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While the macronutrient content of a ketogenic diet specifically utilized for childhood epilepsy is clearly defined in the literature, variations among other ketogenic diets exhibit substantial heterogeneity. Furthermore, studies utilizing ketogenic diets contain several confounders with notable impacts on outcomes, thereby rendering both their findings and those of the meta-analyses less reliable. The objective of this meta-epidemiological assessment was to scrutinize existing clinical trials that investigated the effects of ketogenic diets on patients with obesity and diabetes, thereby determining the feasibility of conducting a meta-analysis. The Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched from 1946 to 24 September 2024. Of the studies reviewed, none met the predefined inclusion criteria. However, seven articles met these criteria very closely. In the future, studies investigating the effects of ketogenic diets containing significant confounding factors should adopt a single definition of a ketogenic diet. Additionally, accurate measurement of actual macronutrient and caloric intake, along with regularly monitored nutritional ketosis, will be essential to highlight the true effects of a ketogenic diet. [ABSTRACT FROM AUTHOR]

Acute ketone monoester (KE) supplementation can alter exercise responses, but the performance effect is unclear. The limited and equivocal data to date are likely related to factors including the KE dose, test conditions, and caliber of athletes studied. We tested the hypothesis that mean power output during a 20-min cycling time trial (TT) would be different after KE ingestion compared to a placebo (PL). A sample size of 22 was estimated to provide 80% power to detect an effect size dz of 0.63 at an alpha level of.05 with a two-tailed paired t test. This determination considered 2.0% as the minimal important difference in performance. Twenty-three trained cyclists (N = 23; peak oxygen uptake: 65 ± 12 ml·kg−1 min−1; M ± SD), who were regularly cycling >5 hr/week, completed a familiarization trial followed by two experimental trials. Participants self-selected and replicated their diet and exercise for ∼24 hr before each trial. Participants ingested either 0.35 g/kg body mass of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate KE or a flavor-matched PL 30 min before exercise in a randomized, triple-blind, crossover manner. Exercise involved a 15-min warm-up followed by the 20-min TT on a cycle ergometer. The only feedback provided was time elapsed. Preexercise venous [β-hydroxybutyrate] was higher after KE versus PL (2.0 ± 0.6 vs. 0.2 ± 0.1 mM, p <.0001). Mean TT power output was 2.4% (0.6% to 4.1%; mean [95% confidence interval]) lower after KE versus PL (255 ± 54 vs. 261 ± 54 W, p <.01; dz = 0.60). The mechanistic basis for the impaired TT performance after KE ingestion under the present study conditions remains to be determined. [ABSTRACT FROM AUTHOR]

It is widely acknowledged that the ketogenic diet (KD) has positive physiological effects as well as therapeutic benefits, particularly in the treatment of chronic diseases. Maintaining nutritional ketosis is of utmost importance in the KD, as it provides numerous health advantages such as an enhanced lipid profile, heightened insulin sensitivity, decreased blood glucose levels, and the modulation of diverse neurotransmitters. Nevertheless, the integration of the KD with pharmacotherapeutic regimens necessitates careful consideration. Due to changes in their absorption, distribution, metabolism, or elimination, the KD can impact the pharmacokinetics of various medications, including anti-diabetic, anti-epileptic, and cardiovascular drugs. Furthermore, the KD, which is characterised by the intake of meals rich in fats, has the potential to impact the pharmacokinetics of specific medications with high lipophilicity, hence enhancing their absorption and bioavailability. However, the pharmacodynamic aspects of the KD, in conjunction with various pharmaceutical interventions, can provide either advantageous or detrimental synergistic outcomes. Therefore, it is important to consider the pharmacokinetic and pharmacodynamic interactions that may arise between the KD and various drugs. This assessment is essential not only for ensuring patients' compliance with treatment but also for optimising the overall therapeutic outcome, particularly by mitigating adverse reactions. This highlights the significance and necessity of tailoring pharmacological and dietetic therapies in order to enhance the effectiveness and safety of this comprehensive approach to managing chronic diseases. [ABSTRACT FROM AUTHOR]

While the macronutrient content of a ketogenic diet specifically utilized for childhood epilepsy is clearly defined in the literature, variations among other ketogenic diets exhibit substantial heterogeneity. Furthermore, studies utilizing ketogenic diets contain several confounders with notable impacts on outcomes, thereby rendering both their findings and those of the meta-analyses less reliable. The objective of this meta-epidemiological assessment was to scrutinize existing clinical trials that investigated the effects of ketogenic diets on patients with obesity and diabetes, thereby determining the feasibility of conducting a meta-analysis. The Ovid Medline, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase databases were searched from 1946 to 24 September 2024. Of the studies reviewed, none met the predefined inclusion criteria. However, seven articles met these criteria very closely. In the future, studies investigating the effects of ketogenic diets containing significant confounding factors should adopt a single definition of a ketogenic diet. Additionally, accurate measurement of actual macronutrient and caloric intake, along with regularly monitored nutritional ketosis, will be essential to highlight the true effects of a ketogenic diet.

Background Previous preclinical and human studies have shown that a high-fat ketogenic diet and ketone supplements (KS) are efficacious in reducing alcohol craving, alcohol consumption, and signs of alcohol withdrawal. However, the effects of KS on alcohol sensitivity are unknown. Methods In this single-blind, cross-over study, 10 healthy participants (3 females) were administered a single, oral dose of a KS (25 g of ketones from D-β-hydroxybutyric acid and R-1,3-butanediol) or placebo 30 minutes before an oral alcohol dose (0.25 g/kg for women; 0.31 g/kg for men). Assessments of breath alcohol concentration and blood alcohol levels (BAL) and responses on the Drug Effect Questionnaire were repeatedly obtained over 180 minutes after alcohol consumption. In a parallel preclinical study, 8 Wistar rats (4 females) received an oral gavage of KS (0.42 g ketones/kg), water, or the sweetener allulose (0.58 g/kg) followed 15 minutes later by an oral alcohol dose (0.8 g/kg). BAL was monitored for 240 minutes after alcohol exposure. Results In humans, the intake of KS before alcohol significantly blunted breath alcohol concentration and BAL, reduced ratings of alcohol liking and wanting more, and increased disliking for alcohol. In rats, KS reduced BAL more than either allulose or water. Conclusion KS altered physiological and subjective responses to alcohol in both humans and rats, and the effects were likely not mediated by the sweetener allulose present in the KS drink. Therefore, KS could potentially reduce the intoxicating effects of alcohol. [ABSTRACT FROM AUTHOR]

In the present study, our team aimed to investigate the effects of acute ingestion of a ketone salt (KS) supplement on the cognitive performance in healthy college-aged males during a dual-stress challenge (DSC). Following a peak oxygen uptake test and DSC familiarization, 16 males completed a DSC while cycling at 60% of their respective peak oxygen uptake after ingesting either a commercially available racemic (D- and L-)β-hydroxybutyrate (β-OHB) KS (0.38 g/kg body mass) or a placebo, using a triple-blinded, crossover, and counterbalanced design. The participants consumed the KS or placebo at −60 and −15 min prior to the start of the DSC. Heart rate, rating of perceived exertion, and blood β-OHB and glucose were sampled throughout. The DSC consisted of a mental arithmetic challenge and a modified Stroop Color Word, which alternated every 2 min for 20 min. Upon completion of the DSC, responses for correct, incorrect, and no responses were recorded for the mental arithmetic challenge and Stroop Color Word. Blood β-OHB was elevated with KS by −15 min and remained so throughout (p <.001), peaking at 0.76 ± 0.32 mM. Blood glucose was lower with KS compared with the placebo at −15 and 10 min by 9% and 5%, respectively (both ps <.05). There were no differences between the treatments for heart rate, rating of perceived exertion, mental arithmetic challenge, or Stroop Color Word. Overall, this study suggests that KSs are not effective aids for enhancing cognitive performance during a DSC, which might partially be explained by the inability of currently available commercial KS supplements to elevate β-OHB blood concentrations above ∼1.0 mM. [ABSTRACT FROM AUTHOR]

Ketone monoester (KE) ingestion can induce hyperketonemia and blood acidosis. We previously found that acute ingestion of 0.6 g·kg−1 body mass KE increased exercise heart rate (HR) compared with placebo. Purpose: This study aimed to examine the effect of KE ingestion on exercise cardiac output (Q˙) and the influence of blood acidosis. We hypothesized that KE versus placebo ingestion would increase Q ˙, and coingestion of the pH buffer bicarbonate would mitigate this effect. Methods: In a randomized, double-blind, crossover manner, 15 endurance-trained adults (peak oxygen uptake (V̇O2peak), 60 ± 9 mL·kg−1·min−1) ingested either 0.2 g·kg−1 sodium bicarbonate or a salt placebo 60 min before exercise, and 0.6 g·kg−1 KE or a ketone-free placebo 30 min before exercise. Supplementation yielded three experimental conditions: basal ketone bodies and neutral pH (CON), hyperketonemia and blood acidosis (KE), and hyperketonemia and neutral pH (KE + BIC). Exercise involved 30 min of cycling at ventilatory threshold intensity, followed by determinations of V̇O2peak and peak Q ˙. Results: Blood [β-hydroxybutyrate], a ketone body, was higher in KE (3.5 ± 0.1 mM) and KE + BIC (4.4 ± 0.2) versus CON (0.1 ± 0.0, P < 0.0001). Blood pH was lower in KE versus CON (7.30 ± 0.01 vs 7.34 ± 0.01, P < 0.001) and KE + BIC (7.35 ± 0.01, P < 0.001). Q ˙ during submaximal exercise was not different between conditions (CON: 18.2 ± 3.6, KE: 17.7 ± 3.7, KE + BIC: 18.1 ± 3.5 L·min−1; P = 0.4). HR was higher in KE (153 ± 9 bpm) and KE + BIC (154 ± 9) versus CON (150 ± 9, P < 0.02). V̇O2peak (P = 0.2) and peak Q ˙ (P = 0.3) were not different between conditions, but peak workload was lower in KE (359 ± 61 W) and KE + BIC (363 ± 63) versus CON (375 ± 64, P < 0.02). Conclusions: KE ingestion did not increase Q ˙ during submaximal exercise despite a modest elevation of HR. This response occurred independent of blood acidosis and was associated with a lower workload at V̇O2peak. [ABSTRACT FROM AUTHOR]

Abstract Background Very low-calorie ketogenic diet (VLCKD) has shown to significantly reduce body weight and fat mass, as well as inflammation. These effects are supported by nutritional ketosis, which triggers the utilization of the ketone body as an energy source. Medium-chain fatty acids (MCTs) might serve as potential enhancers of ketone bodies production with a greater effect on weight loss. Nevertheless, no clinical studies have evaluated the effect of MCTs supplementation in addition to VLCKD. Therefore, the present study aimed to evaluate whether the supplementation with MCTs can induce a greater weight reduction during the ketogenic phase of VLCKD. Methods In this retrospective study, 263 women with overweight/obesity (body mass index, BMI: 35.7 ± 5.3 kg/m2) aged 37.5 ± 14.2 years followed one of these dietary protocols for 45 days: (a) Control group, 83 participants (31.6%) (VLCKD without MCTs), (b) VLCKD + MCTs group, 86 participants (32.7%) (MCTs supplementation − 20 g/day- during VLCKD starting from the first day of the active phase), (c) VLCKD + earlyMCTs, 94 participants (35.7%) (MCTs supplementation − 20 g/day-starting from 5 days before the beginning of the VLCKD active phase. Anthropometric measures, body composition, and c-reactive protein (CRP) concentrations were collected at the beginning and at the end (45 days) of the VLCKD intervention. Results MCTs supplementation significantly decreased body weight, BMI, and waist circumference as compared to the control group, with a greater effect in the VLCKD + earlyMCTs group. A two-fold decrease in fat mass and an increase in muscle mass were observed in the VLCKD + earlyMCTs group as compared to the control group. As for inflammation, hs-CRP concentrations (assessed as absolute percent change) were significantly lower in the VLCKD + MCTs group (p = 0.009) and the VLCKD + earlyMCTs group (p = 0.011) than in the control group. A logistic regression model showed that VLCKD + earlyMCTs increase the likelihood of improvement of BMI classes (OR: 1.85, 95% CI 1.02–3.36) also after adjusting for the potential confounding factors. Conclusion MCTs supplementation (20 g/day) may be a useful tool to enhance the beneficial effect of VLCKD on the reduction of body weight and fat mass. In particular, MCTs supplementation before the beginning of the VLCKD active phase might facilitate ketosis thus contributing to the effectiveness of the nutritional intervention.

Abstract Background Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment. Methods A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment. Results Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored. Conclusions MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.

Background: Very low-calorie ketogenic diet (VLCKD) has shown to significantly reduce body weight and fat mass, as well as inflammation. These effects are supported by nutritional ketosis, which triggers the utilization of the ketone body as an energy source. Medium-chain fatty acids (MCTs) might serve as potential enhancers of ketone bodies production with a greater effect on weight loss. Nevertheless, no clinical studies have evaluated the effect of MCTs supplementation in addition to VLCKD. Therefore, the present study aimed to evaluate whether the supplementation with MCTs can induce a greater weight reduction during the ketogenic phase of VLCKD. Methods: In this retrospective study, 263 women with overweight/obesity (body mass index, BMI: 35.7 ± 5.3 kg/m2) aged 37.5 ± 14.2 years followed one of these dietary protocols for 45 days: (a) Control group, 83 participants (31.6%) (VLCKD without MCTs), (b) VLCKD + MCTs group, 86 participants (32.7%) (MCTs supplementation − 20 g/day- during VLCKD starting from the first day of the active phase), (c) VLCKD + earlyMCTs, 94 participants (35.7%) (MCTs supplementation − 20 g/day-starting from 5 days before the beginning of the VLCKD active phase. Anthropometric measures, body composition, and c-reactive protein (CRP) concentrations were collected at the beginning and at the end (45 days) of the VLCKD intervention. Results: MCTs supplementation significantly decreased body weight, BMI, and waist circumference as compared to the control group, with a greater effect in the VLCKD + earlyMCTs group. A two-fold decrease in fat mass and an increase in muscle mass were observed in the VLCKD + earlyMCTs group as compared to the control group. As for inflammation, hs-CRP concentrations (assessed as absolute percent change) were significantly lower in the VLCKD + MCTs group (p = 0.009) and the VLCKD + earlyMCTs group (p = 0.011) than in the control group. A logistic regression model showed that VLCKD + earlyMCTs increase the likelihood of improvement of BMI classes (OR: 1.85, 95% CI 1.02–3.36) also after adjusting for the potential confounding factors. Conclusion: MCTs supplementation (20 g/day) may be a useful tool to enhance the beneficial effect of VLCKD on the reduction of body weight and fat mass. In particular, MCTs supplementation before the beginning of the VLCKD active phase might facilitate ketosis thus contributing to the effectiveness of the nutritional intervention. [ABSTRACT FROM AUTHOR]

This study assessed the five-year effects of a continuous care intervention (CCI) delivered via telemedicine, counseling people with type 2 diabetes (T2D) on a very low carbohydrate diet with nutritional ketosis. Participants with T2D were enrolled in a 2-year, open-label, non-randomized study comparing CCI and usual care (UC). After 2 years, 194 of the 262 CCI participants were approached for a three-year extension. Of these, 169 consented, and 122 remained in the study for five years. Primary outcomes were changes in diabetes status assessed using McNemars' test, including remission and HbA1c < 6.5 % on no glucose lowering medication or only on metformin at 5 years. Changes in body mass, glycemia, and cardiometabolic markers from baseline to 5 years were assessed using linear mixed-effects models. Twenty percent (n = 24) of the five-year completers achieved remission, with sustained remission observed over three years in 15.8 % (n = 19) and four years in 12.5 % (n = 15). Reversal to HbA1c < 6.5 % without medication or only metformin was seen in 32.5 % (n = 39). Sustained improvements were noted in body mass (−7.6 %), HbA1c (−0.3 %), triglycerides (−18.4 %), HDL-C (+17.4 %), and inflammatory markers, with no significant changes in LDL-C and total cholesterol. Over five years, the very low carbohydrate intervention showed excellent retention and significant health benefits, including diabetes remission, weight loss, and improved cardiometabolic markers. [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) plays a role in the pathogenesis of many diseases, such as type 2 diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, obesity, and neurodegenerative diseases, including Alzheimer's disease. The ketogenic diet (KD) is a low-carbohydrate/high-fat diet that arose in the 1920s as an effective treatment for seizure control. Since then, the KD has been studied as a therapeutic approach for various IR-related disorders with successful results. To date, the use of the KD is still debatable regarding its safety. Some studies have acknowledged its usefulness, while others do not recommend its long-term implementation. In this review, we applied a SWOC (Strengths, Weaknesses, Opportunities, and Challenges) analysis that revealed the positive, constructive strengths of the KD, its potential complications, different conditions that can make used for it, and the challenges faced by both physicians and subjects throughout a KD. This SWOC analysis showed that the KD works on the pathophysiological mechanism of IR-related disorders such as chronic inflammation, oxidative stress and mitochondrial stress. Furthermore, the implementation of the KD as a potential adjuvant therapy for many diseases, including cancer, neurodegenerative disorders, polycystic ovary syndrome, and pain management was proven. On the other hand, the short and long-term possible undesirable KD-related effects, including nutritional deficiencies, growth retardation and nephrolithiasis, should be considered and strictly monitored. Conclusively, this review provides a context for decision-makers, physicians, researchers, and the general population to focus on this dietary intervention in preventing and treating diseases. Moreover, it draws the attention of scientists and physicians towards the opportunities and challenges associated with the KD that requires attention before KD initiation. [ABSTRACT FROM AUTHOR]

Background: Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment.Methods: A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment.Results: Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored.Conclusions: MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging. [ABSTRACT FROM AUTHOR]

Introduction and objective Among the unconventional diets, the ketogenic diet (KD) is currently gaining popularity. The aim of the study was to determine the motivation of active and physically fit women to apply KD, to examine whether the results of KD met the expectations and to assess their diet and nutritional status. Material and methods The study covered 500 women aged 40.5 ± 12.2 years, including: 250 – in the course of KD lasting one and a half month, on average (Group 1), and 250 – who had already completed KD lasting for 3 months, on average (Group 2). The frequency of consumption of products that are a source of fats, proteins and carbohydrates was evaluated in 2 categories: often (several times a week to several times a day) and rarely (once a week – never). Nutritional status was assessed in particular BMI ranges. Results As many as 75% of women from both groups used KD to lose weight and most of them declared that they had achieved the intended goal. Products allowed and recommended in KD were consumed frequently by the majority of women, but nutrition mistakes were also made; 62% of women used dietary supplements. As a result of KD, the percentage of women with excess body weight (obesity and overweight) decreased in Group 1 from 87% – 54%, and in Group 2 – from 87% – 37%. The number of overweight women decreased statistically significantly. The vast majority of women undertook KD without consulting a doctor or a dietician. In Group 2, malaise was a frequent cause of discontinuation of the diet. Conclusions It is necessary to involve physicians and nutritionists more in promoting knowledge about contraindications and possible negative consequences of introducing the body into a state of nutritional ketosis, and the need to check the general health condition before implementation and during the use of KD.

Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases.

Inflammation and oxidative stress are the most probable mechanistic link between obesity and its co-diseases with cancer among them. The aim of this study was to evaluate whether the nutritional ketosis and weight loss induced by a very-low-calorie ketogenic diet (VLCKD) modulates the inflammatory and oxidative stress profile, compared with a standard, balanced hypocaloric diet (LCD) or bariatric surgery (BS) in patients with obesity. The study was performed in 79 patients with overweight or obesity and 32 normal-weight volunteers as the control group. Patients with obesity underwent a weight reduction therapy based on VLCKD, LCD or BS. The quantification of the circulating levels of a multiplexing test of cytokines and carcinogenesis/aging biomarkers, as well as of lipid peroxides and total antioxidant power, was carried out. First, we observed that pro-inflammatory cytokines increase, while anti-inflammatory cytokines decrease under excessive body weight. Relevantly, when patients underwent weight loss strategies, it was shown that energy-restricted and surgical strategies of weight loss induced changes in circulating cytokine and lipid peroxides. This effect was more notable in patients following the VLCKD than the LCD or BS and it was observed mainly in the ketosis phase of the intervention. Particularly, IL-11, IL-12, IL-2, INF-γ, INF-β, Pentraxin-3 or MMP1 changed after VLCKD. Whereas, APRIL, TWEAK, osteocalcin and IL-28A increased after BS. As far as we know, this is the first study that evaluate the time-course of cytokines and oxidative stress markers after a VLCKD as compared with a standard LCD and BS. The observed results support the immunomodulatory effect of nutritional ketosis induced by a VLCKD synergistically with weight loss as a strategy to improve innate-immunity and to prevent infections and carcinogenesis in patients with obesity. [ABSTRACT FROM AUTHOR]

Depressive symptoms are prevalent among people with type 2 diabetes (T2D) and, even at low severity levels, are associated with worse diabetes outcomes. Carbohydrate restriction is an effective treatment for T2D but its long-term impacts on depressive symptoms are unclear. In the current study we explored changes in depressive symptoms over 2 years among 262 primarily non-depressed T2D patients participating in a continuous remote care intervention emphasizing carbohydrate restriction. Subclinical depressive symptoms decreased over the first 10 weeks and reductions were maintained out to 2 years. Increased frequency of blood ketone levels indicative of adherence to low carbohydrate eating predicted decreases in depressive symptoms. Concerns have been raised with recommending restrictive diets due to potential negative impacts on quality-of-life factors such as mood; however, results of the current study support positive rather than negative long-term impacts of closely monitored carbohydrate restriction on depressive symptoms. [ABSTRACT FROM AUTHOR]

BackgroundCoronavirus disease 2019 (COVID-19) pandemic public health measures such as stay-at-home and mandatory work-from-home orders have been associated with obesogenic lifestyle changes, increased risk of weight gain, and their metabolic sequelae. We sought to assess the impact of this pandemic on weight loss from a telemedicine-delivered very-low-carbohydrate intervention targeting nutritional ketosis (NKI).MethodsA total of 746 patients with a BMI ≥25kg/m2, enrolled between January and March 2020 and treated for at least 1 year with the NKI, were classified as pandemic cohort (PC). A separate cohort of 699 patients who received 1 year of the NKI in the preceding years, enrolled between January and March 2018, were identified as pre-pandemic cohort (Pre-PC). Demographic and clinical data were obtained from medical records to compare the cohorts and assess the outcomes. Using propensity score matching (PSM), balanced and matched groups of 407 patients in the Pre-PC and 407 patients in the PC were generated. Longitudinal change in absolute weight and percentage weight change from baseline to 1 year were assessed.ResultsWeight significantly decreased in both PC and Pre-PC at 3, 6, 9, and 12 months. The weight loss trajectory was similar in both PC and Pre-PC with no significant weight differences between the two cohorts at 3, 6, 9, and 12 months. On an average, the PC lost 7.5% body weight while the Pre-PC lost 7.9% over 1 year, and the percent weight loss did not differ between the two cohorts (p = 0.50).ConclusionA very-low-carbohydrate telemedicine intervention delivered comparable and medically significant weight loss independent of pandemic stress and lifestyle limitations.

A 38-year-old male with no history of cardiac disease presented with chest pain typical of acute coronary syndrome. He assumed very-low-carbohydrate ketogenic diet (VLC-KD) 4 weeks prior to admission but no other lifestyle change. Workup showed dynamic ST-T changes on electrocardiogram, significantly elevated troponins, ketonuria, and mild rhabdomyolysis. Transthoracic echocardiogram revealed mild inferior wall hypokinesia and cardiac catheterization showed normal coronaries; hence, the diagnosis of type II myocardial infarction (MI) was established. Although the pathogenesis remains unclear, this temporal association between VLC-KD and type 2 MI raised some concerns about VLC-KD's cardiovascular safety profile. [ABSTRACT FROM AUTHOR]

Abstract Background We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT). Methods Analyses were performed in patients with T2D who completed 2 years of this study (CCI; n = 194; usual care (UC): n = 68). Lipoprotein subfraction particle concentrations were measured by ion mobility at baseline, 1, and 2 years and CIMT was measured at baseline and 2 years. Principal component analysis (PCA) was used to assess changes in independent clusters of lipoprotein particles. Results At 2 years, CCI resulted in a 23% decrease of small LDL IIIb and a 29% increase of large LDL I with no change in total LDL particle concentration or ApoB. The change in proportion of smaller and larger LDL was reflected by reversal of the small LDL subclass phenotype B in a high proportion of CCI participants (48.1%) and a shift in the principal component (PC) representing the atherogenic lipoprotein phenotype characteristic of T2D from a major to a secondary component of the total variance. The increase in LDL-C in the CCI group was mainly attributed to larger cholesterol-enriched LDL particles. CIMT showed no change in either the CCI or UC group. Conclusion Consumption of a very low carbohydrate diet with nutritional ketosis for 2 years in patients with type 2 diabetes lowered levels of small LDL particles that are commonly increased in diabetic dyslipidemia and are a marker for heightened CVD risk. A corresponding increase in concentrations of larger LDL particles was responsible for higher levels of plasma LDL-C. The lack of increase in total LDL particles, ApoB, and in progression of CIMT, provide supporting evidence that this dietary intervention did not adversely affect risk of CVD.

Background A low-carbohydrate ketogenic diet has been reported to improve chronic pain by reducing inflammation, oxidative stress, and sensitivity within the nervous system. The main aim of this trial is to evaluate the effects of a ketogenic diet on reported pain, blood biomarkers and quality of life in patients with chronic pain. Methods Participants with chronic musculoskeletal pain were recruited for a 12-week diet intervention that commenced with a 3-week run-in diet removing ultra-processed foods, followed by randomization to either a whole-food/well-formulated ketogenic diet (WFKD) or to continue with the minimally processed whole-food diet (WFD). Outcome measures included: average pain (visual analogue scale VAS), blood biomarkers, anthropometrics, adherence, depression, anxiety, sleep, ketones, quality of life, diet satisfaction, and macronutrient intake. Results Average weekly pain improved for both groups. WFKD group VAS reduced by 17.9 ± 5.2 mm (P  = .004) and the WFD group VAS reduced 11.0 ± 9.0 mm (P  = .006). Both groups also reported improved quality of life (WFKD = 11.5 ± 2.8%, P  = .001 and WFD = 11.0 ± 3.5%, P  = .014). The WFKD group also demonstrated significant improvements in pain interference (P  = 0.013), weight (P  < .005), depression (P  = .015), anxiety (P  = .013), and inflammation (hsCRP) (P  = .009). Significant average pain reduction remained at three-month follow-up for both groups (WFKD P  = .031, WFD P  = .011). Conclusions The implementation of a whole-food diet that restricts ultra-processed foods is a valid pain management tool; however, a low-carbohydrate ketogenic diets may have potentially greater pain reduction, weight loss and mood improvements. [ABSTRACT FROM AUTHOR]

Critical illness encompasses the dysfunction of vital organs, the risk of death, and potential reversibility; it is a major cause of morbidity and mortality globally. The pathophysiology underlying many critical illnesses includes bioenergetic failure, inflammation, and oxidative stress. This systematic review aims to explore the use of nutritional ketosis (ketogenic feeds and exogenous ketone body administration) as a potential therapy, affecting the aforementioned pathways in patients with critical illnesses. This study was conducted, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search was conducted, systematically using PubMed, PubMed Central (PMC), Google Scholar, and the ScienceDirect databases in February 2024. The inclusion criteria were set to free full-text articles published within the past five years: human and animal studies, literature reviews, systematic reviews, meta-analyses, observational studies, randomized controlled trials, case reports, book chapters, gray literature, studies investigating adult samples, and articles in the English language. Exclusion criteria included pediatric studies as the topic has been studied more extensively in children, and this review aims to explore potential benefits in adult patients. The search was conducted through four databases; after the screening process, the remaining studies were assessed through quality appraisal tools appropriate to each study type. In the end, 11 studies were selected, including eight narrative reviews, one cohort study, one animal study, and one randomized controlled trial. The results of this review demonstrated that nutritional ketosis has potential safe and effective benefits for humans and animals. Nutritional ketosis shows therapeutic benefits for a vast variety of complications commonly associated with critical illness, status epilepticus, sepsis, viral infections, and glycemic control. In the end, both randomized and nonrandomized clinical trials are necessary for more conclusive findings., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Abdelrahim et al.)

Insulin resistance (IR) plays a role in the pathogenesis of many diseases, such as type 2 diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, obesity, and neurodegenerative diseases, including Alzheimer’s disease. The ketogenic diet (KD) is a low-carbohydrate/high-fat diet that arose in the 1920s as an effective treatment for seizure control. Since then, the KD has been studied as a therapeutic approach for various IR-related disorders with successful results. To date, the use of the KD is still debatable regarding its safety. Some studies have acknowledged its usefulness, while others do not recommend its long-term implementation. In this review, we applied a SWOC (Strengths, Weaknesses, Opportunities, and Challenges) analysis that revealed the positive, constructive strengths of the KD, its potential complications, different conditions that can make used for it, and the challenges faced by both physicians and subjects throughout a KD. This SWOC analysis showed that the KD works on the pathophysiological mechanism of IR-related disorders such as chronic inflammation, oxidative stress and mitochondrial stress. Furthermore, the implementation of the KD as a potential adjuvant therapy for many diseases, including cancer, neurodegenerative disorders, polycystic ovary syndrome, and pain management was proven. On the other hand, the short and long-term possible undesirable KD-related effects, including nutritional deficiencies, growth retardation and nephrolithiasis, should be considered and strictly monitored. Conclusively, this review provides a context for decision-makers, physicians, researchers, and the general population to focus on this dietary intervention in preventing and treating diseases. Moreover, it draws the attention of scientists and physicians towards the opportunities and challenges associated with the KD that requires attention before KD initiation.

Ketone bodies are metabolic fuels and endogenous signaling molecules with multi-systemic benefits. β-Hydroxybutyrate, the main circulating one during fasting, calorie restriction, and physical exercise, improves neurological and cardiovascular function and extends lifespan when administered exogenously. It is now clear that there exists bidirectional crosstalk between ketone bodies and the kidney. Ketones serve important energetic roles in the kidney, whereas the kidney contributes to maintaining ketone homeostasis through renal tubular reabsorption. Ketones are also beneficial for the kidney in distinct pathological conditions, including drug-induced nephrotoxicity, renal ischemia and reperfusion injury, nephrocalcinosis, polycystic kidney disease, diabetic nephropathy, hypertension, and renal aging. The underlying mechanisms involve regulating gene expression and modulation of several signal transduction pathways that lead to oxidative stress reduction, suppression of inflammation, prevention of interstitial fibrosis development, and protection of renal cells from apoptosis and pyroptosis. This brief review summarizes all the recent findings in cellular and animal models pointing to the renoprotective effect of ketones. It also considers potential therapeutic limitations and discusses the adverse impact of ketones when out of the physiological range. Finally, we suggest that dietary interventions, lifestyle changes, and pharmacological approaches that increase circulating ketones may be helpful to promote kidney resilience to both stress and disease in the clinical setting.

Nutritional ketosis has promise for treating Parkinson's disease. Three previous studies explored the use of a ketogenic diet in cohorts with Parkinson's disease, and, while not conclusive, the data suggest non-motor symptom benefit. Before the ketogenic diet can be considered as a therapeutic option, it is important to establish with greater certainty that there is a reliable symptomatic benefit: which symptoms or groups of symptoms are impacted (if non-motor symptoms, which ones, and by which mechanism), what timescale is needed to obtain benefit, and how large an effect size can be achieved? To accomplish this, further investigation into the disease mechanisms based on pre-clinical data and hints from the clinical outcomes to date is useful to understand target engagement and gauge which mechanism could lead to a testable hypothesis. We review research pertaining to ketogenic diet, exogenous ketones, fasting, clinical studies, and theoretical review papers regarding therapeutic mechanisms from direct ketone body signaling and indirect metabolic effects. Through discussion of these findings and consideration of whether the ketogenic diet can be regarded as therapeutically useful for adjunctive therapy for Parkinson's disease, we identify remaining questions for the clinician to consider prior to recommending this diet. [ABSTRACT FROM AUTHOR]

Ketogenic diets (KDs) are very high-fat low-carbohydrate diets that promote nutritional ketosis and are widely used for weight loss, although concerns about potential adverse cardiovascular effects remain. We investigated a very high-fat KD's vascular impact and plasma metabolic signature compared to a non-ketogenic high-fat diet (HFD). Apolipoprotein E deficient (ApoE −/−) mice were fed a KD (%kcal:81:1:18, fat/carbohydrate/protein), a non-ketogenic high-fat diet with half of the fat content (HFD) (%kcal:40:42:18, fat/carbohydrate/protein) for 12 weeks. Plasma samples were used to quantify the major ketone body beta−hydroxybutyrate (BHB) and several pro-inflammatory cytokines (IL-6, MCP-1, MIP-1alpha, and TNF alpha), and to targeted metabolomic profiling by mass spectrometry. In addition, aortic atherosclerotic lesions were quantified ex-vivo by magnetic resonance imaging (MRI) on a 14-tesla system. KD was atherogenic when compared to the control diet, but KD mice, when compared to the HFD group (1) had markedly higher levels of BHB and lower levels of cytokines, confirming the presence of ketosis that alleviated the well-established fat-induced systemic inflammation; (2) displayed significant changes in the plasma metabolome that included a decrease in lipophilic metabolites and an increase in hydrophilic metabolites; (3) had significantly lower levels of several atherogenic lipid metabolites, including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides; and (4) presented significantly lower aortic plaque burden. KD was atherogenic and was associated with specific metabolic changes but alleviated the fat-induced inflammation and lessened the progression of atherosclerosis when compared to the HFD. [ABSTRACT FROM AUTHOR]

Introduction: Glucose hypometabolism and insulin resistance increase risk for and accelerate progression in Parkinson's disease and neurocognitive disorders. We conducted a proof of concept trial to determine whether ketogenesis, a metabolic adaptation induced by dietary carbohydrate restriction, can improve cognitive performance in Parkinson's disease patients with mild cognitive impairment. Methods: We enrolled patients with mild cognitive impairment associated with Parkinson's disease in an eight-week nutritional intervention with random assignment to either high-carbohydrate consumption typical of the Western dietary pattern (n = 7) or to a low-carbohydrate, ketogenic regimen (n = 7). We assessed changes in cognitive performance as well as motor function, anthropometrics, and metabolic parameters. Results: Relative to the high-carbohydrate group, the low-carbohydrate group demonstrated improvements in lexical access (p = 0.02, Cohen's f effect size = 0.76) and memory (p = 0.01, f = 0.87) and as well as a trend for reduced interference in memory (p = 0.06, f = 0.60). The low-carbohydrate group also exhibited reduced body weight (p

Objective: The study's purpose was to examine a free-living, ketogenic diet (WFKD) on feasibility, satiety, body composition, and metabolic health in women.Methods: Twenty-two women (age (yr.) 42.2 ± 8.1, Ht. (cm) 164.2 ± 5.9, BMI 27.3 ± 6.0) participated in a 21-day, free-living dietary intervention. Daily ketone measurements and satiety/craving surveys, weekly diet records, and PRE and POST assessments of anthropometrics, body composition, blood pressure, and fasted capillary-blood glucose (BG) and cholesterol panels were collected.Results: Women maintained calories (PRE: 1938 kcal vs POST: 1836 kcal) and protein (PRE: 17% vs POST: 20%) but decreased carbohydrate (PRE: 36% vs POST: 13%) and increased fat (PRE: 45% vs POST: 65%) PRE to POST (p ≤ 0.05). Daily self-reports suggested no changes in satiety or food cravings between PRE, WK 1, WK 2, and WK 3. Ketones increased (PRE 0.3 ± 0.2 mmol vs POST 0.8 ± 0.6 mmol) PRE to POST with significant differences between PRE and all other time points (p ≤ 0.05). Bodyweight (PRE: 73.9 kg vs POST: 72.3 kg) and body fat (PRE: 28.9 ± 13.4 kg vs POST 27. 4 ± 13.5 kg) decreased but there were no differences in fat-free mass PRE to POST (p ≤ 0.05). Systolic blood pressure decreased (PRE: 119.2 ± 8.9 mmHg vs POST: 109.5 ± 10.9 mmHg), diastolic blood pressure increased (PRE: 74.1 ± 7.5 mmHg vs POST: 78.8 ± 7.4 mmHg), and BG improved (94.0 ± 8.3 mg/dL vs POST 89.9 ± 9.0 mg/dL) PRE to POST (p ≤ 0.05). No differences were observed in total cholesterol (TC), high-density lipoprotein (HDL), and triglycerides (TG) but TC/HDL decreased and low-density lipoprotein increased PRE to POST (p ≤ 0.05).Conclusion: Women were able to maintain calories, improve body composition, blood pressure, and BG, increase ketones, and improve some but not all cholesterol markers after 21 days on a free-living WFKD. [ABSTRACT FROM AUTHOR]

Background: We have previously reported that in patients with type 2 diabetes (T2D) consumption of a very low carbohydrate diet capable of inducing nutritional ketosis over 2 years (continuous care intervention, CCI) resulted in improved body weight, glycemic control, and multiple risk factors for cardiovascular disease (CVD) with the exception of an increase in low density lipoprotein cholesterol (LDL-C). In the present study, we report the impact of this intervention on markers of risk for atherosclerotic cardiovascular disease (CVD), with a focus on lipoprotein subfraction particle concentrations as well as carotid-artery intima-media thickness (CIMT). Methods: Analyses were performed in patients with T2D who completed 2 years of this study (CCI; n = 194; usual care (UC): n = 68). Lipoprotein subfraction particle concentrations were measured by ion mobility at baseline, 1, and 2 years and CIMT was measured at baseline and 2 years. Principal component analysis (PCA) was used to assess changes in independent clusters of lipoprotein particles. Results: At 2 years, CCI resulted in a 23% decrease of small LDL IIIb and a 29% increase of large LDL I with no change in total LDL particle concentration or ApoB. The change in proportion of smaller and larger LDL was reflected by reversal of the small LDL subclass phenotype B in a high proportion of CCI participants (48.1%) and a shift in the principal component (PC) representing the atherogenic lipoprotein phenotype characteristic of T2D from a major to a secondary component of the total variance. The increase in LDL-C in the CCI group was mainly attributed to larger cholesterol-enriched LDL particles. CIMT showed no change in either the CCI or UC group. Conclusion: Consumption of a very low carbohydrate diet with nutritional ketosis for 2 years in patients with type 2 diabetes lowered levels of small LDL particles that are commonly increased in diabetic dyslipidemia and are a marker for heightened CVD risk. A corresponding increase in concentrations of larger LDL particles was responsible for higher levels of plasma LDL-C. The lack of increase in total LDL particles, ApoB, and in progression of CIMT, provide supporting evidence that this dietary intervention did not adversely affect risk of CVD. [ABSTRACT FROM AUTHOR]

A maladaptive shift from fat to carbohydrate (CHO) oxidation during exercise is thought to underlie myopathy and exercise‐induced rhabdomyolysis in patients with fatty acid oxidation (FAO) disorders. We hypothesised that ingestion of a ketone ester (KE) drink prior to exercise could serve as an alternative oxidative substrate supply to boost muscular ATP homeostasis. To establish a rational basis for therapeutic use of KE supplementation in FAO, we tested this hypothesis in patients deficient in Very Long‐Chain acyl‐CoA Dehydrogenase (VLCAD). Five patients (range 17‐45 y; 4 M/1F) patients were included in an investigator‐initiated, randomised, blinded, placebo‐controlled, 2‐way cross‐over study. Patients drank either a KE + CHO mix or an isocaloric CHO equivalent and performed 35 minutes upright cycling followed by 10 minutes supine cycling inside a Magnetic Resonance scanner at individual maximal FAO work rate (fatmax; approximately 40% VO2max). The protocol was repeated after a 1‐week interval with the alternate drink. Primary outcome measures were quadriceps phosphocreatine (PCr), Pi and pH dynamics during exercise and recovery assayed by in vivo 31P‐MR spectroscopy. Secondary outcomes included plasma and muscle metabolites and respiratory gas exchange recordings. Ingestion of KE rapidly induced mild ketosis and increased muscle BHB content. During exercise at FATMAX, VLCADD‐specific plasma acylcarnitine levels, quadriceps glycolytic intermediate levels and in vivo Pi/PCr ratio were all lower in KE + CHO than CHO. These results provide a rational basis for future clinical trials of synthetic ketone ester supplementation therapy in patients with FAO disorders. Trial registration: ClinicalTrials.gov. Protocol ID: NCT03531554; METC2014.492; ABR51222.042.14. [ABSTRACT FROM AUTHOR]

We assessed a ketogenic diet (KD) intervention protocol and the cognitive effects of KD in older adults with HIV-associated neurocognitive impairment. Adults older than 50 years and living with HIV and mild-to-moderate neurocognitive impairment were randomized to either a KD or a patient-choice diet for 12 weeks followed by a 6-week washout period. A neurocognitive battery was administered at baseline, Week 12, and Week 18. Paired t tests compared groups at baseline, and multivariate analyses of covariance were used to assess between-group differences on primary outcome variables at Weeks 12 and 18. We enrolled 17 participants, and 14 completed the study. No between-group baseline differences were noted. The KD group demonstrated improved executive function and speed of processing at Week 12, which were negated after participants resumed their usual diets. Our study supports the potential efficacy of a KD for the treatment of HIV-associated neurocognitive impairment. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the effect of the racemic β-hydroxybutyrate precursor, R,S-1,3-butanediol (BD), on T-cell-related cytokine gene expression within stimulated peripheral blood mononuclear cells (PBMC) following prolonged, strenuous exercise.Methods: A repeated-measures, randomised, crossover study was conducted in nine healthy, trained male cyclists (age, 26.7 ± 5.2 years; VO2peak, 63.9 ± 2.5 mL kg-1 min-1). Participants ingested 0.35 g kg-1 of BD or placebo 30 min before and 60 min during 85 min of steady-state (SS) exercise, which preceded a ~ 30 min time-trial (TT) (7 kJ kg-1). Blood samples were collected at pre-supplement, pre-exercise, post-SS, post-TT and 1-h post-TT. Whole blood cultures were stimulated with Staphylococcal enterotoxin B (SEB) for 24 h to determine T-cell-related interleukin (IL)-4, IL-10 and interferon (IFN)-γ mRNA expression within isolated PBMCs in vitro.Results: Serum cortisol, total circulating leukocyte and lymphocyte, and T-cell subset concentrations were similar between trials during exercise and recovery (all p > 0.05). BD ingestion increased T-cell-related IFN-γ mRNA expression compared with placebo throughout exercise and recovery (p = 0.011); however, IL-4 and IL-10 mRNA expression and the IFN-γ/IL-4 mRNA expression ratio were unaltered (all p > 0.05).Conclusion: Acute hyperketonaemia appears to transiently amplify the initiation of the pro-inflammatory T-cell-related IFN-γ response to an immune challenge in vitro during and following prolonged, strenuous exercise; suggesting enhanced type-1 T-cell immunity at the gene level. [ABSTRACT FROM AUTHOR]

The promotion of ketone body (KB) metabolism via ketosis has been suggested as a strategy to increase exercise performance. However, studies in humans and animals have yielded inconsistent results. The purpose of the current study was to examine the effects of ketosis, achieved via fasting or a short-term ketogenic diet (KD), on endurance exercise performance in female mice. After 8 h of fasting, serum KB significantly increased and serum glucose significantly decreased in fasted compared to fed mice. When subjected to an endurance exercise capacity (EEC) test on a motorized treadmill, both fed and fasted mice showed similar EEC performance. A 5-week KD (90% calories from fat) significantly increased serum KB but did not increase EEC times compared to chow-fed mice. KD mice gained significantly more weight than chow-fed mice and had greater adipose tissue mass. Biochemical tissue analysis showed that KD led to significant increases in triglyceride content in the heart and liver and significant decreases in glycogen content in the muscle and liver. Furthermore, KD downregulated genes involved in glucose and KB oxidation and upregulated genes involved in lipid metabolism in the heart. These findings suggest that a short-term KD is not an effective strategy to enhance exercise performance and may lead to increased adiposity, abnormal endogenous tissue storage, and cardiometabolic remodeling.

PurposeThe aim of this non-randomized parallel group study was to examine the 12 week effects of a very low-carbohydrate high-fat diet (VLCHF) on maximal cardiorespiratory capacity, high-intensity interval training (HIIT) performance, and cardiac autonomic regulation.MethodsTwenty-four recreationally trained participants allocated to either a VLCHF (N = 12) or a habitual diet (HD; N = 12) group completed 12 weeks of a diet and exercise (VLCHF) or an exercise only intervention (HD). Maximal graded exercise tests (GXT) were performed at baseline, after 4, 8, and 12 weeks. A supervised HIIT session and the 30-15 Intermittent Fitness Test (30-15IFT) were conducted once a week.ResultsTotal time to exhaustion (TTE) in both GXT and 30-15IFTlargely increased in both VLCHF (p = 0.005, BF10 = 11.30 and p = 0.001, BF10 ≥ 100, respectively) and HD (p = 0.018, BF10 = 3.87 and p = 0.001, BF10 ≥ 100, respectively) groups after 12 weeks. Absolute maximal oxygen uptake (V˙O2max) was not changed in both groups but relative V˙O2max increased in VLCHF in concert with reductions in body mass (66.7 ± 10.2–63.1 ± 8.5 kg). Cardiac autonomic regulation did not reveal any between-group differences after 12 weeks. VLCHF diet induced an increase in β-hydroxybutyrate, which tended to normalize during the intervention period.ConclusionThe 12 week VLCHF diet did not impair high-intensity continuous or intermittent exercise lasting up to 25 min, nor did it impair maximal cardiorespiratory performance or autonomic nervous system (ANS) activity.

Purpose: Studies on long-term sustainability of low-carbohydrate approaches to treat diabetes are limited. We previously reported the effectiveness of a novel digitally-monitored continuous care intervention (CCI) including nutritional ketosis in improving weight, glycemic outcomes, lipid, and liver marker changes at 1 year. Here, we assess the effects of the CCI at 2 years.Materials and methods: An open label, non-randomized, controlled study with 262 and 87 participants with T2D were enrolled in the CCI and usual care (UC) groups, respectively. Primary outcomes were retention, glycemic control, and weight changes at 2 years. Secondary outcomes included changes in body composition, liver, cardiovascular, kidney, thyroid and inflammatory markers, diabetes medication use and disease status.Results: Reductions from baseline to 2 years in the CCI group resulting from intent-to-treat analyses included: HbA1c, fasting glucose, fasting insulin, weight, systolic blood pressure, diastolic blood pressure, triglycerides, and liver alanine transaminase, and HDL-C increased. Spine bone mineral density in the CCI group was unchanged. Use of any glycemic control medication (excluding metformin) among CCI participants declined (from 55.7 to 26.8%) including insulin (-62%) and sulfonylureas (-100%). The UC group had no changes in these parameters (except uric acid and anion gap) or diabetes medication use. There was also resolution of diabetes (reversal, 53.5%; remission, 17.6%) in the CCI group but not in UC. All the reported improvements had p < 0.00012.Conclusion: The CCI group sustained long-term beneficial effects on multiple clinical markers of diabetes and cardiometabolic health at 2 years while utilizing less medication. The intervention was also effective in the resolution of diabetes and visceral obesity with no adverse effect on bone health.Clinical Trial Registration:Clinicaltrials.gov NCT02519309

As a journal page for full details. The ketogenic diet (KD) has been established as a treatment for epilepsy, but more recently it has been explored as an alternative or add-on therapy for many other diseases ranging from weight loss to neurological disorders. Animal models are widely used in studies investigating the therapeutic effects of the KD as well as underlying mechanisms. Especially in the context of neurological, psychiatric, and neurodevelopmental disorders essential endpoints are assessed by behavioral and motor tests. Here we summarized research evaluating the influence of the KD on cognition, depressive and anxiety-related behaviors, and social and nutritional behaviors of laboratory rodents. Each section contains a brief description of commonly used behavioral tests highlighting their limitations. Ninety original research articles, written in English, performed on mice or rats, providing measurement of blood beta-hydroxybutyrate (BHB) levels and behavioral evaluation were selected for the review. The majority of research performed in various disease models shows that the KD positively impacts cognition. Almost an equal number of studies report a reduction or no effect of the KD on depressive-related behaviors. For anxiety-related behaviors, the majority of studies show no effect. Despite the increasing use of the KD in weight loss and its appetite-reducing properties the behavioral evaluation of appetite regulation has not been addressed in preclinical studies. This review provides an overview of the behavioral effects of nutritional ketosis addressed to a broad audience of scientists interested in the KD field but not necessarily specializing in behavioral tests., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Grabowska, Grabowski, Przybyła, Pondel, Barski, Nowacka-Chmielewska and Liśkiewicz.)

Background The high-fat ketogenic diet (KD) has become an increasingly popular diet not only in overweight/obese populations, or those with clinical conditions, but also in healthy non-overweight populations. Objective Because there are concerns about the association between high-fat diets and cognitive decline, this study aimed to determine the effects of a KD compared with an isocaloric high-carbohydrate, low-fat (HCLF) diet on cognitive function, sleep, and mood in healthy, normal-weight individuals. Methods Eleven healthy, normal-weight participants (mean age: 30 ± 9 y) completed this randomized, controlled, crossover study. Participants followed 2 isocaloric diets—an HCLF diet (55% carbohydrate, 20% fat, and 25% protein) and a KD (15% carbohydrate, 60% fat, and 25% protein)—in a randomized order for a minimum of 3 wk, with a 1-wk washout period between diets. Measures of β-hydroxybutyrate confirmed that all participants were in a state of nutritional ketosis during post-KD assessments (baseline: 0.2 ± 0.2 mmol/L; KD: 1.0 ± 0.5 mmol/L; washout: 0.2 ± 0.1 mmol/L; and HCLF: 0.3 ± 0.2 mmol/L). Cognitive function was assessed using a validated, psychological computer-based test battery before and after each diet. Subjective measures of mood and sleep were also monitored throughout the study using validated scales. Results Three weeks of sustained nutritional ketosis, compared with the HCLF diet, had no effect on speed and accuracy responses in tasks designed to measure vigilance (speed: P  = 0.39, Cohen's d  = 0.26; accuracy: P  = 0.99, Cohen's d  = 0.04), visual learning and memory (speed: P  = 0.99, Cohen's d  = 0.04; accuracy: P  = 0.99, Cohen's d  = 0.03), working memory (speed: P  = 0.62, Cohen's d  = 0.26; accuracy: P  = 0.98, Cohen's d  = 0.07), and executive function (speed: P  = 0.60, Cohen's d  = 0.31; accuracy: P  = 0.90, Cohen's d  = 0.19). Likewise, mood, sleep quality, and morning vigilance did not differ (P  > 0.05) between the dietary interventions. Conclusion The results of our randomized, crossover, controlled study suggest that 3 wk of sustained nutritional ketosis had no effect on cognitive performance, mood, or subjective sleep quality in a sample of healthy individuals. This trial was registered in the Pan African Clinical Trial Registry as PACTR201707002406306. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this non-randomized parallel group study was to examine the 12 week effects of a very low-carbohydrate high-fat diet (VLCHF) on maximal cardiorespiratory capacity, high-intensity interval training (HIIT) performance, and cardiac autonomic regulation. Methods: Twenty-four recreationally trained participants allocated to either a VLCHF (N = 12) or a habitual diet (HD; N = 12) group completed 12 weeks of a diet and exercise (VLCHF) or an exercise only intervention (HD). Maximal graded exercise tests (GXT) were performed at baseline, after 4, 8, and 12 weeks. A supervised HIIT session and the 30-15 Intermittent Fitness Test (30-15IFT) were conducted once a week. Results: Total time to exhaustion (TTE) in both GXT and 30-15IFT largely increased in both VLCHF (p = 0.005, BF10 = 11.30 and p = 0.001, BF10 ≥ 100, respectively) and HD (p = 0.018, BF10 = 3.87 and p = 0.001, BF10 ≥ 100, respectively) groups after 12 weeks. Absolute maximal oxygen uptake (V ˙ O2max) was not changed in both groups but relative V ˙ O2max increased in VLCHF in concert with reductions in body mass (66.7 ± 10.2–63.1 ± 8.5 kg). Cardiac autonomic regulation did not reveal any between-group differences after 12 weeks. VLCHF diet induced an increase in β-hydroxybutyrate, which tended to normalize during the intervention period. Conclusion: The 12 week VLCHF diet did not impair high-intensity continuous or intermittent exercise lasting up to 25 min, nor did it impair maximal cardiorespiratory performance or autonomic nervous system (ANS) activity. [ABSTRACT FROM AUTHOR]

Purpose: Studies on long-term sustainability of low-carbohydrate approaches to treat diabetes are limited. We previously reported the effectiveness of a novel digitally-monitored continuous care intervention (CCI) including nutritional ketosis in improving weight, glycemic outcomes, lipid, and liver marker changes at 1 year. Here, we assess the effects of the CCI at 2 years. Materials and methods: An open label, non-randomized, controlled study with 262 and 87 participants with T2D were enrolled in the CCI and usual care (UC) groups, respectively. Primary outcomes were retention, glycemic control, and weight changes at 2 years. Secondary outcomes included changes in body composition, liver, cardiovascular, kidney, thyroid and inflammatory markers, diabetes medication use and disease status. Results: Reductions from baseline to 2 years in the CCI group resulting from intent-to-treat analyses included: HbA1c, fasting glucose, fasting insulin, weight, systolic blood pressure, diastolic blood pressure, triglycerides, and liver alanine transaminase, and HDL-C increased. Spine bone mineral density in the CCI group was unchanged. Use of any glycemic control medication (excluding metformin) among CCI participants declined (from 55.7 to 26.8%) including insulin (-62%) and sulfonylureas (-100%). The UC group had no changes in these parameters (except uric acid and anion gap) or diabetes medication use. There was also resolution of diabetes (reversal, 53.5%; remission, 17.6%) in the CCI group but not in UC. All the reported improvements had p < 0.00012. Conclusion: The CCI group sustained long-term beneficial effects on multiple clinical markers of diabetes and cardiometabolic health at 2 years while utilizing less medication. The intervention was also effective in the resolution of diabetes and visceral obesity with no adverse effect on bone health. Clinical Trial Registration: Clinicaltrials.gov NCT02519309 [ABSTRACT FROM AUTHOR]

Objective: Sleep disruption is frequently associated with type 2 diabetes (T2D) and hyperglycemia. We recently reported the effectiveness of a continuous care intervention (CCI) emphasizing nutritional ketosis for improving HbA1c, body weight and cardiovascular risk factors in T2D patients. The present study assessed the effect of this CCI approach on sleep quality using a subjective patient-reported sleep questionnaire.Methods: A non-randomized, controlled longitudinal study; 262 T2D and 116 prediabetes patients enrolled in the CCI and 87 separately recruited T2D patients continued usual care (UC) treatment. Patients completed the Pittsburgh Sleep Quality Index (PSQI) questionnaire. A PSQI score of >5 (scale 0 to 21) was used to identify poor sleepers.Results: Global sleep quality improved in the CCI T2D (p < 0.001) and prediabetes (p < 0.001) patients after one year of intervention. Subjective sleep quality (component 1), sleep disturbance (component 5) and daytime dysfunction (component 7), also showed improvements in the CCI T2D (p < 0.01 for sleep quality and sleep disturbance; and p < 0.001 for daytime dysfunction) and prediabetes patients (p < 0.001 for all three components); compared to the UC T2D group after one year. The proportion of patients with poor sleep quality was significantly reduced after one year of CCI (T2D; from 68.3% at baseline to 56.5% at one year, p = 0.001 and prediabetes; from 77.9% at baseline to 48.7% at one year, p < 0.001).Conclusion: This study demonstrates improved sleep quality as assessed by PSQI in patients with T2D and prediabetes undergoing CCI including nutritional ketosis but not in T2D patients receiving UC. The dietary intervention benefited both sleep quality and the severity of T2D symptoms suggesting that nutritional ketosis improves overall health via multiple mechanisms. [ABSTRACT FROM AUTHOR]

Nutritional ketosis may enhance cerebral energy metabolism and has received increased interest as a way to improve or preserve performance and resilience. Most studies to date have focused on metabolic or neurological disorders while anecdotal evidence suggests that ketosis may enhance performance in the absence of underlying dysfunction. Moreover, decreased availability of glucose in the brain following stressful events is associated with impaired cognition, suggesting the need for more efficient energy sources. We tested the hypotheses that ketosis induced by endogenous or exogenous ketones could: (a) augment cognitive outcomes in healthy subjects; and (b) prevent stress-induced detriments in cognitive parameters. Adult, male, Sprague Dawley rats were used to investigate metabolic and behavioral outcomes in 3 dietary conditions: ketogenic (KD), ketone supplemented (KS), or NIH-31 control diet in both control or chronic stress conditions. Acute administration of exogenous ketones resulted in reduction in blood glucose and sustained ketosis. Chronic experiments showed that in control conditions, only KD resulted in pronounced metabolic alterations and improved performance in the novel object recognition test. The hypothalamic-pituitary-adrenal (HPA) axis response revealed that KD-fed rats maintained peripheral ketosis despite increases in glucose whereas no diet effects were observed in ACTH or CORT levels. Both KD and KS-fed rats decreased escape latencies on the third day of water maze, whereas only KD prevented stress-induced deficits on the last testing day and improved probe test performance. Stress-induced decrease in hippocampal levels of β-hydroxybutyrate was attenuated in KD group while both KD and KS prevented stress effects on BDNF levels. Mitochondrial enzymes associated with ketogenesis were increased in both KD and KS hippocampal samples and both endothelial and neuronal glucose transporters were affected by stress but only in the control diet group. Our results highlight the complex relationship between peripheral metabolism, behavioral performance and biochemical changes in the hippocampus. Endogenous ketosis improved behavioral and metabolic parameters associated with energy metabolism and cognition while ketone supplementation replicated the biochemical effects within the hippocampus but only showed modest effects on behavioral improvements.

Ketogenic diet (KD) is a high‑fat, adequate‑protein, and low‑carbohydrate diet that leads to nutritional ketosis, long known for antiepileptic effects and has been used therapeutically to treat refractory epilepsy. This review attempts to summarize the evidence and clinical application of KD in diabetes, obesity, and other endocrine disorders. KD is usually animal protein based. An empiric vegetarian Indian variant of KD has been provided keeping in mind the Indian food habits. KD has beneficial effects on cardiac ischemic preconditioning, improves oxygenation in patients with respiratory failure, improves glycemic control in diabetics, is associated with significant weight loss, and has a beneficial impact on polycystic ovarian syndrome. Multivitamin supplementations are recommended with KD. Recently, ketones are being proposed as super‑metabolic fuel; and KD is currently regarded as apt dietary therapy for “diabesity.” [ABSTRACT FROM AUTHOR]

Nutritional ketosis may enhance cerebral energy metabolism and has received increased interest as a way to improve or preserve performance and resilience.Most studies to date have focused on metabolic or neurological disorders while anecdotal evidence suggests that ketosis may enhance performance in the absence of underlying dysfunction. Moreover, decreased availability of glucose in the brain following stressful events is associated with impaired cognition, suggesting the need for more efficient energy sources. We tested the hypotheses that ketosis induced by endogenous or exogenous ketones could: (a) augment cognitive outcomes in healthy subjects; and (b) prevent stress-induced detriments in cognitive parameters. Adult, male, Sprague Dawley rats were used to investigate metabolic and behavioral outcomes in 3 dietary conditions: ketogenic (KD), ketone supplemented (KS), or NIH-31 control diet in both control or chronic stress conditions. Acute administration of exogenous ketones resulted in reduction in blood glucose and sustained ketosis. Chronic experiments showed that in control conditions, only KD resulted in pronounced metabolic alterations and improved performance in the novel object recognition test. The hypothalamic-pituitary-adrenal (HPA) axis response revealed that KD-fed rats maintained peripheral ketosis despite increases in glucose whereas no diet effects were observed in ACTH or CORT levels. Both KD and KS-fed rats decreased escape latencies on the third day of water maze, whereas only KD prevented stress-induced deficits on the last testing day and improved probe test performance. Stress-induced decrease in hippocampal levels of b-hydroxybutyrate was attenuated in KD group while both KD and KS prevented stress effects on BDNF levels. Mitochondrial enzymes associated with ketogenesis were increased in both KD and KS hippocampal samples and both endothelial and neuronal glucose transporters were affected by stress but only in the control diet group. Our results highlight the complex relationship between peripheral metabolism, behavioral performance and biochemical changes in the hippocampus. Endogenous ketosis improved behavioral and metabolic parameters associated with energy metabolism and cognition while ketone supplementation replicated the biochemical effects within the hippocampus but only showed modest effects on behavioral improvements. [ABSTRACT FROM AUTHOR]

Background: Ketogenic diets are high fat and low carbohydrate or very low carbohydrate diets, which render high production of ketones upon consumption known as nutritional ketosis (NK). Ketosis is also produced during fasting periods, which is known as fasting ketosis (FK). Recently, the combinations of NK and FK, as well as NK alone, have been used as resources for weight loss management and treatment of epilepsy. Methods: A crossover study design was applied to 11 healthy individuals, who maintained moderately sedentary lifestyle, and consumed three types of diet randomly assigned over a three-week period. All participants completed the diets in a randomized and counterbalanced fashion. Each weekly diet protocol included three phases: Phase 1 - A mixed diet with ratio of fat: (carbohydrate + protein) by mass of 0.18 or the equivalence of 29% energy from fat from Day 1 to Day 5. Phase 2- A mixed or a high-fat diet with ratio of fat: (carbohydrate + protein) by mass of approximately 0.18, 1.63, or 3.80 on Day 6 or the equivalence of 29%, 79%, or 90% energy from fat, respectively. Phase 3 - A fasting diet with no calorie intake on Day 7. Caloric intake from diets on Day 1 to Day 6 was equal to each individual's energy expenditure. On Day 7, ketone buildup from FK was measured. Results: A statistically significant effect of Phase 2 (Day 6) diet was found on FK of Day 7, as indicated by repeated analysis of variance (ANOVA), F(2,20) = 6.73, p < 0.0058. Using a Fisher LDS pair-wise comparison, higher significant levels of acetone buildup were found for diets with 79% fat content and 90% fat content vs. 29% fat content (with p = 0.00159**, and 0.04435**, respectively), with no significant difference between diets with 79% fat content and 90% fat content. In addition, independent of the diet, a significantly higher ketone buildup capability of subjects with higher resting energy expenditure (R² = 0.92), and lower body mass index (R² = 0.71) was observed during FK. [ABSTRACT FROM AUTHOR]

Ketogenic diets and orally administered exogenous ketone supplements are strategies to increase serum ketone bodies serving as an alternative energy fuel for high energy demanding tissues, such as the brain, muscles, and the heart. The ketogenic diet is a low-carbohydrate and fat-rich diet, whereas ketone supplements are usually supplied as esters or salts. Nutritional ketosis, defined as serum ketone concentrations of ≥ 0.5 mmol/L, has a fasting-like effect and results in all sorts of metabolic shifts and thereby enhancing the health status. In this review, we thus discuss the different interventions to reach nutritional ketosis, and summarize the effects on heart diseases, epilepsy, mitochondrial diseases, and neurodegenerative disorders. Interest in the proposed therapeutic benefits of nutritional ketosis has been growing the past recent years. The implication of this nutritional intervention is becoming more evident and has shown interesting potential. Mechanistic insights explaining the overall health effects of the ketogenic state, will lead to precision nutrition for the latter diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saris and Timmers.)