiotherapy, by exploiting the reprogrammed metabolism of cancer cells and shifting the metabolic state from glucose reliance to KB utilization, rendering it a promising candidate for adjunct cancer therapy. Nonetheless, numerous questions remain regarding the expression of key metabolic genes across different tumors, the regulation of their activities, and the impact of individual KBs on various tumor types. Further investigation is imperative to resolve the conflicting data concerning KB synthesis and functionality within tumors. This review aims to encapsulate the intricate roles of KBs in cancer metabolism, elucidating a comprehensive grasp of their mechanisms and highlighting emerging clinical applications, thereby setting the stage for future investigations into their therapeutic potential. Full article

Background: The ketogenic diet (KD), high in fat and low in carbohydrates, was introduced in the 1920s as a non-pharmacological treatment for refractory epilepsy. Although its mechanism of action is not fully understood, beneficial effects have been observed in neurological diseases such as epilepsy, Alzheimer’s disease, and Parkinson’s disease. Objective: This review examines the impact of the ketogenic diet and its molecular and neuroglial effects as a complementary therapy for neurological diseases. Discussion: KD is associated with neuroprotective and antioxidant effects that improve mitochondrial function, regulate neurotransmitter flow, and reduce neuroinflammation and oxidative stress. Glial cells play an essential role in the utilization of ketone bodies (KBs) within the central nervous system’s metabolism, particularly during ketosis induced by the KD. Thus, the KD represents a broad and promising strategy that involves both neurons and glial cells, with a molecular impact on brain metabolism and neuroinflammatory homeostasis. Conclusion: Multiple molecular mechanisms have been identified to explain the benefits of the KD in neurological diseases; however, further experimental and clinical studies are needed to address various molecular pathways in order to achieve conclusive results. Full article

Background: Recent findings have highlighted that abnormal energy metabolism is a key feature of autosomal-dominant polycystic kidney disease (ADPKD). Emerging evidence suggests that nutritional ketosis could offer therapeutic benefits, including potentially slowing or even reversing disease progression. This systematic review aims to synthesise the literature on ketogenic interventions to evaluate the impact in ADPKD. Methods: A systematic search was conducted in Medline, Embase, and Scopus using relevant Medical Subject Headings (MeSH) and keywords. Studies assessing ketogenic interventions in the management of ADPKD in both human and animal models were selected for data extraction and analysis. Results: Three animal reports and six human studies were identified. Ketogenic diets (KD) significantly slowed polycystic kidney disease (PKD) progression in rats with improved renal function and reduced cystic areas. There was reduced renal fibrosis and cell proliferation. The supplementation of beta-hydroxybutyrate (BHB) in rats also reduced PKD progression in a dose-dependent manner. Human studies (n = 129) on KD in ADPKD reported consistent body mass index (BMI) reduction across trials, with an average weight loss of ∼4 kg. Improvements in blood pressure were also noted. Ketosis was achieved in varying degrees. Effects on kidney function (eGFR) were beneficial. Results for kidney volume were mixed but most studies were underpowered for this outcome. Lipid profiles showed increases in total cholesterol (∼1 mmol/L) and LDL cholesterol (∼0.4 mmol/L) in most studies. Safety concerns such as “keto flu” symptoms, elevated uric acid levels, and occasional kidney stones were noted. Overall feasibility and adherence to the KD were rated positively by most participants. Conclusions: Human studies are promising; however, they have been limited by small sample sizes and short durations. Larger, long-term trials are needed to assess the efficacy, adherence, and safety of ketogenic diets in people with ADPKD. Full article

Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have greatly improved outcomes in persons with CF (pwCF); however, there is still significant heterogeneity in clinical responses, particularly with regard to respiratory infection and inflammation. Exogenous administration of ketones has profound systemic anti-inflammatory effects and produces several nutrient-signaling and metabolic effects that may benefit multiple organ systems affected in pwCF. This pilot study was designed to determine the feasibility of administration of a ketone monoester (KME) to increase circulating D-beta hydroxybutyrate concentrations (D-βHB) and to improve subjective measures of CF-specific quality of life and markers of inflammation in serum and sputum in adults with CF. Methods: Fourteen participants receiving modulator therapy were randomized to receive either KME (n = 9) or placebo control (PC, n = 5) for 5–7 days during hospitalization for treatment of acute pulmonary exacerbation or as outpatients under standard care. Results: The KME was well tolerated, with only mild reports of gastrointestinal distress. D-βHB concentrations increased from 0.2 ± 0.1 mM to 1.6 ± 0.6 mM in the KME group compared to 0.2 ± 0.0 to 0.3 ± 0.1 in the PC group (p = 0.011) within 15 min following consumption and remained elevated, relative to baseline, for over 2 h. Pulmonary function was not altered after single- or short-term KME administration, but participants in the KME group self-reported higher subjective respiratory scores compared to PC in both cases (p = 0.031). Plasma inflammatory markers were not statistically different between groups following the short-term (5–7 d) intervention (p > 0.05). However, an exploratory analysis of plasma pre- and post-IL-6 concentrations was significant (p = 0.028) in the KME group but not PC. Sputum IFNγ (p = 0.057), IL-12p70 (p = 0.057), IL-1β (p = 0.100), IL-15 (p = 0.057), IL-1α (p = 0.114), and MPO (p = 0.133) were lower in the KME group compared to PC but did not achieve statistical significance. Conclusions: With the emerging role of exogenous ketones as nutrient signaling molecules and mediators of metabolism, we showed that KME is well tolerated, increases circulating D-βHB concentrations, and produces outcomes that justify the need for large-scale clinical trials to investigate the role of KME on whole-body and tissue lipid accumulation and inflammation in pwCF. Full article

Background/Objectives: People with type 1 diabetes have an unmet need for cardiovascular protection due to the lack of new recommended antidiabetic therapies with cardiovascular benefits. We examined whether the addition of an empagliflozin/metformin combination, and each drug alone, can complement insulin to improve glucometabolic parameters in overweight people with type 1 diabetes at high cardiovascular risk. Methods: This pilot, single-center double-blind randomized controlled trial included 40 people with type 1 diabetes. In addition to insulin, they received empagliflozin (25 mg daily), metformin (2000 mg daily), an empagliflozin/metformin combination, or a placebo. The intervention period was 12 weeks. Glycemic parameters, insulin requirements, and blood and urine samples were analyzed. Indices for liver fibrosis were calculated. Due to potential safety concerns, participants regularly measured blood ketone values. Results: The empagliflozin/metformin combination decreased HbA1c (−0.6%, p < 0.05) and weight (−6.1 kg, p < 0.05). Empagliflozin decreased the urinary albumin-to-creatinine ratio (−31.4 ± 4.9%, p = 0.002). The empagliflozin/metformin combination and empagliflozin decreased the estimated daily proteinuria (−34.6 ± 5.0%, p = 0.006 and −35.9 ± 6.2%, p = 0.03, respectively), the calculated FIB-4 (up to −17.8 ± 5.2%, p = 0.04 and −10.7 ± 3.7%, p = 0.02, respectively), and other liver fibrosis indices and uric acid values. No significant side effects occurred during the study. Conclusions: The empagliflozin/metformin combination improved glycemic control, reduced weight and insulin requirements, and produced several additional beneficial metabolic effects in overweight people with type 1 diabetes with increased cardiovascular risk. Full article

Background/Objectives: Diabetic ketoacidosis (DKA) is an acute and potentially life-threatening complication characterized by the accumulation of ketone bodies in the blood, primarily occurring in patients with type 1 diabetes and occasionally in those with type 2 diabetes under certain conditions. DKA presents with symptoms such as polyuria, polydipsia, polyphagia, and, in severe cases, mental status changes. Identifying the triggering factor is crucial to prevent complications and effectively manage this medical emergency. Methods: This report describes the case of a 58-year-old male patient with stage IIIb nodular melanoma, diagnosed in November 2022. Results: After receiving five cycles of pembrolizumab, the patient developed de novo DKA, presenting with blurred vision, asthenia, adynamia, polyuria, and polydipsia. He was admitted to the emergency department with a blood glucose level of 764 mg/dL, confirming hyperglycemia and metabolic acidosis. He was transferred to the intensive care unit for fluid resuscitation and insulin infusion. After adequate clinical evolution and meeting the criteria for DKA resolution, possible autoimmune endocrinopathies secondary to immunotherapy were considered. Due to this complication, the oncological treatment was changed. Finally, the patient was discharged with the need to continue insulin therapy and oral hypoglycemic agents, along with thyroid hormone supplementation. Conclusions: The novelty of this case lies in the presentation of DKA as an immune-mediated complication induced by pembrolizumab, highlighting the importance of closely monitoring patients receiving immune checkpoint inhibitors to detect and manage emerging autoimmune endocrinopathies. It is essential to adjust oncological treatment according to the patient’s response and promptly manage autoimmune endocrinopathies to improve clinical outcomes and the patient’s quality of life. Full article

Background/Objectives: Elevating ketone levels with therapeutic nutritional ketosis can help to metabolically manage disease processes associated with epilepsy, diabetes, obesity, cancer, and neurodegenerative disease. Nutritional ketosis can be achieved with various dieting strategies such as the classical ketogenic diet, the modified Atkins diet, caloric restriction, periodic fasting, or the consumption of exogenous ketogenic supplements such as medium-chain triglycerides (MCTs). However, these various strategies can be unpleasant and difficult to follow, so that achieving and sustaining nutritional ketosis can be a major challenge. Thus, investigators continue to explore the science and applications of exogenous ketone supplementation as a means to further augment the therapeutic efficacy of this metabolic therapy. Methods: Here, we describe a structurally new synthetic triglyceride, glycerol tri-acetoacetate (Gly-3AcAc), that we prepared from glycerol and an acetoacetate precursor that produces hyperketonemia in the therapeutic range (2–3 mM) when administered to mice under both fasting and non-fasting conditions. Animal studies were undertaken to evaluate the potential effects of eliciting a ketogenic response systemically. Acute effects (24 h or less) were determined in male VM/Dk mice in both fasted and unfasted dietary states. Results: Concentration levels of β-hydroxybutyrate in blood were elevated (βHB; 2–3 mM) under both conditions. Levels of glucose were reduced only in the fasted state. No detrimental side effects were observed. Conclusions: Pending further study, this novel compound could potentially add to the repertoire of methods for inducing therapeutic nutritional ketosis. Full article