Search Results (15)

Background/Objectives: Epigenetic clocks have emerged as a tool to quantify biological age, providing a more accurate estimate of an individual’s health status than chronological age, helping to identify risk factors for accelerated aging and evaluating the reversibility of therapeutic strategies. This study aimed to evaluate the potential association between epigenetic acceleration of biological age and obesity, as well as to determine whether nutritional interventions for body weight loss could slow down this acceleration. Methods: Biological age was estimated using three epigenetic clocks (Horvath (Hv), Hannum (Hn), and Levine (Lv)) based on the leukocyte methylome analysis of individuals with normal weight (n = 20), obesity (n = 24), and patients with obesity following a VLCKD (n = 10). We analyzed differences in biological age estimates, the relationship between age acceleration and obesity, and the impact of VLCKD. Correlations were assessed between age acceleration, BMI, and various metabolic parameters. Results: Analysis of the epigenetic clocks revealed an acceleration of biological age in individuals with obesity (Hv = +3.4(2.5), Hn = +5.7(3.2), Lv = +3.9(2.7)) compared to a slight deceleration in individuals with normal weight. This epigenetic acceleration correlated with BMI (p < 0.0001). Interestingly, patients with obesity following a VLCKD showed a deceleration in estimated biological age, both in nutritional ketosis (Hv = −3.3(4.0), Hn = −6.3(5.3), Lv = −8.8(4.5)) and at endpoint (Hv = −1.1(4.3), Hn = −7.4(5.6), Lv = −8.2(5.3)). Relevantly, this slowdown in age is associated with BMI (p < 0.0001), ketonemia (p ≤ 0.001), and metabolic parameters (p < 0.05). Conclusions: Our findings highlight the applicability of epigenetic clocks to monitor obesity-related biological aging in precision medicine and show the potential efficacy of the VLCKD in slowing obesity-related epigenetic aging. Full article

Background: There is a growing consensus that fasting-induced ketosis has beneficial effects on human physiology. Despite these compelling benefits, fasting-induced ketosis raises concerns in some clinicians because it is often inappropriately compared with the pathologic uncontrolled ketone production in diabetic ketoacidosis. The determinants of the inter-individual differences in the intensity of ketosis during long-term fasting is unknown. Methods: We monitored daily variations in fasting ketonemia, as well as ketonuria, which is less invasive, in a large cohort of 1610 subjects, fasting between 4 and 21 days with the Buchinger Wilhelmi program, minimally supplemented with ~75–250 kcal (daily fruit juice, vegetable soup, and honey). Results: Ketonuria was detected in more than 95% of fasting subjects from day 4 onwards. Subjects consuming only soups, without fruit juice or honey, exhibited reduced caloric intake (72 kcal instead of 236 kcal) and carbohydrate intake (15.6 g instead of 56.5 g), leading to more intense ketonuria. Participants with high ketonuria were, in the majority, males, young, had a higher body weight, and had lower HDL-C and urea values. They had a larger decrease in blood glucose, glycated haemoglobin levels, body weight, and waist circumference. Furthermore, in the high-ketonuria group, a larger increase in blood uric acid concentration was observed. Conclusion: Our study showed that long-term fasting triggered ketosis, never reaching pathological levels, and that ketosis is influenced by age, gender, health, and the level of physical activity. Furthermore, it is modulated but not suppressed by minimal carbohydrate intake. Our study paves the way for better understanding how supplementation can modulate the therapeutic effects and tolerability of long-term fasting. Full article

Heart failure (HF) management in type 1 diabetes (T1D) is particularly challenging due to its increased prevalence and the associated risks of hospitalization and mortality, driven by diabetic cardiomyopathy. Sodium–glucose cotransporter-2 inhibitors (SGLT2-is) offer a promising avenue for treating HF, specifically the preserved ejection fraction variant most common in T1D, but their utility is hampered by the risk of euglycemic diabetic ketoacidosis (DKA). This review investigates the potential of SGLT2-is in T1D HF management alongside emergent Continuous Ketone Monitoring (CKM) technology as a means to mitigate DKA risk through a comprehensive analysis of clinical trials, observational studies, and reviews. The evidence suggests that SGLT2-is significantly reduce HF hospitalization and enhance cardiovascular outcomes. However, their application in T1D patients remains limited due to DKA concerns. CKM technology emerges as a crucial tool in this context, offering real-time monitoring of ketone levels, which enables the safe incorporation of SGLT2-is into treatment regimes by allowing for early detection and intervention in the development of ketosis. The synergy between SGLT2-is and CKM has the potential to revolutionize HF treatment in T1D, promising improved patient safety, quality of life, and reduced HF-related morbidity and mortality. Future research should aim to employ clinical trials directly assessing this integrated approach, potentially guiding new management protocols for HF in T1D. Full article

Introduction: Diabetic ketoacidosis (DKA) is associated with volume depletion and hemodynamic alterations. Changes in systemic microcirculation during DKA have not been described so far. Methods: In this case report, we describe the evolution of sublingual microcirculatory changes, monitored using sidestream dark field (SDF) imaging during the treatment of severe diabetic ketoacidosis in a 13-year-old girl. The patient presented a pH of 6.84, a glycemia level of 27.2 mmol/L, a ketonemia level of 5.6 mmol/L, a base excess of −29.4 mmol/L, hypernatremia, hyperosmolality due to acute gastritis, and a malfunction of the glucose sensor. Sublingual microcirculation measurements using an SDF probe were initiated 60 min after the initiation of treatment, which was then repeated 2, 3, 4, 6, 12, and 24 h after treatment initiation, as well as on the day of discharge. Results: Substantial alterations of microvascular perfusion parameters, both total and small vessel densities, perfused vessel densities, and the DeBacker score, were observed during the first 6 to 12 h of treatment. The degree of microcirculatory alteration was strongly negatively correlated with calculated osmolality, sodium levels, ketone and lactate levels, and blood pressure values. Conclusions: DKA is, in its complexity, associated with a serious microcirculatory alteration. SDF imaging provides insight into the severity of the patient’s microcirculatory alteration and its evolution during treatment. Full article

In glucose-deprived conditions, ketone bodies are produced by the liver mitochondria, through the catabolism of fatty acids, and are used peripherally, as an alternative energy source. Ketones are produced in the body under normal conditions, including during pregnancy and the neonatal period, when following a ketogenic diet (KD), fasting, or exercising. Additionally, ketone synthesis is also augmented under pathological conditions, including cases of diabetic ketoacidosis (DKA), alcoholism, and several metabolic disorders. Nonetheless, diet is the main regulator of total body ketone concentrations. The KDs are mimicking the fasting state, altering the default metabolism towards the use of ketones as the primary fuel source. Recently, KD has gained recognition as a medical nutrition therapy for a plethora of metabolic conditions, including obesity and diabetes mellitus (DM). The present review aims to discuss the role of ketones, KDs, ketonemia, and ketonuria in DM, presenting all the available new evidence in a comprehensive manner. Full article

Ketogenic dietary therapies (KDTs) are an effective and safe non-pharmacological treatment for drug-resistant epilepsy, but adherence can be challenging for both patients and caregivers. In Europe, there are no adequate tools to measure it other than monitoring ketosis. This study aimed to adapt and validate the Brazilian adherence questionnaire, Keto-check, into the Italian version: iKetoCheck. Using the Delphi technique, 12 judges validated the contents through agreement rates and the Content Validity Index (CVI). The iKetocheck was self-completed electronically by 61 drug-resistant epilepsy or GLUT1 deficiency patients within an interval of 15 days to measure its reproducibility. The test–retest reliability was evaluated using Pearson’s correlation and relative significance test. Exploratory and confirmatory factorial analyses were made using Factor software version 12.03.02. The final tool, iKetoCheck, consists of 10 questions with 5-point Likert scale answers. It evaluates various aspects such as informing caregivers about the diet, organization of meals, measurement of ketosis, weighing food consumed, diet negligence, use of carbohydrate-free medications, attending follow-up visits, reading food labels, consulting an expert for dietary concerns, and cooking at home. The factorial analysis resulted in three factors: “attention,” “organization,” and “precision,” with satisfactory results for indices in exploratory and confirmatory analyses. Although higher mean values of ketonemia measurement were observed in patients with a higher adherence score, these values were not statistically significant (p = 0.284). In conclusion, despite the small sample size, iKetoCheck is a valid tool for evaluating KDTs’ adherence in Italian drug-resistant epilepsy or GLUT1 deficiency patients. It can provide valuable information to improve patient management and optimize the effectiveness of KDTs. Full article

Background: several strategies are used to assess adherence to ketogenic dietary therapies (KDTs), the most commonly used being ketonemia or ketonuria, despite their limitations. The purpose of this article is to carry out an exploratory and confirmatory factor analysis on the proposed Keto-check (adherence’s KDT Brazilian questionnaire). Methods: there was a methodological study of a quantitative nature, complementary to the analysis realized previously, with a complimentary sample. The factorial analysis was performed with Factor software for parallel exploratory analysis, replicability, and confirmatory factor analysis. Graphical representation was created according to the number of factors resulting from the analysis. Results: 116 questionnaires were reached by complementary data collection (n = 69 actual data, complementing n = 47 previous data) through online forms. A polychoric correlation matrix suitability analysis resulted in a significant Bartlett statistic (p = 0.0001) and a Kaiser–Meyer–Olkin (KMO) test of 0.56. The parallel factorial analysis resulted in two factors, graphically represented as “efficacy” and “adherence”. A confirmatory factor analysis, considered fair, indicated an RMSEA of 0.063, NNFI resulted in 0.872, CFI in 0.926, and GFI in 0.897. Conclusion: this study confirms the validity of Keto-check through a more detailed analysis. Adherence is the key to improving the effectiveness of KDTs; therefore, improving knowledge about it can lead to a better healthcare approach. Full article

The epidemic of obesity, type 2 diabetes and nonalcoholic liver disease (NAFLD) favors drug consumption, which augments the risk of adverse events including liver injury. For more than 30 years, a series of experimental and clinical investigations reported or suggested that the common pain reliever acetaminophen (APAP) could be more hepatotoxic in obesity and related metabolic diseases, at least after an overdose. Nonetheless, several investigations did not reproduce these data. This discrepancy might come from the extent of obesity and steatosis, accumulation of specific lipid species, mitochondrial dysfunction and diabetes-related parameters such as ketonemia and hyperglycemia. Among these factors, some of them seem pivotal for the induction of cytochrome P450 2E1 (CYP2E1), which favors the conversion of APAP to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). In contrast, other factors might explain why obesity and NAFLD are not always associated with more frequent or more severe APAP-induced acute hepatotoxicity, such as increased volume of distribution in the body, higher hepatic glucuronidation and reduced CYP3A4 activity. Accordingly, the occurrence and outcome of APAP-induced liver injury in an obese individual with NAFLD would depend on a delicate balance between metabolic factors that augment the generation of NAPQI and others that can mitigate hepatotoxicity. Full article

The original nutrition approach for the treatment of gestational diabetes mellitus (GDM) was to reduce total carbohydrate intake to 33–40% of total energy (EI) to decrease fetal overgrowth. Conversely, accumulating evidence suggests that higher carbohydrate intakes (60–70% EI, higher quality carbohydrates with low glycemic index/low added sugars) can control maternal glycemia. The Institute of Medicine (IOM) recommends ≥175 g/d of carbohydrate intake during pregnancy; however, many women are consuming lower carbohydrate (LC) diets (<175 g/d of carbohydrate or <40% of EI) within pregnancy and the periconceptual period aiming to improve glycemic control and pregnancy outcomes. This report systematically evaluates recent data (2018–2020) to identify the LC threshold in pregnancy in relation to safety considerations. Evidence from 11 reports suggests an optimal carbohydrate range of 47–70% EI supports normal fetal growth; higher than the conventionally recognized LC threshold. However, inadequate total maternal EI, which independently slows fetal growth was a frequent confounder across studies. Effects of a carbohydrate intake <175 g/d on maternal ketonemia and plasma triglyceride/free fatty acid concentrations remain unclear. A recent randomized controlled trial (RCT) suggests a higher risk for micronutrient deficiency with carbohydrate intake ≤165 g/d in GDM. Well-controlled prospective RCTs comparing LC (<165 g/d) and higher carbohydrate energy-balanced diets in pregnant women are clearly overdue. Full article

Adaptive homeostasis declines with age and this leads to, among other things, the appearance of chronic age-related pathologies such as cancer, neurodegeneration, osteoporosis, sarcopenia, cardiovascular disease and diabetes. Grape seed-derived procyanidins (GSPE) have been shown to be effective against several of these pathologies, mainly in young animal models. Here we test their effectiveness in aged animals: 21-month-old female rats were treated with 500 mg GSPE/kg of body weight for ten days. Afterwards they were kept on a chow diet for eleven weeks. Food intake, body weight, metabolic plasma parameters and tumor incidence were measured. The GSPE administered to aged rats had an effect on food intake during the treatment and after eleven weeks continued to have an effect on visceral adiposity. It prevented pancreas dysfunction induced by ageing and maintained a higher glucagon/insulin ratio together with a lower decrease in ketonemia. It was very effective in preventing age-related tumor development. All in all, this study supports the positive effect of GSPE on preventing some age-related pathologies. Full article

Objective: To describe families’ experiences in managing epileptic patients undergoing ketogenic dietary therapies (KDTs) in acute medical settings. Methods: We conducted a short online survey addressed to the families of patients undergoing a classic ketogenic diet (cKD) for at least three months. The survey was composed of 18 questions exploring the following issues: demographic characteristics, epilepsy diagnosis, ketogenic-diet treatment history, the reason for emergency-ward admission and patient management, surgery-procedure management, and outcomes. Results: A sample of 50 families agreed to participate. Out of 50 patients, 33 (66%) had been undergoing a cKD for more than two years. Fifteen (30%) patients had been admitted at least once to the Emergency Room (ER), and 8.2% had undergone surgical procedures during cKD treatment. The causes of ER admission were the following: seizures, infection, trauma, and gastrointestinal or respiratory problems. In 75% of cases, blood ketonemia was not monitored during ER admission, and according to 46% of responders, the medical staff intervening did not have a basic knowledge of KDTs. Conclusions: According to both our experience and caregivers’ reports, it might be useful to search for standardized specific approaches to patients undergoing KDTs in the emergency setting. Full article

Background and Objective: Lactation ketoacidosis is a rare cause of high anion gap metabolic acidosis affecting breastfeeding mothers. We aim to review and analyze all cases of lactation ketoacidosis reported. Materials and Methods: A systematic search of PubMed/MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL), identifying relevant case reports published from 1 January 1970 to 31 December 2019. We extracted the following data: the first author, country, year of publication, age of the mother, age of the child, weight/body mass index (BMI) of the mother, precipitating factors, presenting symptoms, biochemical results, treatment, breastfeeding, and time from presentation to the resolution of ketoacidosis. Results: Sixteen case reports and 1 case series reporting 18 cases of lactation ketoacidosis were found. Presenting symptoms were nausea (72%, 13/18), vomiting (67%, 12/18), malaise (56%, 10/18), abdominal pain (44%, 8/18), dyspnea (33%, 6/18), headache (22%, 4/18), and palpitation (11%, 2/18). Dieting and physical exercise to lose weight were reported in 76% (14/18). The treatments included IV dextrose, sodium bicarbonate, insulin, rehydration, monitoring and replacement of electrolytes, and resumption of a balanced diet. The prognoses were good, with no mortalities. Conclusions: lactation ketoacidosis should be suspected in unwell breastfeeding women with high anion gap metabolic acidosis, after excluding other causes. Full article

Excessive mobilization of adipose tissue in high milk producing dairy cows predisposes to metabolic diseases. The aim of this research was to identify the plasma fatty acids in four lipid classes as biomarkers for the diagnosis of hyperketonemia in bovines using thin layer chromatography and gas chromatographic techniques (TLC-GC). Sixty multiparous Holstein–Friesian dairy cows were enrolled in the study. Blood samples from the coccygeal vein were collected and β-hydroxybutyrate (BHB) was evaluated. All animals were divided into three groups on the basis of ketonemia: BHB < 0.50 mmol/L, 0.50 < BHB < 1.0 mmol/L, and BHB > 1.0 mmol/L. Plasma fatty acid concentrations were evaluated in four lipid classes: Free Fatty Acids (FFA), Triglycerides (TG), Cholesterol Esters (CE) And Phospholipids (PL). The concentration of fatty acids was analyzed using TLC-GC. The results showed the following significance in the lipid classes: 19 fatty acids were significant (p < 0.053) in FFA, nine fatty acids were significant (p < 0.050) in TG, eight fatty acids were significant (p < 0.050) in CE and three fatty acids were significant (p < 0.049) in PL. Eleven parameters were considered as predictive fatty acids related to animals in hyperketonemia. The FFA increased simultaneously with blood BHB levels, although the identified predictive fatty acids related to the TG and CE lipid classes decreased, meanwhile the BHB values increased. In the PL lipid class, no fatty acids were predictive. Full article

This study was performed to evaluate anti-obesity potential of Commiphora myrrha resin ethanolic extract (CME) with the respect to expression of leptin, adiponectin and uncoupling protein 1 (UCP1) in rats. Control rats fed basal diet. Second group fed basal diet and administered CME (500 mg/kg bw) orally for 14 weeks. Third group fed high fat diet (HFD) for 14 weeks. Fourth group fed HFD and administered CME as second group. Fifth group fed HFD for 8 weeks then fed basal diet and administered CME as third group for another 6 weeks. Phytochemical analysis of CME identified the presence of germacrene B, 1,4-benzoquinone, benzofuran, hexadecanoic acid, 9,12-octadecnoic acid methyl ester, reynosin, 11, 14-eicosadienoic acid, isochiapin B, bisabolene epixod, elemene and 1-heptatriacotanol. High fat diet significantly increased food intake, body weight, hyperglycemia, serum levels of total cholesterol, triacylglycerol, low density lipoprotein and ketone bodies, AST and AST activities, concentration of malondialdehyde and histopathological changes in hepatic tissues. However, it significantly reduced serum levels of high density lipoprotein, leptin and adiponectin, activity of hepatic glutathione reductase (GR) and brown adipose tissue UCP1 protein expression. In contrast, CME ameliorated HFD increased body weight, hyperglycemia, dyslipidemia, ketonemia, hepatic tissues lipid peroxidation, restored hepatic tissue architecture and enhanced protein expression of leptin, adiponectin and UCP1 and activity of hepatic GR. This study indicated that CME ameliorated HFD induced hyperglycemia and dyslipidemia through normalization of HFD reduced leptin, adiponectin and UCP1 proteins production and antioxidant activity. Full article

We determined the short- and long-term effects of a ketogenic diet (KD) or ketone salt (KS) supplementation on multi-organ oxidative stress and mitochondrial markers. For short-term feedings, 4 month-old male rats were provided isocaloric amounts of KD (n = 10), standard chow (SC) (n = 10) or SC + KS (~1.2 g/day, n = 10). For long-term feedings, 4 month-old male rats were provided KD (n = 8), SC (n = 7) or SC + KS (n = 7) for 8 months and rotarod tested every 2 months. Blood, brain (whole cortex), liver and gastrocnemius muscle were harvested from all rats for biochemical analyses. Additionally, mitochondria from the brain, muscle and liver tissue of long-term-fed rats were analyzed for mitochondrial quantity (maximal citrate synthase activity), quality (state 3 and 4 respiration) and reactive oxygen species (ROS) assays. Liver antioxidant capacity trended higher in short-term KD- and SC + KS-fed versus SC-fed rats, and short-term KD-fed rats exhibited significantly greater serum ketones compared to SC + KS-fed rats indicating that the diet (not KS supplementation) induced ketonemia. In long term-fed rats: (a) serum ketones were significantly greater in KD- versus SC- and SC + KS-fed rats; (b) liver antioxidant capacity and glutathione peroxidase protein was significantly greater in KD- versus SC-fed rats, respectively, while liver protein carbonyls were lowest in KD-fed rats; and (c) gastrocnemius mitochondrial ROS production was significantly greater in KD-fed rats versus other groups, and this paralleled lower mitochondrial glutathione levels. Additionally, the gastrocnemius pyruvate-malate mitochondrial respiratory control ratio was significantly impaired in long-term KD-fed rats, and gastrocnemius mitochondrial quantity was lowest in these animals. Rotarod performance was greatest in KD-fed rats versus all other groups at 2, 4 and 8 months, although there was a significant age-related decline in performance existed in KD-fed rats which was not evident in the other two groups. In conclusion, short- and long-term KD improves select markers of liver oxidative stress compared to SC feeding, although long-term KD feeding may negatively affect skeletal muscle mitochondrial physiology. Full article