Ketone Bodies as a Possible Adjuvant to Ketogenic Diet in PDHc Deficiency but Not in GLUT1 Deficiency

Introduction Monoterpene perillyl alcohol (POH) is cytotoxic to temozolomide-resistant glioma cells, regardless of its O6-methylguanine-methyltransferase (MGMT) promoter methylation status. Moreover, adherence to a ketogenic diet (KD) produced successful outcomes in preclinical and clinical studies in the glioma setting. Case Presentation A 54-year-old Caucasian man had a confirmed diagnosis of refractory glioblastoma multiforme (GBM). The immunohistochemical evaluation was negative for methylation, and failed to detect mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. In January 2016, the patient was enrolled in a clinical trial combining daily intranasal delivery of POH in combination with a KD. The KD was administered concomitantly with inhalation of POH (55 mg, 4 times a day) in an uninterrupted administration schedule for 3 months. Results The combination treatment was well-tolerated. The nutritional status and anthropometric measurements of the patient were measured. Adherence to the KD was confirmed by measuring the levels of ketone bodies in the urine. Throughout the treatment, a reduced frequency of seizures was observed. After three months of adherence to the treatment, the patient presented with weight loss, reduced body fat, increased water retention, and a slight increase in bone and muscle mass. A follow-up magnetic resonance imaging (MRI) scan after 3 months of treatment revealed marked reduction of the enhancing lesion. Conclusion Intranasal delivery of POH combined with concomitant adherence to a KD appeared to have a beneficial therapeutic effect in a patient with recurrent GBM. Further studies are needed to evaluate the efficacy of this therapeutic strategy in a larger cohort of treatment-refractory GBM patients.

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Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth Allowing Progression during Ketogenic Diet Therapy

iScience ◽

10.1016/j.isci.2020.101453 ◽

2020 ◽

Vol 23 (9) ◽

pp. 101453

Author(s):

Jantzen Sperry ◽

Michael C. Condro ◽

Lea Guo ◽

Daniel Braas ◽

Nathan Vanderveer-Harris ◽

...

Keyword(s):

Fatty Acids ◽

Ketogenic Diet ◽

Ketone Bodies ◽

Diet Therapy

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Satiating Effect of a Ketogenic Diet and Its Impact on Muscle Improvement and Oxidation State in Multiple Sclerosis Patients

Nutrients ◽

10.3390/nu11051156 ◽

2019 ◽

Vol 11 (5) ◽

pp. 1156 ◽

Cited By ~ 9

Author(s):

María Benlloch ◽

María Mar López-Rodríguez ◽

María Cuerda-Ballester ◽

Eraci Drehmer ◽

Sandra Carrera ◽

...

Keyword(s):

Multiple Sclerosis ◽

Body Composition ◽

Ketogenic Diet ◽

Oxidation State ◽

Lean Mass ◽

Ketone Bodies ◽

Paraoxonase 1 ◽

Before And After ◽

Multiple Sclerosis Patients ◽

Beta Hydroxybutyrate

Background: It was previously established that Multiple sclerosis (MS) generates energy alterations at the mitochondrial level related to the loss of muscle mass. Ketone bodies, mainly beta-hydroxybutyrate (BHB), re-establish this energy alteration causing satiety, changes in body composition and a decrease in hormone-dependant hunger, such as ghrelin. The aim of this study was to establish possible improvements in body composition and the level of oxidation in patients with MS, by means of the satiating effect of a ketogenic diet. Methods: A pilot study was carried out with 27 MS patients who were given a Mediterranean isocaloric and ketogenic diet for 4 months. Anthropometric measurements, as well as satiety and hunger perception (VAS scale), were taken. In addition, BHB and paraoxonase 1 (PON1), as an oxidation marker, were measured by spectrophotometric automated assays, and ghrelin was determined by an enzyme immunoassay in the serum. All measurements were taken before and after the intervention. Results: A significant increase in satiety perception at lunch and dinner and of BHB in the blood was obtained. Hunger perception decreased significantly at lunch and dinner with similar levels of ghrelin. In addition, an important increase in lean mass and PON1 was observed. To our knowledge, this is the first study addressing improvements in body composition, oxidation state and metabolism in MS patients, based on the satiating effect of a Mediterranean isocaloric diet. Conclusion: A ketogenic diet increases lean mass and decreases inflammation and oxidation possibly as a consequence of an increase in satiety and decrease in hunger in MS patients.

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Transition from ketogenic diet to triheptanoin in patients with GLUT1 deficiency syndrome

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2019-321694 ◽

2019 ◽

Vol 91 (4) ◽

pp. 444-445 ◽

Cited By ~ 1

Author(s):

Elodie Hainque ◽

Aurélie Meneret ◽

Domitille Gras ◽

Mariana Atencio ◽

Marie-Pierre Luton ◽

...

Keyword(s):

Ketogenic Diet ◽

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

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KETOGENIC DIET | Dietary Management of Epilepsy: Role of Glucose and Ketone Bodies

Encyclopedia of Basic Epilepsy Research ◽

10.1016/b978-012373961-2.00174-0 ◽

2009 ◽

pp. 687-693 ◽

Cited By ~ 2

Author(s):

T.N. Seyfried ◽

J.G. Mantis ◽

M.T. Todorova ◽

A.E. Greene

Keyword(s):

Ketogenic Diet ◽

Ketone Bodies ◽

Dietary Management

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Neutropenia responsive to ketogenic diet in an infant with GLUT1 deficiency syndrome

Journal of Pediatric Epilepsy ◽

10.3233/pep-13053 ◽

2015 ◽

Vol 02 (02) ◽

pp. 137-140

Author(s):

Marianne Ifversen ◽

Jakob Ek ◽

Peter Uldall ◽

Henrik Simonsen ◽

Cristel Sørensen

Keyword(s):

Ketogenic Diet ◽

Deficiency Syndrome ◽

Glut1 Deficiency ◽

Glut1 Deficiency Syndrome

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Ketogenic Diet, Aging, and Neurodegeneration

10.1093/med/9780190497996.003.0024 ◽

2016 ◽

Cited By ~ 1

Author(s):

Kui Xu ◽

Joseph C. LaManna ◽

Michelle A. Puchowicz

Keyword(s):

Oxidative Stress ◽

Energy Source ◽

Blood Flow ◽

Ketogenic Diet ◽

Ketone Bodies ◽

Neurovascular Unit ◽

Cerebral Metabolic Rate ◽

Downstream Effects ◽

Atp Supply ◽

The Brain

The brain is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet. Research has shown that ketosis is neuroprotective against ischemic insults in rodents. This review focuses on investigating the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiological conditions in the aged is challenging. Cerebral metabolic rate for glucose, cerebral blood flow, and the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxic inducible factor-1alpha (HIF1α‎) and its downstream effects on intermediary metabolism. The chapter hypothesizes that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply) and act as signaling molecules through the up-regulation of salvation pathways targeted by HIF1α‎.

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Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e13558 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e13558-e13558

Author(s):

Frederic Anthony Vallejo ◽

Sumedh Shah ◽

Winston Walters ◽

Katrina Kostenko ◽

Ingrid Torrens ◽

...

Keyword(s):

Stem Cell ◽

Western Blot ◽

Ketogenic Diet ◽

Ketone Bodies ◽

Combined Treatment ◽

Glycolytic Enzymes ◽

Parp Cleavage ◽

Low Carbohydrate Diet ◽

Dose Dependent Decrease ◽

Dose Dependent

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.

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