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Ketogenic Dietary Therapies: Recent Findings and Future Perspectives

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A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (10 March 2019) | Viewed by 102553

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Special Issue Editors

Prof. Dr. Anna Tagliabue

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Guest Editor

Human Nutrition and Eating Disorders Research Centre, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, 27100 Pavia PV, Italy
Interests: ketogenic dietary treatments; gut microbiota; obesity and eating disorders; assessment of nutritional status; body composition and energy expenditure
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Simona Bertoli

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Guest Editor

ICANS-DIS, Department of Food Environmental and Nutritional Sciences, University of Milan, 20133 Milan, Italy
Interests: body composition; obesity; ketogenic diet; metabolic syndrome; eating behavior; Mediterranean diet
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy and some neurometabolic disorders. Specifically, the classic ketogenic diet has been used to treat epilepsy in children continuously since 1921. Variations of this diet include the modified Atkins diet, low glycemic index treatment, and medium-chain triglyceride diet. More recently, KDT have also been studied for their therapeutic effects in other neurological disorders as well as in chronic systemic metabolic diseases and cancer.

The primary mechanism through which these diets are thought to exert their effects is a reduction in glycolysis and a promotion of ketone body formation, which can be used by the brain to generate cellular energy. This shift in energy metabolism appears to reset cellular metabolic dysfunction and neuronal activity, although the exact mechanisms remain unclear and are currently the subject of further research.

Nutritional ketosis is currently under investigation for the improvement of metabolic and inflammatory markers, including lipids, HbA1c, high-sensitivity CRP, fasting insulin and glucose levels, and as an aid in weight management.

To obtain a therapeutic effect, low amounts of carbohydrates and high amounts of fat are administered in different controlled ratios. The use of such unbalanced diets in children and adults requires particular attention in implementation and monitoring. The main nutritional problems that require careful monitoring arise from marginal or overt nutritional deficits (energy, proteins, minerals and vitamins) or from excess nutrients (lipids, saturated fat and cholesterol) that are peculiar to these diets. In addition, the usefulness of different nutritional supplements and special foods deserves deeper discussion. The long-term adverse and beneficial effects of KDT is an unexplored research fields that must receive urgent attention.

Prof. Anna Tagliabue
Dr. Bertoli Simona
Guest Editors

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Keywords

ketogenic diet
low-glycemic diet
MCT
Atkins
ketone supplements
ketogenic foods
epilepsy
gut-brain axix
cancer
diabetes
autoimmune diseases
glycemic control
dietary protocols
mechanisms of action
supplementation
nutritional status
indications and contraindications
adverse effects
software for diet calculation

Published Papers (9 papers)

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Research

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17 pages, 1466 KiB

Open AccessArticle

Effect of a Very-Low-Calorie Ketogenic Diet on Circulating Myokine Levels Compared with the Effect of Bariatric Surgery or a Low-Calorie Diet in Patients with Obesity

by Ignacio Sajoux, Paula M. Lorenzo, Diego Gomez-Arbelaez, M. Angeles Zulet, Itziar Abete, Ana I. Castro, Javier Baltar, María P. Portillo, Francisco J. Tinahones, J. Alfredo Martinez, Ana B. Crujeiras and Felipe F. Casanueva

Nutrients 2019, 11(10), 2368; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11102368 - 04 Oct 2019

Cited by 42 | Viewed by 8575

Abstract

The preservation of muscle mass and muscle function after weight loss therapy is currently a considerable challenge in the fight against obesity. Muscle mass secretes proteins called myokines that have relevant functions in the regulation of metabolism and health. This study was aimed to evaluate whether a very low-calorie ketogenic (VLCK) diet may modulate myokine levels, in addition to changes in body composition, compared to a standard, balanced low-calorie (LC) diet or bariatric surgery in patients with obesity. Body composition, ketosis, insulin sensitivity and myokines were evaluated in 79 patients with overweight/obesity after a therapy to lose weight with a VLCK diet, a LC diet or bariatric surgery. The follow-up was 6 months. The weight loss therapies induced changes in myokine levels in association with changes in body composition and biochemical parameters. The effects on circulating myokine levels compared to those at baseline were stronger after the VLCK diet than LC diet or bariatric surgery. Differences reached statistical significance for IL-8, MMP2 and irisin. In conclusion, nutritional interventions or bariatric surgery to lose weight induces changes in circulating myokine levels, being this effect potentially most notable after following a VLCK diet. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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15 pages, 288 KiB

Open AccessArticle

Long-Term Effects of a Classic Ketogenic Diet on Ghrelin and Leptin Concentration: A 12-Month Prospective Study in a Cohort of Italian Children and Adults with GLUT1-Deficiency Syndrome and Drug Resistant Epilepsy

by Ramona De Amicis, Alessandro Leone, Chiara Lessa, Andrea Foppiani, Simone Ravella, Stefano Ravasenghi, Claudia Trentani, Cinzia Ferraris, Pierangelo Veggiotti, Valentina De Giorgis, Anna Tagliabue, Alberto Battezzati and Simona Bertoli

Nutrients 2019, 11(8), 1716; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11081716 - 25 Jul 2019

Cited by 20 | Viewed by 7153

Abstract

The classical ketogenic diet (cKD) is an isocaloric, high fat, very low-carbohydrate diet that induces ketosis, strongly influencing leptin and ghrelin regulation. However, not enough is known about the impact of a long-term cKD. This study evaluated the effects of a 12-month cKD on ghrelin and leptin concentrations in children, adolescents and adults affected by the GLUT1-Deficiency Syndrome or drug resistant epilepsy (DRE). We also investigated the relationship between the nutritional status, body composition and ghrelin and leptin variations. We carried out a longitudinal study on 30 patients: Twenty-five children and adolescents (15 females, 8 ± 4 years), and five adults (two females, 34 ± 16 years). After 12-monoths cKD, there were no significant changes in ghrelin and leptin, or in the nutritional status, body fat, glucose and lipid profiles. However, a slight height z-score reduction (from −0.603 ± 1.178 to −0.953 ± 1.354, p ≤ 0.001) and a drop in fasting insulin occurred. We found no correlations between ghrelin changes and nutritional status and body composition, whereas leptin changes correlated positively with variations in the weight z-score and body fat (ρ = 0.4534, p = 0.0341; ρ = 0.5901, p = 0.0135; respectively). These results suggest that a long-term cKD does not change ghrelin and leptin concentrations independently of age and neurological condition. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

14 pages, 599 KiB

Open AccessArticle

Quality of Life in Chronic Ketogenic Diet Treatment: The GLUT1DS Population Perspective

by Costanza Varesio, Ludovica Pasca, Stefano Parravicini, Martina Paola Zanaboni, Elena Ballante, Silvia Masnada, Cinzia Ferraris, Simona Bertoli, Anna Tagliabue, Pierangelo Veggiotti and Valentina De Giorgis

Nutrients 2019, 11(7), 1650; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11071650 - 19 Jul 2019

Cited by 11 | Viewed by 5151

Abstract

Background: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare, genetically determined neurological disorder, for which Ketogenic Diet (KD) represents the gold standard life-long treatment. The aim of this study is to investigate health related quality of life in a well characterized cohort of patients affected by GLUT1DS treated with KD, evaluating factors that can influence patients’ and parents’ quality of life perception. Methods: This is a double center exploratory research study. A postal survey with auto-administrable questionnaires was conducted among 17 subjects (aged 3–22 years) with diagnosis of GLUT1DS, receiving a stable KD treatment for more than 1 year. The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales was adopted. Clinical variables analyzed in relation to quality of life were frequency of epileptic seizures and movement disorder since KD introduction, presence of intellectual disability (ID), and KD ratio. Results: Quality of life global scores were impaired both in parents’ and children’s perspectives, with a significant concordance. Taking into consideration subscales, the average was 64.17 (range 10–100) for physical functioning, 74.23 (range 30–100) for emotional functioning, 62.64 (range 10–100) for social functioning, and 56 (range 15–92) for school functioning. Conclusions: In patients with GLUT1DS the quality of life perception is comparable to that of other patients with chronic disease. In our sample, the presence of movement disorder seems to be a crucial element in quality of life perception. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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9 pages, 736 KiB

Open AccessArticle

A Prospective Study on Changes in Nutritional Status and Growth Following Two Years of Ketogenic Diet (KD) Therapy in Children with Refractory Epilepsy

by Marisa Armeno, Antonella Verini, Mariana del Pino, Maria Beatriz Araujo, Graciela Mestre, Gabriela Reyes and Roberto Horacio Caraballo

Nutrients 2019, 11(7), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11071596 - 14 Jul 2019

Cited by 21 | Viewed by 4979

Abstract

Introduction: Epilepsy is a neurological disorder characterized by an increased susceptibility to seizures. The ketogenic diet (KD) is currently the most important alternative non-pharmacological treatment. Despite its long history of clinical use, it is not clear how this diet affects longitudinal growth in children. Methods: A prospective study was designed to evaluate growth and nutritional status in 45 children on KD. Growth was assessed by measuring weight, height, and body mass index (BMI). Standard deviation scores (SDS) were calculated for all measurement parameters at KD initiation and at a two-year follow-up. Results: Overall, 45 patients who completed 24 months on KD were enrolled. Median age was 6.6 years (0.8 to 17.3), with a male predominance (n = 23); 74% of the 45 patients were responders on seizure reduction at three months; 26% of patients were non-responders. In our study, using −1 SDS as a cut-off point, growth deceleration was observed in 9% (n: 4) of the patients; however, the nutritional status was maintained or even improved. No correlation with age, sex, or ambulatory status was found. Conclusions: The nutritional follow-up of these patients was helpful to improve overweight and thinness but could not avoid growth deceleration in some of them. These findings confirm that children with refractory epilepsy on KD treatment require careful growth monitoring. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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12 pages, 280 KiB

Open AccessFeature PaperArticle

Impact of the Ketogenic Diet on Linear Growth in Children: A Single-Center Retrospective Analysis of 34 Cases

by Cinzia Ferraris, Monica Guglielmetti, Ludovica Pasca, Valentina De Giorgis, Ottavia Eleonora Ferraro, Ilaria Brambilla, Alessandro Leone, Ramona De Amicis, Simona Bertoli, Pierangelo Veggiotti and Anna Tagliabue

Nutrients 2019, 11(7), 1442; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11071442 - 26 Jun 2019

Cited by 33 | Viewed by 6186

Abstract

Data on the impact of the ketogenic diet (KD) on children’s growth remain controversial. Here, we retrospectively investigated the occurrence of linear growth retardation in 34 children (47% males; age range: 2−17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20) who had been treated with the KD for 12 months. The general characteristics of children with and without growth retardation were also compared. All participants received a full-calorie, traditional KD supplemented with vitamins, minerals, and citrate. Most children (80%; 11/14 in the DRE subgroup and 16/20 in the GLUT1-DS subgroup) treated with the KD did not show growth retardation at 12 months. Although participants with and without delay of growth did not differ in terms of baseline clinical characteristics, dietary prescriptions, or supplementation patterns, marked ketosis at 12 months tended to occur more frequently in the latter group. Altogether, our results indicate that growth retardation may occur in a minority of children treated with the KD. However, further research is required to identify children at risk and to clarify how increased ketones levels may affect endocrine pathways regulating growth during KD administration. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

Review

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22 pages, 1325 KiB

Open AccessReview

Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry

by Raffaella Longo, Carolina Peri, Dalma Cricrì, Lara Coppi, Donatella Caruso, Nico Mitro, Emma De Fabiani and Maurizio Crestani

Nutrients 2019, 11(10), 2497; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11102497 - 17 Oct 2019

Cited by 59 | Viewed by 27381

Abstract

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid β-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. β-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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24 pages, 655 KiB

Open AccessReview

Dietary Neuroketotherapeutics for Alzheimer’s Disease: An Evidence Update and the Potential Role for Diet Quality

by Matthew K. Taylor, Russell H. Swerdlow and Debra K. Sullivan

Nutrients 2019, 11(8), 1910; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11081910 - 15 Aug 2019

Cited by 35 | Viewed by 10309

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease with growing prevalence as the global population ages. Currently available treatments for AD have minimal efficacy and there are no proven treatments for its prodrome, mild cognitive impairment (MCI). AD etiology is not well understood and various hypotheses of disease pathogenesis are currently under investigation. A consistent hallmark in patients with AD is reduced brain glucose utilization; however, evidence suggests that brain ketone metabolism remains unimpaired, thus, there is a great deal of increased interest in the potential value of ketone-inducing therapies for the treatment of AD (neuroketotherapeutics; NKT). The goal of this review was to discuss dietary NKT approaches and mechanisms by which they exert a possible therapeutic benefit, update the evidence available on NKTs in AD and consider a potential role of diet quality in the clinical use of dietary NKTs. Whether NKTs affect AD symptoms through the restoration of bioenergetics, the direct and indirect modulation of antioxidant and inflammation pathways, or both, preliminary positive evidence suggests that further study of dietary NKTs as a disease-modifying treatment in AD is warranted. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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21 pages, 442 KiB

Open AccessReview

Food and Food Products on the Italian Market for Ketogenic Dietary Treatment of Neurological Diseases

by Alessandro Leone, Ramona De Amicis, Chiara Lessa, Anna Tagliabue, Claudia Trentani, Cinzia Ferraris, Alberto Battezzati, Pierangelo Veggiotti, Andrea Foppiani, Simone Ravella and Simona Bertoli

Nutrients 2019, 11(5), 1104; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11051104 - 17 May 2019

Cited by 17 | Viewed by 6297

Abstract

The ketogenic diet (KD) is the first line intervention for glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency, and is recommended for refractory epilepsy. It is a normo-caloric, high-fat, adequate-protein, and low-carbohydrate diet aimed at switching the brain metabolism from glucose dependence to the utilization of ketone bodies. Several variants of KD are currently available. Depending on the variant, KDs require the almost total exclusion, or a limited consumption of carbohydrates. Thus, there is total avoidance, or a limited consumption of cereal-based foods, and a reduction in fruit and vegetable intake. KDs, especially the more restrictive variants, are characterized by low variability, palatability, and tolerability, as well as by side-effects, like gastrointestinal disorders, nephrolithiasis, growth retardation, hyperlipidemia, and mineral and vitamin deficiency. In recent years, in an effort to improve the quality of life of patients on KDs, food companies have started to develop, and commercialize, several food products specific for such patients. This review summarizes the foods themselves, including sweeteners, and food products currently available for the ketogenic dietary treatment of neurological diseases. It describes the nutritional characteristics and gives indications for the use of the different products, taking into account their metabolic and health effects. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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20 pages, 1156 KiB

Open AccessReview

Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention

by Elena C. Gross, Rainer J. Klement, Jean Schoenen, Dominic P. D’Agostino and Dirk Fischer

Nutrients 2019, 11(4), 811; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11040811 - 10 Apr 2019

Cited by 48 | Viewed by 25447

Abstract

An increasing amount of evidence suggests that migraines are a response to a cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity. The ketogenic diet (KD), a diet mimicking fasting that leads to the elevation of ketone bodies (KBs), is a therapeutic intervention targeting cerebral metabolism that has recently shown great promise in the prevention of migraines. KBs are an alternative fuel source for the brain, and are thus likely able to circumvent some of the abnormalities in glucose metabolism and transport found in migraines. Recent research has shown that KBs—D-β-hydroxybutyrate in particular—are more than metabolites. As signalling molecules, they have the potential to positively influence other pathways commonly believed to be part of migraine pathophysiology, namely: mitochondrial functioning, oxidative stress, cerebral excitability, inflammation and the gut microbiome. This review will describe the mechanisms by which the presence of KBs, D-BHB in particular, could influence those migraine pathophysiological mechanisms. To this end, common abnormalities in migraines are summarised with a particular focus on clinical data, including phenotypic, biochemical, genetic and therapeutic studies. Experimental animal data will be discussed to elaborate on the potential therapeutic mechanisms of elevated KBs in migraine pathophysiology, with a particular focus on the actions of D-BHB. In complex diseases such as migraines, a therapy that can target multiple possible pathogenic pathways seems advantageous. Further research is needed to establish whether the absence/restriction of dietary carbohydrates, the presence of KBs, or both, are of primary importance for the migraine protective effects of the KD. Full article

(This article belongs to the Special Issue Ketogenic Dietary Therapies: Recent Findings and Future Perspectives)

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