Ketogenic Diet - Powerful Dietary Strategy for Certain Conditions

Re: Ketogenic Diet - Path To Transformation?

Prometeo said:
-Drink at least 5 liters of water (specially on days I do cardio)
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That seems like an absurd amount of water to me unless you're very active.

Drinking that amount of water may be a big problem if you have stomach acid deficiency.
 
Re: Ketogenic Diet - Path To Transformation?

I can't believe how amazing my skin looks and feels since being on the keto diet. It is smooth, soft and acne free. I have always had trouble with acne, and now I have really nice skin. The dark circles under my eyes are diminishing as well. It's only been about 5 weeks, but I feel like I am even starting to look a little younger.
 
Re: Ketogenic Diet - Path To Transformation?

Prometeo said:
-Drink at least 5 liters of water (specially on days I do cardio)
[...]
-Drink lemons.
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5 litres of water sounds a bit excessive to me too - maybe your dizziness is related to that. If you drink 2 litres of water that should be plenty, plus cover the losses by sweating on top of that. And it is a good idea to put some high-quality salt into the water as well to replenish trace elements.

As to lemons, be careful, lots of people don't tolerate these very well. Maybe try to leave them away for a month and see if your symptoms change.
 
Re: Ketogenic Diet - Path To Transformation?

Monotonic, if the dizziness is still ongoing - for me it's always a sign that I haven't had enough fat. As soon as I eat fat in whatever form, but butter works best in these instances, the dizziness goes away like magic.

M.T.
 
Re: Ketogenic Diet - Path To Transformation?

Hello there
nyvf5 joined the Forum today

I would like to join the conversation about this very interesting topic

Thank you very much
 
Re: Ketogenic Diet - Path To Transformation?

Welcome to the forum, nyvf5.

We ask that new forum members introduce themselves in the Newbies section. Take a moment to post your own thread there. Nothing personal, just a little bit about yourself and how you found the forum. If you are unsure of what to write, take a look at how others on the board have done it.

:)
 
Re: Ketogenic Diet - Path To Transformation?

I have been in Ketosis since April 15th and would like to give an update about what happened so far ...

I had some pretty bad eczema on my elbows for at least twenty years. They got better with cutting out gluten and sugar and generally shrank in size by a half while being Paleo, but they never disappeared completely. Also they would break out occasionally, itching like mad. I somehow gave up on them even though they were not a nice sight in summer when wearing short sleeves :(. Anyway, only a week into the KD diet I observed that new skin had started to grow over where they are! As of today, they are only an estimated 20% of what they were before. Of course one can see a shadow of where they had been, and it will take a while until the skin renews completely, but I can't believe that these things are actually going away for good!

I had quite a stressful few weeks (also a reason why I couldn't post here), BUT felt much more resilient than before in similar situations. There was a lot of mental work to do, but, man, did I have the power! It wasn't a problem to concentrate for hours on end, drink a cup of buttered tea and concentrate more! And then do the same the next day. I am taking a second university degree and was much fitter than when I took my first (when I was twenty years younger :lol:).

There has been a serious improvement with my neck and shoulder tension in these situations (sitting on the computer a lot) as well. At first I didn't lose much weight, but intermittent fasting did the trick, by the way (only wanted to lose 5-6 kg that have been bothering me for a long time).

So, well, I wish, I had started this earlier!

M.T.
 
Re: Ketogenic Diet - Path To Transformation?

The diet has definitely speeded up my previously long and slow recovery from whiplash (bike accident).

Only trouble is, maybe faster than my body has been used to, i began feeling fluey yesterday and quite achy this morning, i fat bomb and stretch for 2 hours (low impact) and literally as i'm about to finish i feel my neck throb, throat get scratchy and my body just felt achey ALL over and i felt weak. Same deal yesterday. It feels like flu does.

I've read this: _http://www.reddit.com/r/keto/comments/1b89uv/science_avoiding_keto_flu_explained/ which advises potassium and salt.
So i've had a second (half portion) fat bomb with cocoa and ate a small slice of buckwheat toast and butter and a good grind of sea salt, and i'll shot a tea spoon on Cream of Tartar for the potassium.

I also pipe breath before bed and when i stretch, if that's anything.

I feel a little better, the salt was tasty, but for the moment i can't pin point whats exactly wrong.

Anyway, just to note the goings on and i'll report back. It feels like flu, so i suspect keto flu, but could just be my muscles, for now, i lie down.
 
Re: Ketogenic Diet - Path To Transformation?

Buckwheat toast is carbs and also has gluten.
 
Re: Ketogenic Diet - Path To Transformation?

Ok i just dropped an F-bomb, yes Gaby did mention something about it being similar.

I was too weak to do anything else - and i didn't think it would be so bad - and it was ultra thin and a quarter size of a normal slice (homemade), and it was my salt delivery system! But there you go. Damn. :evil:

I defintely don't have an appetite today so i'm going with something fluey till i know more.
 
Re: Ketogenic Diet - Path To Transformation?

itellsya said:
Ok i just dropped an F-bomb, yes Gaby did mention something about it being similar.

I was too weak to do anything else - and i didn't think it would be so bad - and it was ultra thin and a quarter size of a normal slice (homemade), and it was my salt delivery system! But there you go. Damn. :evil:

I defintely don't have an appetite today so i'm going with something fluey till i know more.
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Yeah, that is understandable. But keep in mind that a gluten reaction can take months to calm down. Once the immune cells get fired up, it takes 6 months or so to replace them anew so to speak. This is specially problematic for people who are very sensitive.

I think the best thing is to just get rid of all temptations. When it is not in your kitchen counter, then you eventually forget about it ;)
 
Re: Ketogenic Diet - Path To Transformation?

Interesting article, burt not sure what to make of it:

Psychoneuroendocrinology. 2014 Jul;45:43-8. doi: 10.1016/j.psyneuen.2014.03.008. Epub 2014 Mar 28.

Rise of ketone bodies with psychosocial stress in normal weight men.

Kubera B1, Hubold C1, Wischnath H1, Zug S1, Peters A2.

Abstract
BACKGROUND:
Ketone bodies are known as alternative cerebral energy substrates to glucose. During psychosocial stress, the brain of a normal weight subject demands for extra glucose from the body to satisfy its increased needs. In contrast, the brain of an obese subject organizes its need, supply and demand in a low-reactive manner. The present study aimed at investigating (i) whether psychosocial stress increases ketone body concentrations and (ii) whether ketone reactivity to a psychosocial challenge differs between normal weight and obese people.
METHODS:
Ten normal weight and ten obese men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess serum β-hydroxybutyrate concentrations and stress hormone profiles.
RESULTS:
Our main finding was that social stress markedly increased concentrations of serum β-hydroxybutyrate by 454% in normal weight men. The increase in ketone bodies during stress in normal weight subjects was associated with an increase in ACTH, norepinephrine and epinephrine concentrations. Interestingly, we could not detect any increase in serum β-hydroxybutyrate concentrations during stress in obese men.
CONCLUSION:
Normal weight men showed high ketone reactivity to a psychosocial challenge.

Copyright © 2014 Elsevier Ltd. All rights reserved.
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Re: Ketogenic Diet - Path To Transformation?

Found another great article - a review article about the potential neuroprotective effects of a ketogenic diet and purported mechanisms of action.

Ketogenic Diets, Mitochondria and Neurological Diseases

Lindsey B. Gano1, Manisha Patel1, Jong M. Rho2
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado, Denver, Colorado, USA; 2Departments of Pediatrics and Clinical Neurosciences, Alberta Children’s Hospital Research Institute for Child and Maternal Health, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada.

Abstract
The ketogenic diet (KD) is a broad‐spectrum therapy for medically intractable epilepsy and is receiving growing attention as a potential treatment for neurological disorders arising in part from bioenergetic dysregulation. The high‐fat, low‐carbohydrate “classic KD” – as well as dietary variations such as the medium‐chain triglyceride diet, the modified Atkins diet, the low‐ glycemic index treatment, and caloric restriction – enhance cellular metabolic and mitochondrial function. Hence, the broad neuroprotective properties of such therapies may stem from improved cellular metabolism. Data from clinical and preclinical studies indicate that these diets restrict glycolysis and increase fatty acid oxidation, actions which result in ketosis, replenishment of the TCA cycle (i.e., anaplerosis), restoration of neurotransmitter and ion channel function, and enhanced mitochondrial respiration. Further, there is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis. These pathways, which include peroxisome proliferator‐activated receptors, AMP‐activated kinase, mammalian target of rapamycin, and the sirtuins, have all been recently implicated in the neuroprotective effects of the KD. Further research in this area may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

Introduction
The ketogenic diet (KD) is a high‐fat, low‐carbohydrate therapy for drug‐resistant epilepsy (1, 2), and is increasingly being studied for therapeutic efficacy in a number of neurological disorders, including epilepsy, headache, neurotrauma, Alzheimer disease (AD), Parkinson disease (PD), sleep disorders, brain cancer, autism, pain, and amyotrophic lateral sclerosis (ALS) (3, 4). This is a result of growing experimental evidence for the broad neuroprotective properties of the KD, and mechanistic linkages to key cellular signaling pathways and fundamental bioenergetics processes, notably within mitochondria (5, 6). In recent years, the field of neurometabolism has been greatly amplified by interest in dietary treatments such as the KD (6), and by the recognition that bioenergetic dysregulation may be a critical pathophysiological factor in diseases of the nervous system (7, 8). Indeed, there is increasing appreciation for the concept of energy failure – principally from mitochondrial dysfunction – as a key mechanism resulting in neuronal death seen in neurodegenerative diseases (8).
That diet and nutrition should influence brain function should not be altogether surprising, and there exist much clinical and laboratory data linking disturbances in energy metabolism to a variety of clinical disorders (5, 9, 10). Fundamentally, any disease in which the pathogenesis is affected by disturbances in cellular energy utilization – and this could apply to almost every known medical condition – would potentially be amenable to treatments that restore normal metabolism. A common thread of such diet‐based therapies for brain diseases is that metabolic substrates and nutrients can exert profound effects on neuronal plasticity, modifying neural circuits and cellular properties to enhance and normalize function. Further, as there is increasing evidence for diet‐induced epigenetic mechanisms contributing causally to the development of common chronic diseases (11, 12), greater knowledge of processes and players such as DNA methylation, histone modifications and non‐coding microRNAs will be needed to understand the relationships between energy dysregulation and therapeutic strategies to counter such impairment (11, 13).
This article explores the rationale and evidence for using the KD and related dietary treatments in a broad range of neurological disorders, and highlights novel mechanisms that have been implicated in their actions. However, it is important to recognize that much of the data discussed herein remain preliminary in nature. Nevertheless, the therapeutic potential for dietary therapies for neurological disorders remains almost limitless when viewed from the perspective of salvaging neuronal bioenergetic dysfunction (6, 8, 14).

Ketogenic Diet and Epilepsy: Historical Aspects
The use of dietary manipulations to treat epilepsy – in particular, controlling seizures through sustained fasting – dates back to the time of Hippocrates (15‐17). In modern times, reports of modifying diets to treat seizures emerged in the early 20th century both in France and in the United States (15, 17‐20). Importantly, in the 1920s, several researchers made significant discoveries regarding the physiological changes associated with the anti‐seizure effects of starvation. At Harvard Medical School, Drs. Stanley Cobb and William G. Lennox conducted studies on changes in blood chemistry and metabolism during fasting in epileptic patients (15, 17, 21). They noted that the effects of fasting, such as increases in serum acidosis, were seen within 2‐3 days coincident with seizure reductions, and were abolished with carbohydrate intake, but not with a fat diet (15, 21). During this time, it was also recognized by Dr. R.T. Woodyatt at Rush Medical College that in the fasted state, the body produced ketone bodies (β‐hydroxybutyrate [BHB], acetoacetate [ACA] and acetone) through the liver, and that a diet high in fats but low in carbohydrates could replicate this metabolic effect (17, 22). It was then suggested by Dr. Russell Wilder at the Mayo Clinic that consumption of a high‐fat/low‐ carbohydrate diet, and the resulting increase in serum ketone bodies, could possibly mimic the effects of starvation and he proposed that this diet should be tested in epileptic patients (23, 24). Subsequently, Dr. Wilder was the first to refer to this special high‐fat diet as the “ketogenic diet” (17). Collectively, Drs. Lennox, Cobb and Wilder believed the KD could be as effective as fasting and more appropriate for long‐term suppression of seizures (15, 21, 24).
The first results demonstrating the beneficial effects of the KD on seizure reduction in epileptic children were published by Dr. M.G. Peterman, a pediatrician from the Mayo Clinic (25, 26). And during an era when anti‐seizure drugs (ASDs) were scarce, the KD became quickly popularized in large medical centers. However, with the advent of diphenylhydantoin in 1938, the KD quickly fell out of favor due to the simplicity of prescribing an oral medication as opposed to a strict and exacting dietary regimen. Nevertheless, a variation of the KD – i.e., the medium‐chain triglyceride (MCT) diet – emerged later as yet another dietary option for medically intractable epilepsy (27), and remains today as an alternative to the classic KD (28).
In recent years, there has been an explosion in clinical use of the KD and of its variants (29, 30), as well as in scientific interest regarding the mechanisms underlying their action (14, 31). Even beyond this resurgence in popularity for epilepsy, the diet has been increasingly found to exert protective effects in a variety of neurological diseases (3, 4) and new mechanistic insights have steadily emerged.

Efficacy in Epilepsy: Clinical Studies
The classic KD utilizes a fat‐to‐carbohydrate plus protein ratio of 4:1 by weight, with approximately 90% of daily caloric intake coming from fat, and the inclusion of a small amount of protein (~1 g/kg body weight) to ensure adequate growth in pediatric patients (32‐34). A fat‐ to‐carbohydrate ratio of 3:1 may be utilized based on patient’s needs and efficacy, which underscores the importance of the need for a dietician to implement and monitor the patient while on the diet (32‐34). The classic KD is primarily based on ingestion of saturated long‐chain fatty acids (FA) (32). Upon restriction of carbohydrates, ketogenesis occurs in the liver and ketone bodies are exported to the circulation (Figure 1). Circulating concentrations of the major ketone bodies, BHB, ACA, and acetone have been shown to significantly increase within 1‐3 days after initiation of the KD.
A key aspect of the KD includes partial caloric restriction (CR). Prior to starting the diet, a fasting period of 24‐48 hours is typical (35), but the need for this requirement has been debated (36). An initial period of fasting may accelerate seizure control, and is therefore recommended for patients with a greater need for immediate seizure reduction (37, 38). A decrease in daily caloric intake of 10‐25% is typical with the diet. Gluconeogenesis may result from consumption of excess calories, and therefore this slight reduction in calories is thought to increase the efficacy of the diet by maintaining ketosis (14, 39). After initiation of the diet, seizure control slowly increases within the first few days to weeks (37, 38). This is believed to be due to the gradual elevation of circulating ketone bodies. However, since serum levels of ketone bodies do not correlate tightly with seizure control, it is unknown whether these substrates are directly responsible for the clinical effects observed (32). Despite this uncertainty, it is known that a break from the diet by ingestion of carbohydrates rapidly reverses the anti‐seizure effects of the diet. In fact, the onset of seizures can occur less than an hour after administration of glucose (40).
Historically, the KD has been primarily used to treat epilepsy in pediatric patients. Efficacy in seizure control with the KD is assumed to be enhanced in younger patients, and is thought to reflect age‐dependent changes in the expression of monocarboxylate transporters which transfer ketone bodies across the blood‐brain barrier from the systemic circulation (41, 42) (Figure 1). However, in spite of the challenges in maintaining the diet in older patients – mostly due to compliance issues – improved seizure control has been reported as well in adolescents and adults (43‐45).
Despite numerous clinical reports documenting the efficacy of the KD against intractable epilepsy (32), very few Class 1 and 2 studies exist. After nearly a century of use, the strongest evidence only became available as recently as 2008. In this randomized controlled trial of 145 children, aged 2‐16 years old with daily seizures and who did not respond to at least two ASDs, it was shown that those who maintained the KD for greater than three months had a significant reduction in the mean percentage of baseline seizures (2). Seven percent of children on the KD demonstrated a greater than 90% reduction in seizures, compared with 0% on the control diet, and there was a more than 50% reduction in seizures in 38% of the patients on the KD versus 6% on the control diet (2).
As the KD is a high‐fat diet, concerns exist regarding the development of dyslipidemia, insulin resistance or increased serum biomarkers for cardiovascular diseases (CVD). However, this issue is controversial and definitive clinical data to either support or refute the development of risk factors for metabolic syndrome or CVD in patients on the KD do not exist. In the few studies that have examined CVD or metabolic syndrome risk factors with the KD, the results have been variable. A large study in children found elevated levels of total and low‐ density lipoprotein (LDL) cholesterol and triglycerides, with a reduction in high‐density lipoprotein (HDL) cholesterol after 6, 12 and 24 months on the KD (46). However, a longer‐term study in children on the KD for at least 6 years, demonstrated no change in levels of cholesterol or triglycerides compared to baseline values (47). A short‐term study in healthy men on the KD for 6 weeks found a decrease in fasting serum insulin levels without a change in estimated insulin resistance, as well as a trend towards increased HDL cholesterol without a change in total and LDL cholesterol concentrations (47). To date, it is not known if the KD leads to the accelerated development of atherosclerotic lesions, arterial stiffness and vascular endothelial dysfunction in those patients that demonstrate dyslipidemia and elevated levels of CVD risk factors.

[...]

Caloric Restriction
As the KD was originally designed to mimic the effects of fasting, it was postulated that CR (or intermittent fasting) may provide similar results without the need for a large regular intake of fats. CR involves a reduction in total daily caloric intake below the ad libitum level without the risk of malnutrition (58, 66). CR is well known to ameliorate many age‐related and metabolic diseases, and is the only natural method known to increase life‐span across multiple species (60). As such, comparisons of the KD and CR on seizure control have been performed in animal models of epilepsy. However, clinical studies involving CR or intermittent fasting for epilepsy have yet to be conducted (67).
A study in rats of varying ages treated with mild calorically‐restricted standard chow diet (90% of recommended daily calories) and an isocaloric KD showed protection against PTZ‐ induced seizures (68). Rats fed the isocaloric KD exhibited a greater threshold to PTZ‐induced seizures compared to CR‐standard chow animals, which in turn demonstrated greater protection than those fed the same standard chow ad libitum (68).
In the EL genetic mouse model of epilepsy, CR (15% or 30%) delayed the development and frequency of seizures in both juvenile and adult animals (63). Additionally, when compared with a previous study by the same group that utilized the typical KD in EL mice (69), the authors found that the mild form of CR (15%) resulted in greater protection than the KD in juvenile mice. A follow‐up study in adult EL mice showed that CR in the context of both a ketogenic and a high‐carbohydrate/low‐fat diet reduced seizure susceptibility (70), leading the authors to conclude that restriction of calories, not the composition of the diet per se, is the key determinant of seizure control.

Mechanistic Overview: Ketogenesis
Sustained intake of a high‐fat, low‐carbohydrate diet increases the rates of FA oxidation (FAO) and gluconeogenesis. The end product of FAO is acetyl‐Coenzyme A (acetyl‐CoA), which can enter the TCA cycle and reacts with oxaloacetate to form citrate. However, under these metabolic conditions, oxaloacetate is also diverted to gluconeogenesis, and is therefore exported out of the mitochondria after conversion to aspartate by aspartate aminotransferase, in a process that requires glutamate which is subsequently transformed to α‐ketoglutarate. In the liver, increased production of acetyl‐CoA results in levels that exceed the amount of oxaloacetate available for entry into the TCA cycle, and ketogenesis is then initiated when two acetyl‐CoA molecules are combined to form acetoacetyl‐CoA (Figure 1). Acetoacetyl‐CoA is then condensed with another molecule of acetyl‐CoA to form 3‐hydroxy‐3‐methylglutaryl CoA (HMG‐ CoA), in a non‐reversible step catalyzed by the rate‐limiting enzyme HMG‐CoA synthase 2 (HMG‐CoAS2). The ketone body ACA is then produced via the breakdown of HMG‐CoA, releasing a molecule of acetyl‐CoA. ACA can be further reduced to the ketone body BHB by BHB dehydrogenase (BDH1) in a reaction that is coupled to the ratio of the oxidized to reduced forms of nicotinamide adenine dinucleotide (NAD+), i.e. NAD+/NADH, and the spontaneous decarboxylation of ACA can yield acetone, another ketone body. BHB and ACA are the major ketone bodies, and levels of BHB have been shown to greatly exceed those of ACA in tissues and the circulation making it the predominant ketone body (71, 72). All three ketone bodies can then be exported from the liver into the circulation for uptake by tissues with high‐metabolic demands, such as the heart, skeletal muscle and the brain. In extra‐hepatic tissues, BDH1 catalyzes the first reaction in ketone body oxidation from BHB to ACA, which makes it an important regulator of mitochondrial NAD+/NADH status (73). In the second reaction of ketone body oxidation, ACA is then converted to acetoacetyl‐CoA by succinyl‐CoA3‐oxoacid CoA transferase in a reaction that transfers a molecule of CoA from succinyl‐CoA and therefore also yields succinate. It is important to note that deficiency of the enzyme succinyl‐CoA3‐oxoacid CoA transferase has been observed in rare cases and this can result in ketoacidosis, seizures and other pathologies due to an inability to oxidize ketone bodies (73). In the final step of ketone body oxidation, mitochondrial acetoacetyl‐CoA thiolase converts acetoacetyl‐CoA to two molecules of acetyl‐CoA for incorporation into the TCA cycle by citrate synthase (73).

Ketone Bodies
The earliest demonstration of ketone bodies inducing anti‐seizure effects was made by Keith in the 1930’s. Acetoacetate was shown to protect against thujone‐induced seizures in rabbits (74). This was followed decades later by two additional studies demonstrating in vivo anti‐seizure effects of ketone bodies (75, 76). In the Frings audiogenic seizure‐susceptible mouse (a model of sensory‐evoked reflex seizures), acute administration of acetone and ACA led to an elevation in seizure threshold, whereas the more prevalent ketone body BHB had no effect on sound‐ induced seizures. In a separate study, acetone displayed dose‐dependent anti‐seizure effects in four diverse rodent models of epilepsy, including maximal electroshock seizures, subcutaneous PTZ, amygdala kindling, and the AY‐9944 (an inhibitor of cholesterol biosynthesis) model of atypical absences seizures (76). Curiously, studies showing anti‐seizure properties of the major ketone, BHB, have not yet been forthcoming.

Neurotransmitters and Ion Channel Regulation
One hypothesis for KD action involves changes in the levels of certain neurotransmitters (NT), as a result of altered synthesis and/or clearance from the synaptic cleft. The production of the major excitatory NT glutamate is paradoxically linked to the synthesis of the main inhibitory NT GABA via the action of the biosynthetic enzyme for GABA, glutamate decarboxylase (GAD). The KD has been proposed to alter the metabolism of glutamate – in response to ketosis – resulting in increased levels of GABA and enhanced inhibitory neurotransmission (77).
[...]

Bioenergetic and Mitochondrial Changes
Pathological changes in mitochondrial energy metabolism and reactive oxygen species (ROS) production are known to occur with epileptogenesis, and intriguingly the KD has been found to profoundly affect these processes (93). In addition to enhancing energy reserves, ATP levels and the expression of many enzymes involved in multiple metabolic pathways in the mitochondria, the KD has also been shown to increase mitochondrial biogenesis in the hippocampus (48). Additionally, multiple studies have demonstrated elevated antioxidant activity, diminished production of ROS, and decreased ROS‐induced damage with the KD (6, 14, 94).
[...]

Antioxidant Activity, Reactive Oxygen Species and the Redox State
Several studies indicate that the KD decreases the production of ROS and limits ROS‐ mediated damage, possibly by enhancing antioxidant activity.
[...]
This study highlights the disparities in susceptibility to oxidative damage in various brain regions possibly as a result of differential effects of the KD on antioxidant enzyme activities in certain tissues.
The KD has also been shown to change the mitochondrial production of hydrogen peroxide (H2O2) as a function of treatment duration. A decrease in substrate‐driven mitochondrial H2O2 production was shown in rats after 3 weeks on the diet, and this was associated with increased mitochondrial glutathione (GSH) levels, depletion of which is known to occur with seizures (96). The increase in GSH was associated with elevated activity of the rate‐limiting enzyme in GSH biosynthesis, glutamate cysteine ligase (GCL), and enhanced expression of the GCL catalytic subunit, GCLC, and modulatory subunit, GCLM, in rats fed the KD (96).
The increase in GSH and levels of the GCL subunits GCLC and GCLM observed by Jarrett et al. (2008) prompted an investigation to examine the role of NF E2‐related factor 2 (Nrf2), as activation of this redox‐sensitive transcription factor is the primary mechanism that induces this antioxidant pathway (97). Nrf2 is activated by cellular stress and initiates transcription of a diverse set of genes, such as antioxidant defense, drug transporters, metabolic enzymes and transcription factors, by binding to the antioxidant or electrophile response elements (ARE/EpRE) (98). This study demonstrated that production of mitochondrial‐derived H2O2 was initially enhanced after 1 day on the diet, but was significantly decreased at the 3‐week time‐ point {Link to the KD flu symptoms?}(97). This initial increase in H2O2 was accompanied by an elevation in the lipid peroxidation product 4‐hydroxy‐2‐nonenal (4‐HNE), both of which stimulate Nrf2 activity through oxidation of the inhibitory binding partner Kelch‐like ECH‐associated protein 1 (Keap1), resulting in the release and nuclear translocation of Nrf2 (99). The acute rise in H2O2 and 4‐HNE with the KD coincided with increased hippocampal nuclear expression of Nrf2 after 1 week on the KD, indicative of enhanced Nrf2 activation. Levels of Nrf2 remained elevated after 3 weeks on the KD and this was associated with increased activity of NAD(P)H:quinone oxidoreductase (NQO1), a prototypical Nrf2 target. Although GSH was depleted in liver homogenates at all time‐points examined (3 days, 1 week, 3 weeks), levels of reduced Coenzyme A (CoASH), a measure of mitochondrial antioxidant capacity, was decreased at 3 days, but elevated after 3 weeks. Likewise in liver, nuclear extracts demonstrated increased Nrf2 expression after 1 and 3 weeks on the diet, accompanied by elevations in both NQO1 activity and the expression of Nrf2 target heme oxygenase‐1 (HO‐1) after 3 weeks on the diet (97). Interestingly, a recent study found that increasing Nrf2 expression in a rat model of temporal lobe epilepsy decreased spontaneous seizures (100).
[...]
Recently, BHB was shown to be an inhibitor of class I histone deacetylases (HDAC) in vitro and in vivo (107), and this activity was associated with increased resistance to oxidative stress. Specifically, BHB increased acetylation of histone H3 lysine 9 (H3K9) and histone H3 lysine 14 (H3K14) and enhanced transcription of genes regulated by FOXO3A, including the antioxidant enzymes manganese superoxide dismutase (MnSOD) and catalase. Further, BHB (administered in vivo for 24 hours via an osmotic pump) decreased protein carbonylation, 4‐ HNE and lipid peroxides in the kidney. Although the authors did not report such effects in neuronal tissue or cells, it is possible that direct inhibition of HDACs and the ensuing transcriptional changes may mediate some of the antioxidant effects known to occur in the brain with the KD.

Mitochondrial Permeability Transition
ACA and BHB both blocked neuronal death in response to diamide, a mitochondrial permeability transition (mPT) activator, in a mechanism independent of oxidative stress. [...]

Glycolytic Restriction/Diversion
A key feature of the KD is a relative reduction in glycolysis and an increase in non‐ glucose sources of fuel through the oxidation of FA and ketone bodies which ultimately feed the TCA cycle through a process known as anaplerosis (i.e., the replenishing of depleted metabolic cycle intermediates). Glycolytic restriction is thought to be an important mechanism mediating the anti‐seizure properties of the KD. As mentioned above, CR has been shown in a mouse model of epilepsy to render anti‐seizure, and possibly anti‐epileptogenic, effects (70). The earliest clinical observation supporting this notion is the rapid reversal of seizure control upon ingestion of carbohydrates or glucose in patients on the KD (40). Additionally, studies utilizing labeled metabolic precursors have shown reduced oxidative metabolism of glucose (77, 79).
[...]

Bioenergetics Reserve and Mitochondrial Respiration
Alterations in bioenergetic metabolites by the KD have been shown in several animal studies. DeVivo and colleagues (1978) first demonstrated significant increases in ATP and the ATP/ADP ratio (and other parameters of bioenergetic reserve capacity) in the brain of rats fed the KD for 3 weeks (88). Further, decreases in creatine with no change in phosphocreatine were noted in this study. However, while a later study failed to confirm elevations in ATP and ATP/ADP ratios, the KD was shown to increase the ratio of phosphocreatine‐to‐creatine (48). In vitro studies have further supported the concept that KD metabolites can enhance bioenergetic function. For example, BHB and ACA prevented depletion of ATP in hippocampal slices in response to H2O2 and inhibitors of complex I (rotenone) and complex II (3‐nitropropionic acid [3‐NP]) of the electron transport chain (ETC) (89). In a mouse model of global cerebral ischemia, administration of BHB immediately following bilateral common carotid artery ligation ameliorated the decline in tissue levels of ATP (124). Thus, collectively, there is both in vivo and in vitro evidence for the KD and ketone bodies enhancing ATP production in brain.
[...]

Mammalian Target Of Rapamycin
The mammalian target of rapamycin (mTOR) is another protein kinase that exerts multiple effects on energy metabolism through the actions of two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (139). Unlike the PPARs and AMPK, however, mTOR is activated during high‐energy states and this results in an induction of protein synthesis and mRNA translation, among other actions that promote growth and cellular proliferation (139). Importantly, AMPK inhibits mTORC1 through direct phosphorylation of both a subunit of this complex and an upstream regulatory protein (139). In rats, the KD inhibited activation of the mTOR pathway in liver and brain (138). Additionally, in the KA model, enhanced activation of mTOR was found in the hippocampus of rats fed a standard diet and this effect was blocked after 7 days on the KD (138). Given that mTOR inhibition is believed to retard the processes of epileptogenesis (140) and that the KD can decrease mTOR signaling, it is conceivable that metabolism‐based treatments could render anti‐epileptogenic effects.

Sirtuins
The sirtuins (SIRT1‐7) are a family of NAD‐dependent enzymes known to influence multiple aspects of cellular homeostasis, including metabolism and antioxidant activity. The sirtuins were originally classified as Class III HDACs; however, it is now known that individual isoforms also demonstrate desuccinylase, demalonylase and ADP‐ribosyltransferase activities (60). The sirtuins are direct sensors of the energetic and redox state of the cell, principally through NAD+, which is required for their catalytic activity. Additionally, the beneficial effects of CR may be mediated by the sirtuins, as well as the AMPK and mTOR pathways (66, 141). The diversity and abundance of their histone and non‐histone substrates, as well as their specific localization within different cellular compartments reflect the extent of their broad influence on energy metabolism (66, 142). Collectively, the sirtuins are known to enhance oxidative phosphorylation and reduce glycolysis, in addition to providing increased resistance to oxidative stress (60). The substantial overlap in the activities of these regulators of cellular homeostasis with the known mechanisms of the KD suggests possible involvement of the sirtuins in the effects of this dietary modification. Certainly, the observation the BHB is a Class I HDAC inhibitor (107) is compelling in this regard.

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Evidence and Implications for Other Neurological Disorders
Mitochondrial Dysfunction in Neurological Diseases
Mitochondrial dysfunction has recently been recognized as a common mechanism underlying many neurological disorders (7, 8, 147, 148). The role for mitochondrial energetics and signaling as important mediators of neuronal death, a common feature of neurodegenerative diseases (149), is increasingly being understood. Specific pathological changes include a reduction in ATP production via oxidative phosphorylation or direct inhibition of specific complexes of the ETC, and elevations in the production of mitochondrial‐derived ROS, which can alter cellular signaling. Additionally, given the similar mechanisms of these processes in neurodegenerative diseases, and the beneficial effects of the KD and ketone bodies on multiple aspects of mitochondrial function, there has been an increase in the use of metabolism‐based treatments for neurological diseases (3, 4).

Alzheimer Disease
AD is characterized by an accumulation of neurofibrillary tangles and amyloid plaques comprised of misfolded aggregates of tau and amyloid‐β (Aβ) proteins, respectively, resulting in neuronal death (130). AD is an age‐related neurodegenerative disease and is known to arise from both genetic and environmental influences. Older adults with AD are at increased risk for the development of epilepsy and similar mechanisms, such as deficits in mitochondrial energy metabolism and elevations in oxidative stress, are thought to contribute to both pathological states (130, 150). Therefore, there is growing interest in the use of the KD to delay the progression of AD.
In fasted patients with AD or mild cognitive impairment (MCI), acute ingestion of a MCT drink increased BHB levels and cognitive function compared to placebo (151). Further, in a separate study of older adults with MCI, a low‐carbohydrate (5‐10% of calories) diet for 6 weeks enhanced a measure of verbal memory versus pre‐intervention scores, whereas there was no change in those assigned to the high‐carbohydrate (50% of calories) diet (152). Additionally, the improvement in memory in those on the low‐carbohydrate diet was positively correlated with levels of urinary ketones (152). Finally, Henderson and colleagues treated 152 patients having mild‐to‐moderate AD daily with 20 g of MCT for 3 months, and found that MCT‐treated patients (lacking the APOE4 allele) achieved significantly higher ADAS‐cog (Alzheimer’s Disease Assessment Scale – cognitive subscale) scores at two different time‐points vs. placebo‐treated controls. Interestingly, post‐dose serum BHB levels correlated positively with improvement in ADAS‐Cog scores (153).
[...] Taken together, there are an increasing number of studies pointing to the neuroprotective benefits of the KD and its metabolic substrates.

Parkinson Disease
The hallmark neuropathological finding in PD is the degeneration of dopaminergic neurons in the substantia nigra. A main mechanism thought to contribute to this excitotoxic cell death is defects in complex I of the ETC (149). Hence, it follows that metabolism of ketone bodies may circumvent this deficit and allow for oxidative phosphorylation to occur possibly by enhancing the activity of complex II in the ETC (3).
[...]

Brain Cancer
Cancer cells are known to undergo dramatic metabolic alterations, including a preference for ATP production via glycolysis and enhanced lactic acid production, despite the presence of oxygen for oxidative phosphorylation (159). This shift in metabolism was first noted by Otto Warburg and was subsequently coined the “Warburg effect” (160). Defects in mitochondrial function resulting in diminished oxidative phosphorylation are thought to be main contributors to cancer cell metabolism. Since cancer cells preferentially use glucose for energy, and the KD reduces glycolytic flux and enhances oxidative metabolism, high‐fat KDs may represent potentially viable treatments to limit oncogenesis (161). Indeed, this conceptual approach was demonstrated in a compelling manner in a mouse astrocytoma model, indicating that plasma glucose is an accurate predictor of tumor growth more than the specific origin of dietary calories (162).
In a later study employing a mouse model of malignant glioma, the KD decreased tumor growth and improved survival, and this was associated with a reduction in tissue levels of ROS (163). Additionally, the KD induced gene expression changes in the tumor tissue to more closely resemble the pattern found in normal brain. Further, the KD also caused an up‐regulation of enzymes involved in oxidative stress resistance, such as glutathione peroxidase 7 and peroxiredoxin 4, in tumor tissue, but not normal specimens (163). The authors speculated that the effects of the KD are not just due to reductions in glucose, but alterations in cellular signaling pathways associated with enhanced homeostasis, and this leads to increased survival and reduced tumor growth.
[...]

Neurotrauma
Acute neurotrauma results in metabolic changes in the brain, including diminished glycolysis, and also activates excitotoxic and neuroinflammatory cascades (166, 167). In spite of the glycolytic restriction observed, the KD – through a multiplicity of other neuroprotective mechanisms – may counter the pathophysiological changes seen after traumatic brain injury (TBI). [...] Additionally, initiation of the KD four days before insulin‐induced hypoglycemia reduced neuronal death in rats (171). Further support for a metabolic approach toward TBI treatment is provided by Davis and colleagues (2008) who showed that fasting for 24 hours following controlled cortical impact in rats resulted in increased tissue sparing and improvements in mitochondrial function, and that these effects were a result of ketones and not hypoglycemia (172).

Amyotrophic Lateral Sclerosis
Mitochondrial dysfunction is also thought to contribute to the progression of ALS, a disease characterized by degeneration of motor neurons in the cortex and spinal cord (173). In ALS mice, the KD improved motor function, as evidenced by increased time to failure on rotorod performance and this was associated with preservation of motor neurons in the ventral horn of the spinal cord (174). In mitochondria isolated from the spinal cord of a transgenic mouse model of ALS (SOD1‐G93A), addition of BHB in vitro enhanced ATP production and this effect was maintained in the presence of the complex I inhibitor rotenone, but not the complex II inhibitor malonate (174). Additionally, the preservation of ATP levels by BHB was associated with increased neuronal survival in the presence of rotenone, but not malonate (174).

Pain and Inflammation
Multiple lines of experimental evidence suggest shared fundamental mechanisms responsible for chronic pain syndromes and epilepsy, particularly the involvement of cellular membrane‐bound ion channels (175). Specifically, both chronic pain and epilepsy are characterized by enhanced neuronal excitability, and whatever the relevant mechanisms may be, metabolic approaches toward treatment (e.g., the KD, inhibition of glycolysis through fasting or 2‐DG, etc.) can alleviate neuropathic pain (14, 176).

Other disorders
There are a number of other reports suggesting that the KD (or other dietary manipulations) can effectively treat diverse neurological disorders such as autism and migraine.

Summary
The KD is a broad‐spectrum therapy for multiple forms of epilepsy in both children and adults. The utility of the KD and variations of this diet for the treatment of a variety of neurodegenerative disorders suggests common central mechanisms that restore imbalances in energy metabolism (Figure 4). The numerous mechanisms known to partially mediate the effects of the KD (such as increases in FAO, reductions in glycolysis and an enhancement of the cellular responses to oxidative stress, etc.), indicate that manipulation of these specific pathways may represent an attractive paradigm for experimental therapeutics. Specifically, bioenergetic substrates and enzymes may be desirable drug targets for the treatment of many neurological diseases. Additionally, the signaling pathways that evolved to sense the cellular energetic state and provide resistance to metabolic stress may provide the best means to mimic the KD. Future research in this burgeoning area may lead to the elucidation of additional novel mechanisms that mediate the pleiotropic neuroprotective effects of the KD.

[References]
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I have considerably shortened the article, if you wish to read the full text, it can be downloaded here
 
Re: Ketogenic Diet - Path To Transformation?

The effects of a KD, even for a short duration, are pretty damn good. Sounds like skin benefits are just the beginning so congratulations Angela and M.T. :D

Minas Tirith said:
I had quite a stressful few weeks (also a reason why I couldn't post here), BUT felt much more resilient than before in similar situations. There was a lot of mental work to do, but, man, did I have the power! It wasn't a problem to concentrate for hours on end, drink a cup of buttered tea and concentrate more! And then do the same the next day. I am taking a second university degree and was much fitter than when I took my first (when I was twenty years younger :lol:).

There has been a serious improvement with my neck and shoulder tension in these situations (sitting on the computer a lot) as well. At first I didn't lose much weight, but intermittent fasting did the trick, by the way (only wanted to lose 5-6 kg that have been bothering me for a long time).

So, well, I wish, I had started this earlier!

M.T.
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And yeah, I feel the same about starting earlier with this. We're here now ;)

Does anyone have any idea concerning the effects of glucosamine and N-acetylglucosamine (NAG) on the ketogenic diet? They are amino sugars used widely for arthritic conditions and pain.

I have pelvic joint and sciatica-like pain and circulatory problems that cause trouble with sleep. I can toss and turn for hours (putting essential oils on my pillow has helped oddly) - the entire right side of my body from the chest down and left side from the chest upwards is relentless! I've got an ECG and X-rays booked for a closer look into what's up with this; wondering if there might are ascites and cardiovascular abnormalities in the mix.

So KD has helped reduce pains greatly. At the same time, I think it is something that needs time really to heal in a holistic sense. When I took NAG while in ketosis for a period, I put on ~2-3kg and upper left side of the body found relief from this (fractured left clavicle, thoracic/cervical issues, fractured right wrist mainly). Yet the chest down on right side and left pelvis - same as before. All these latter parts were spared.

Bone broth definitely helps! I think I may just have to do IF with just broth and copious amounts of fats - that's when my joints are best able to handle physical movements (can't comment on sleep, haven't kept a log of that) as opposed to higher protein intake, less broth etc.

MB wrote about broth's effectiveness in this regard on page 34, quoting from the book Deep Nutrition. Makes sense to me :)

Actually found partial answers on this thread about lectins too. The main query I have is about glucose metabolism vs. fat metabolism. They are metabolized differently in the body, as discussed in this thread.

This article discusses glucosamine and n-acetylglucosamine effects on carbohydrate metabolism (in rat liver).

Useless in a KD thread but follow me here: it concluded glucosamine and N-acetylglucosamine have an inhibitory effect on glucose metabolism. There is little to no studies that I have been able to find regarding fat metabolism, which occurs in the mitochrondria as opposed to the cytoplasm.

How are they used in the presence of ketone bodies, particularly if or when you contrast it with drinking bone broth, for example?

I got some Comfrey oil, which I will be testing out soon. After some digging, the Arthritis thread also came in handy; doing some successive reading on that and seeing what it can offer.

There is also the perplexing 'sulphur/sulphites' issue. Think I'll take a miss on that one in this post though.

So kind of extending my initial question here, anyone have any ideas, pointers or suggestions regarding any of this (even if it's redirecting me to a previous part of this thread)?

nicklebleu said:
Interesting article, burt not sure what to make of it:

Psychoneuroendocrinology. 2014 Jul;45:43-8. doi: 10.1016/j.psyneuen.2014.03.008. Epub 2014 Mar 28.

Rise of ketone bodies with psychosocial stress in normal weight men.

Kubera B1, Hubold C1, Wischnath H1, Zug S1, Peters A2.

Abstract
BACKGROUND:
Ketone bodies are known as alternative cerebral energy substrates to glucose. During psychosocial stress, the brain of a normal weight subject demands for extra glucose from the body to satisfy its increased needs. In contrast, the brain of an obese subject organizes its need, supply and demand in a low-reactive manner. The present study aimed at investigating (i) whether psychosocial stress increases ketone body concentrations and (ii) whether ketone reactivity to a psychosocial challenge differs between normal weight and obese people.
METHODS:
Ten normal weight and ten obese men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess serum β-hydroxybutyrate concentrations and stress hormone profiles.
RESULTS:
Our main finding was that social stress markedly increased concentrations of serum β-hydroxybutyrate by 454% in normal weight men. The increase in ketone bodies during stress in normal weight subjects was associated with an increase in ACTH, norepinephrine and epinephrine concentrations. Interestingly, we could not detect any increase in serum β-hydroxybutyrate concentrations during stress in obese men.
CONCLUSION:
Normal weight men showed high ketone reactivity to a psychosocial challenge.

Copyright © 2014 Elsevier Ltd. All rights reserved.
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Thanks for the article finds, nickelbleu! My guess would be obese men have higher stores of 'fat', or glycogen, that can be used for energy when psychosocial stress increases. It sounds almost too simple as a tentative conclusion though...

Hope I find some time to fully digest the article about neuroprotective effects of the ketogenic diet too!
 
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