Dietary Ketosis Research Articles

Impact of dietary ketosis on volatile anesthesia toxicity in a model of Leigh syndrome.

Genetic mitochondrial diseases impact over 1 in 4000 individuals, most often presenting in infancy or early childhood. Seizures are major clinical sequelae in some mitochondrial diseases including Leigh syndrome, the most common pediatric presentation of mitochondrial disease. Dietary ketosis has been used to manage seizures in mitochondrial disease patients. Mitochondrial disease patients often require surgical interventions, leading to anesthetic exposures. Anesthetics have been shown to be toxic in the setting of mitochondrial disease, but the impact of a ketogenic diet on anesthetic toxicities in this setting has not been studied. Our aim in this study was to determine whether dietary ketosis impacts volatile anesthetic toxicities in the setting of genetic mitochondrial disease. The impact of dietary ketosis on toxicities of volatile anesthetic exposure in mitochondrial disease was studied by exposing young Ndufs4(-/-) mice fed ketogenic or control diet to isoflurane anesthesia. Blood metabolites were measured before and at the end of exposures, and survival and weight were monitored. Compared to a regular diet, the ketogenic diet exacerbated hyperlactatemia resulting from isoflurane exposure (control vs. ketogenic diet in anesthesia mean difference 1.96 mM, Tukey's multiple comparison adjusted p = .0271) and was associated with a significant increase in mortality during and immediately after exposures (27% vs. 87.5% mortality in the control and ketogenic diet groups, respectively, during the exposure period, Fisher's exact test p = .0121). Our data indicate that dietary ketosis and volatile anesthesia interact negatively in the setting of mitochondrial disease. Our findings suggest that extra caution should be taken in the anesthetic management of mitochondrial disease patients in dietary ketosis.

Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington's disease.

Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington's disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of β-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.

Differential effects of mTOR inhibition and dietary ketosis in a mouse model of subacute necrotizing encephalomyelopathy

Genetic mitochondrial diseases are the most frequent cause of inherited metabolic disorders and one of the most prevalent causes of heritable neurological disease. Leigh syndrome is the most common clinical presentation of pediatric mitochondrial disease, typically appearing in the first few years of life, and involving severe multisystem pathologies. Clinical care for Leigh syndrome patients is difficult, complicated by the wide range of symptoms including characteristic progressive CNS lesion, metabolic sequelae, and epileptic seizures, which can be intractable to standard management. While no proven therapies yet exist for the underlying mitochondrial disease, a ketogenic diet has led to some reports of success in managing mitochondrial epilepsies, with ketosis reducing seizure risk and severity. The impact of ketosis on other aspects of disease progression in Leigh syndrome has not been studied, however, and a rigorous study of the impact of ketosis on seizures in mitochondrial disease is lacking. Conversely, preclinical efforts have identified the intracellular nutrient signaling regulator mTOR as a promising therapeutic target, with data suggesting the benefits are mediated by metabolic changes. mTOR inhibition alleviates epilepsies arising from defects in TSC, an mTOR regulator, but the therapeutic potential of mTOR inhibition in seizures related to primary mitochondrial dysfunction is unknown. Given that ketogenic diet is used clinically in the setting of mitochondrial disease, and mTOR inhibition is in clinical trials for intractable pediatric epilepsies of diverse causal origins, a direct experimental assessment of their effects is imperative. Here, we define the impact of dietary ketosis on survival and CNS disease in the Ndufs4(KO) mouse model of Leigh syndrome and the therapeutic potential of both dietary ketosis and mTOR inhibition on seizures in this model. These data provide timely insight into two important clinical interventions.

The Role of Very Low Calorie Ketogenic Diet in Sympathetic Activation through Cortisol Secretion in Male Obese Population.

Adipose tissue is considered an endocrine organ, and its excess compromises the immune response and metabolism of hormones and nutrients. Furthermore, the accumulation of visceral fat helps to increase the synthesis of cortisol. The hypothalamus-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in maintaining homeostasis in humans under physiological conditions and stress, and cortisol is the main hormone of the HPA axis. It is known that a stress-induced diet and cortisol reactivity to acute stress factors may be related to dietary behavior. In obesity, to reduce visceral adipose tissue, caloric restriction is a valid strategy. In light of this fact, the aim of this study was to assess the effects of a commercial dietary ketosis program for weight loss on the sympathetic nervous system and HPA axis, through evaluation of salivary cortisol and GSR levels. Thirty obese subjects were recruited and assessed before and after 8 weeks of Very Low Calorie Ketogenic Diet (VLCKD) intervention to evaluate body composition and biochemical parameters. Salivary cortisol levels and GSR significantly decreased after dietary treatment; in addition, body composition and biochemical features were ameliorated. The VLCKD had a short-term positive effect on the SNS and HPA axes regulating salivary cortisol levels. Finally, the effects of the VLCKD on the SNS and HPA axis may lead to more individualized treatment strategies that integrate obesity and stress and support the usefulness of such therapeutic interventions in promoting the reduction of the individual disease burden.

Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics.

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood β-hydroxybutarate (β-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. β-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of β-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

Diet-Induced Mild Hyperhomocysteinemia in Mice Fed a Ketogenic Diet Does Not Alter the Development of Atherosclerosis nor Specific Epigenetic Content

ObjectivesElevated plasma homocysteine (Hcy), or hyperhomocysteinemia (HHcy), is a risk factor for atherosclerosis by mechanisms still elusive. A possibility includes the alteration of specific epigenetic tags at lysine 27 of histone H3 (H3K27) due to hypomethylating stress. Similarly, ketogenic diets (KD), or very-low carbohydrate diets, which stimulate ketosis, and may also affect the epigenetic content on the H3K27 residue. Studies connecting the effects of dietary ketosis, mild HHcy, and specific epigenetic dysregulation are lacking. We hypothesize that diet-induced HHcy and ketosis will induce H3K27 hypomethylation combined with increased acetylation to produce a pro-atherogenic phenotype. MethodsSeven-week-old male apoe–/– (apolipoprotein E-deficient) mice, a model for human atherosclerosis, were fed ad libitum a KD (in %kcal: fat, 81; carbohydrate, 1; protein, 18; n = 4–6) or HHcy-KD (same macronutrients, with added methionine and reduced methyl donors; n = 4). After 4, 8 and 12 wk of diet treatment, plasma was collected to quantify ketosis via beta-hydroxybutyrate levels (OH-But) by a colorimetric assay, and measure Hcy by HPLC. At the endpoint, mice were euthanized and aortas were collected for quantification of the vascular methylation index, S-adenosylmethionine to S-adenosylHcy ratio by LC-MS-MS; 3-D analysis of the atherosclerotic plaque burden by magnetic resonance imaging; and quantification of the epigenetic tags H3K27me3 and H3K27ac using immunohistochemistry. ResultsA sustained ketosis was detected through elevated OH-But levels in both KD and HHcy-KD mice. HHcy was mildly but significantly (P < 0.05) elevated in HHcy-KD-mice compared to KD-mice after 4 wk (19.5 ± 2.3 vs 4.5 ± 0.6 μM) and 12 wk (17.2 ± 2.1 vs 4.4 ± 0.9 μM). Nevertheless, no significant differences were observed in aortic methylation index, plaque accumulation, or content of the H3K27me3 or H3K27ac epigenetic tags between the two groups of mice. ConclusionsWhile mild HHcy was achieved in HHcy-KD mice, this phenotype failed to induce vascular hypomethylation, atherosclerosis progression or specific epigenetic dysregulation, suggesting that a more severe Hcy accumulation may be necessary to cause vascular toxicity and specific epigenetic dysregulation. Funding SourcesHuck Institutes of the Life Sciences

Effects of Very Low Calorie Ketogenic Diet on the Orexinergic System, Visceral Adipose Tissue, and ROS Production.

Background: Caloric restriction is a valid strategy to reduce the visceral adipose tissue (VAT) content in obese persons. Hypocretin-1 (orexin-A) is a neuropeptide synthesized in the lateral hypothalamus that strongly modulates food intake, thus influencing adipose tissue accumulation. Therapeutic diets in obesity treatment may combine the advantages of caloric restriction and dietary ketosis. The current study aimed to evaluate the effect of a very low calorie ketogenic diet (VLCKD) in a population of obese patients. Methods: Adiposity parameters and orexin-A serum profiling were quantified over an 8 week period. The effect of the VLCKD on reactive oxygen species (ROS) production and cell viability was evaluated, in vitro, by culturing Hep-G2 cells in the presence of VLCKD sera. Results: Dietary intervention induced significant effects on body weight, adiposity, and blood chemistry parameters. Moreover, a selective reduction in VAT was measured by dual-energy X-ray absorptiometry. Orexin-A levels significantly increased after dietary treatment. Hep-G2 cell viability was not affected after 24, 48, and 72 h incubation with patients’ sera, before and after the VLCKD. In the same model system, ROS production was not significantly influenced by dietary treatment. Conclusion: The VLCKD exerts a positive effect on VAT decrease, ameliorating adiposity and blood chemistry parameters. Furthermore, short-term mild dietary ketosis does not appear to have a cytotoxic effect, nor does it represent a factor capable of increasing oxidative stress. Finally, to the best of our knowledge, this is the first study that shows an effect of the VLCKD upon the orexinergic system, supporting the usefulness of such a therapeutic intervention in promoting obesity reduction in the individual burden of this disease.

Ketogenic Diet: an Endocrinologist Perspective.

Obesity and its related comorbidities make up a large part of healthcare expenditures. Despite a wide array of options for treatment of obesity, rates of sustained weight loss continue to be low, leading patients to seek alternative treatment options. Although the first medically utilized ketogenic diet was described nearly 100 years ago, it has made a resurgence as a treatment option for obesity. Despite increased popularity in the lay public and increased use of ketogenic dietary strategies for metabolic therapy, we are still beginning to unravel the metabolic impact of long-term dietary ketosis. There are a number of recent trials that have highlighted the short- and long-term benefits of ketogenic diet on weight, glycemic control, and other endocrine functions including reproductive hormones. This review is a summary of available data on the effectiveness and durability of the ketogenic diet when compared to conventional interventions. Ketogenic dietary strategies may play a role in short-term improvement of important metabolic parameters with potential for long-term benefit. However, response may vary due to inter-individual ability to maintain long-term carbohydrate restriction.

Another "D" in MUDPILES? A Review of Diet-Associated Nondiabetic Ketoacidosis.

Ketogenic diet or very-low-carbohydrate diet gained widespread popularity in the 1990s due to their favorable effects on weight loss and diabetes among others with good short-term safety data. People on ketogenic diets exist in a state of “dietary ketosis” in which the body production of ketone is equal to consumption and no harmful effects of ketonemia occur. However, in face of stress, the harmless “dietary ketosis” can lead to profound acid-base disturbances due to massive overproduction of ketone bodies that overwhelms the acid buffer system of the body. A handful of case reports have been published on this topic calling the safety of ketogenic diet into question. In this article, we chronicle a unique case of ketogenic (Atkins) diet–associated ketoacidosis, and we present a comprehensive literature review on the etiology of ketoacidosis.

Ketone Body Acetoacetate Buffers Methylglyoxal via a Non-enzymatic Conversion during Diabetic and Dietary Ketosis

The α-oxoaldehyde methylglyoxal is a ubiquitous and highly reactive metabolite known to be involved in aging- and diabetes-related diseases. If not detoxified by the endogenous glyoxalase system, it exerts its detrimental effects primarily by reacting with biopolymers such as DNA and proteins. We now demonstrate that during ketosis, another metabolic route is operative via direct non-enzymatic aldol reaction between methylglyoxal and the ketone body acetoacetate, leading to 3-hydroxyhexane-2,5-dione. This novel metabolite is present at a concentration of 10%-20% of the methylglyoxal level in the blood of insulin-starved patients. By employing a metabolite-alkyne-tagging strategy it is clarified that 3-hydroxyhexane-2,5-dione is further metabolized to non-glycating species in human blood. The discovery represents a new direction within non-enzymatic metabolism and within the use of alkyne-tagging for metabolism studies and it revitalizes acetoacetate as a competent endogenous carbon nucleophile.

Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies

A worsening epidemic of diabetes and its precursor, metabolic syndrome (MetS) is engulfing America. A healthy individual, with proper glucose regulation has an ability to switch between burning fat and carbohydrates. It has been suggested that signaling errors within this homeostatic system, characterized by impaired switching of substrate oxidation from glucose to fat in response to insulin, can contribute to the etiology of metabolic syndrome and occurs before the development of type II diabetes.Glucose regulation with restored insulin sensitivity facilitated through clinically regulated, benign dietary ketosis (BDK), may significantly reduce, regulate and reverse the adverse pathologies common to MetS and obesity. The study assessed if prolonged maintenance of induced and controlled physiological, dietary ketosis, would reverse pathological processes induced by MetS including a reduction in fasting triglycerides, BMI (body mass index) and body fat mass (BFM), weight, a significant decrease and/or normalization of hemoglobin A1c (HgA1c) and an increase in resting metabolic rate (RMR) and blood ketones. A group of 30 adults, previously diagnosed with MetS by their primary care physician, were randomly prescribed to one of three groups: a sustained ketogenic diet with no exercise, standard American diet (SAD) with no exercise or SAD with 3-5 days per week of exercise (30 min.). The results demonstrated that the change over time from week 0 to week 10 was significant (p=0.001) in the ketogenic group for weight, body fat percentage, BMI, HgA1c and ketones. All variables for the ketogenic group out-performed those of the exercise and non-exercise groups, with five of the seven demonstrating statistical significance.

Energetic Constraints Produce Self-sustained Oscillatory Dynamics in Neuronal Networks.

Overview: We model energy constraints in a network of spiking neurons, while exploring general questions of resource limitation on network function abstractly.Background: Metabolic states like dietary ketosis or hypoglycemia have a large impact on brain function and disease outcomes. Glia provide metabolic support for neurons, among other functions. Yet, in computational models of glia-neuron cooperation, there have been no previous attempts to explore the effects of direct realistic energy costs on network activity in spiking neurons. Currently, biologically realistic spiking neural networks assume that membrane potential is the main driving factor for neural spiking, and do not take into consideration energetic costs.Methods: We define local energy pools to constrain a neuron model, termed Spiking Neuron Energy Pool (SNEP), which explicitly incorporates energy limitations. Each neuron requires energy to spike, and resources in the pool regenerate over time. Our simulation displays an easy-to-use GUI, which can be run locally in a web browser, and is freely available.Results: Energy dependence drastically changes behavior of these neural networks, causing emergent oscillations similar to those in networks of biological neurons. We analyze the system via Lotka-Volterra equations, producing several observations: (1) energy can drive self-sustained oscillations, (2) the energetic cost of spiking modulates the degree and type of oscillations, (3) harmonics emerge with frequencies determined by energy parameters, and (4) varying energetic costs have non-linear effects on energy consumption and firing rates.Conclusions: Models of neuron function which attempt biological realism may benefit from including energy constraints. Further, we assert that observed oscillatory effects of energy limitations exist in networks of many kinds, and that these findings generalize to abstract graphs and technological applications.

Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study

Ketones (principally β-hydroxybutyrate and acetoacetate (AcAc)) are an important alternative fuel to glucose for the human brain, but their utilisation by the brain remains poorly understood. Our objective was to use positron emission tomography (PET) to assess the impact of diet-induced moderate ketosis on cerebral metabolic rate of acetoacetate (CMRa) and glucose (CMRglc) in healthy adults. Ten participants (35 ± 15 y) received a very high fat ketogenic diet (KD) (4.5:1; lipid:protein plus carbohydrates) for four days. CMRa and CMRglc were quantified by PET before and after the KD with the tracers, 11C-AcAc and 18F-fluorodeoxyglucose (18F-FDG), respectively. During the KD, plasma ketones increased 8-fold (p = 0.005) while plasma glucose decreased by 24% (p = 0.005). CMRa increased 6-fold (p = 0.005), whereas CMRglc decreased by 20% (p = 0.014) on the KD. Plasma ketones were positively correlated with CMRa (r = 0.93; p < 0.0001). After four days on the KD, CMRa represented 17% of whole brain energy requirements in healthy adults with a 2-fold difference across brain regions (12–24%). The CMR of ketones (AcAc and β-hydroxybutyrate combined) while on the KD was estimated to represent about 33% of brain energy requirements or approximately double the CMRa. Whether increased ketone availability raises CMR of ketones to the same extent in older people as observed here or in conditions in which chronic brain glucose hypometabolism is present remains to be determined.

Enhancement of Wound Healing with Dietary Ketosis: in vivo and in vitro Experiments

Chronic wounds create a substantial burden to patients and health care professionals, affecting 1.8 million new patients per year and costing $25 billion annually. The majority of chronic wounds occur in the elderly. Key features associated with age-related impairment of wound healing include limited energy and nutrient exchange, increased reactive oxygen species (ROS), and diminished blood flow. Ketone bodies, including β-Hydroxybutyrate (βHB), are naturally occurring energy substrates. We previously reported that oral ketone supplementation without dietary restriction enhanced wound closure and increased blood flow in young and aged Fisher rats. We hypothesized that improved wound closure was due to a ketone-induced favorable shift in metabolic parameters and a decrease in ROS production. Following a 28-day administration of oral ketone supplements in young rats, serum was analyzed by Metabolon using GC/MS. Ketone supplementation significantly increased TCA cycle intermediates, antioxidants carnosine an...

Effect of Sustaining Dietary Ketosis on the Hippocampal and Serum Metabolome of Sprague‐Dawley Rats

The ketogenic diet (KD) has been successfully used to treat pediatric refractory epilepsy since the 1920s and is currently being investigated as an adjunct treatment for many disease states. The therapeutic efficacy of the KD results from an elevation of blood ketones. We previously reported that oral administration of ketone supplements produced nutritional ketosis (>0.5 mM) without carbohydrate restriction and the effects of a 28-day administration of five ketone supplements on blood glucose, ketones, and lipids in male Sprague-Dawley rats. We hypothesized that the 28-day administration would affect metabolomic markers. Serum (~300 μL) and hippocampal tissues for ketone supplements 1,3 butanediol acetoacetate diester (KE) and (1:1 mixture of sodium/potassium beta-hydroxybutyrate mineral salt solution (BMS) and medium chain triglyceride oil (MCT)) BMS+MCT were collected on day 28 at 4 hours post-intragastric gavage (peak ketone elevation). Metabolon analyzed samples by gas and liquid chromatography in tandem with mass spectrometry. Both ketone supplements significantly increased serum TCA cycle intermediates: citrate, fumarate and malate. KE supplement significantly increased alpha-ketoglutarate and BMS+MCT supplement significantly increased succinate in the rat serum. Additionally, both supplements affected medium chain fatty acids, dicarboxylic acids, adenosine, inflammatory mediators, antioxidants, and bile acids in both serum and hippocampal tissue. Although both forms of ketone supplementation increased brain and blood ketone levels, the global metabolic profiles were different.

Methods of sustaining dietary ketosis in Sprague‐Dawley rats (643.5)

The ketogenic diet (KD) has been successfully used to treat pediatric refractory epilepsy since the 1920s and is currently being investigated as an adjunct treatment for cancer and neurological disorders. The therapeutic efficacy of the ketogenic diet results from an elevation of blood ketones. Concerns regarding this treatment include low compliance due to restrictive diet and adverse effects on blood lipids. We hypothesized ketone precursor supplementation would elevate blood ketone levels to therapeutic ranges (2‐5mM) without need for dietary restriction. We tested the effects of the following ketone precursors on blood glucose, ketones, and lipids with a 28‐day dose escalation study in male Sprague‐Dawley rats: R,S‐1,3‐Butandiol (BD), a mineral (Na+/K+) salt of β‐hydroxybutyrate (βHB) (SO), medium chain triglyceride (MCT) oil (MO), SO+MO 1:1 mixture (SM), acetoacetate ketone ester (KE), and control (H2O) (n 蠅8). Days 1‐14, rats received a daily 5g/kg intragastric gavage, and days 15‐28 rats received a 10g/kg dose of their respective test substances. BD and KE rats were not increased to 10g/kg based on previous toxicology studies and were administered a 5g/kg dose for the duration of the study. Once weekly, whole blood samples (10 μl) were acquired for analysis of glucose and βHB at 0, 0.5, 1, 4, 8, and 12 hours after test substance administration, or until βHB returned to baseline. At day 1 and 28, 10 μL of whole blood were collected to measure triglycerides, total cholesterol, and HDL concentration. At days 1, 7, 14, 21 and 28 substances significantly decreased blood glucose and elevated βHB without dietary restriction. There were no significant elevations in the lipid panel for any of the substances.Grant Funding Source: Funded by the Office of Naval Research

Sustaining dietary ketosis to improve blood flow and wound healing in young and aged Fisher rats (734.7)

Increasing evidence shows that limited energy and nutrient exchange is associated with age‐related impairment of wound healing. Ketone bodies, including β‐Hydroxybutyrate (βHB), are naturally occurring energy substrates, which may augment wound healing. We hypothesized that oral ketone supplementation without dietary restriction would enhance wound closure in young and aged Fisher rats by improving blood flow and supplying an alternative energy substrate. In our preliminary studies, we measured the magnitude and duration of ketosis following administration of a single 6.5g/kg dose of ketone precursors: R,S‐1,3‐Butanediol (KS1), Na+/K+ βHB salt and medium chain triglyceride (MCT) oil 1:1 mixture (KS2), or water in young and aged fisher 344 rats (n=6). Substances were administered through an intragastric gavage and whole blood samples (10 μl) were acquired for analysis of glucose and βHB at 0, 0.5, 1, 1.5, 2, 4, 8, and 12 hours following administration. Using an ischemic wound‐healing model, the ketogenic supplements were added to a standard diet fed ad libitum for 28 days. Laser Doppler imaging of the ischemic peri‐wound tissue every 7 days demonstrated significantly increased blood flow in young rats (n=10) fed KS1 at day 14 and 28 (p&lt;0.001) and KS2 at day 7, 14, and 28 (p&lt;0.01). In aged rats, blood flow was significantly increased in KS1‐fed at day 14 and KS2‐fed at days 7 and 14 (p&lt;0.05). Wound size was significantly smaller in young rats fed KS1 and KS2 at 11 and 14 days following wound creation (p&lt;0.05). In aged rats, KS1‐fed wounds were significantly smaller at days 11 and 14 (p&lt;0.05) and in KS2‐fed at days 11, 14, and 28 (p&lt;0.05). Wound healing improved by 3 days in aged KS1‐fed, 7 days in young KS2‐fed, and 10 days in aged KS2‐fed.Grant Funding Source: Funded by the Office of Naval Research

Enhanced cerebral bioenergetics with dietary ketosis in Mild Cognitive Impairment

BACKGROUND: Metabolic disturbance is associated with risk for neurodegeneration, and cerebral glucose hypometabolism is prominent in Alzheimer’s disease (AD). Ketone metabolism can compensate for glucose hypometabolism and confers other benefits pertinent to neurodegeneration, among them reduction of oxidative stress and AD pathological factors, suggesting its potential as a therapeutic intervention. In a prior controlled trial, we showed that six weeks’ carbohydrate restriction induced ketogenesis and produced improvements in metabolic parameters and memory performance in older adults with Mild Cognitive Impairment (MCI). Those benefits were attributed to the correction of hyperinsulinemia and to the presumed enhancement of cerebral bioenergetic function associated with ketone metabolism. OBJECTIVE: To assess the effect of dietary ketosis on cerebral metabolites in older adults with MCI. METHODS: We enrolled a sample of five MCI participants in a ketogenic dietary regimen and performed pre- and postintervention proton magnetic resonance spectroscopy to investigate changes in neurochemical metabolites. We also assessed cognitive function and metabolic and anthropometric factors. RESULTS: We observed a significant increase in myo-inositol (p = 0.02) and trends for increases in N-acetyl-aspartate (p = 0.09) and creatine + phosphocreatine (p = 0.11) after six weeks on the ketogenic regimen. Working memory (p = 0.01) and long-term memory (p = 0.07) performances also improved. CONCLUSIONS: This study offers novel, preliminary evidence of cerebral bioenergetic enhancement with mild dietary ketosis in aging humans. Further investigation in controlled trials is warranted to assess the preventive and treatment implications of this intervention for age-related memory decline and dementia.

Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients

ObjectiveMost aggressive cancers demonstrate a positive positron emission tomographic (PET) result using 18F-2-fluoro-2-deoxyglucose (FDG), reflecting a glycolytic phenotype. Inhibiting insulin secretion provides a method, consistent with published mechanisms, for limiting cancer growth. MethodsEligible patients with advanced incurable cancers had a positive PET result, an Eastern Cooperative Oncology Group performance status of 0 to 2, normal organ function without diabetes or recent weight loss, and a body mass index of at least 20 kg/m2. Insulin inhibition, effected by a supervised carbohydrate dietary restriction (5% of total kilocalories), was monitored for macronutrient intake, body weight, serum electrolytes, β-hydroxybutyrate, insulin, and insulin-like growth factors-1 and -2. An FDG-PET scan was obtained at study entry and exit. ResultsTen subjects completed 26 to 28 d of the study diet without associated unsafe adverse effects. Mean caloric intake decreased 35 ± 6% versus baseline, and weight decreased by a median of 4% (range 0.0–6.1%). In nine patients with prior rapid disease progression, five with stable disease or partial remission on PET scan after the diet exhibited a three-fold higher dietary ketosis than those with continued progressive disease (n = 4, P = 0.018). Caloric intake (P = 0.65) and weight loss (P = 0.45) did not differ in those with stable disease or partial remission versus progressive disease. Ketosis was associated inversely with serum insulin levels (P = 0.03). ConclusionPreliminary data demonstrate that an insulin-inhibiting diet is safe and feasible in selected patients with advanced cancer. The extent of ketosis, but not calorie deficit or weight loss, correlated with stable disease or partial remission. Further study is needed to assess insulin inhibition as complementary to standard cytotoxic and endocrine therapies.

Ketosis, ketoacidosis and very-low-calorie diets: putting the record straight

Summary Very-low-calorie diets (VLCDs) are used to treat obesity, often in a non-clinical setting, and the typical formulation of a minimum of 50 g carbohydrates daily can induce a mild dietary ketosis. This clinically benign state is sometimes confused with the non-metabolically adapted state of ketoacidosis, and this misunderstanding may lead to the rejection of VLCDs as a suitable obesity treatment. This paper summarises and discusses the difference between physiological ketosis and pathological ketoacidosis, the benefits of ketosis-inducing weight-loss regimen such as VLCDs and why ketoacidosis should never be the diagnosis in a non-type 1 diabetic on a carbohydrate-restricted diet.