Benefits Of A Ketone Ester Drink

Utility of a ketone ester drink, along with adequate glucose, in enhancing muscle glycogen synthesis is shown here, abstract:

INTRODUCTION:

Physical endurance can be limited by muscle glycogen stores, in that glycogen depletion markedly reduces external work. During carbohydrate restriction, the liver synthesises the ketone bodies, D-β-hydroxybutyrate and acetoacetate, from fatty acids. In animals and in the presence of glucose, D-β-hydroxybutyrate promotes insulin secretion and increases glycogen synthesis. Here we determined whether a dietary ketone ester, combined with plentiful glucose, can increase post-exercise glycogen synthesis in human skeletal muscle.

METHODS:

Following an interval-based glycogen-depletion exercise protocol, 12 well-trained male athletes completed a randomized, 3-arm, blinded crossover recovery study that consisted of consumption of either a taste-matched, zero-calorie control or a ketone monoester drink, followed by a 10 mM glucose clamp or saline infusion for two hours. The three post-exercise conditions were; control drink then saline infusion, control drink then hyperglycemic clamp or ketone ester drink then hyperglycemic clamp. Skeletal muscle glycogen content was determined in muscle biopsies of vastus lateralis taken before and after the two-hour clamps.

RESULTS:

The ketone ester drink increased blood D-β-hydroxybutyrate concentrations to a maximum of 5.3 vs. 0.7 mM for the control drink (p < 0.0001). During the two-hour glucose clamps, insulin levels were two-fold higher (31 vs. 16 mU/l, p < 0.01) and glucose uptake 32% faster (1.66 vs. 1.26 g/kg, p<0.001). The ketone drink increased by 61 g the total glucose infused over 2 h, from 197 g to 258 g, and muscle glycogen was 50% higher (246 vs.164 mmoles glycosyl units/kg dry weight, p < 0.05) than after the control drink.

CONCLUSION:

In the presence of constant high glucose concentrations, a ketone ester drink increased endogenous insulin levels, glucose uptake and muscle glycogen synthesis.

Ketogenic Diet And Resistance Training

From several years ago, we read this (abstract):

This study investigated the impact of an isocaloric and isonitrogenous ketogenic diet (KD) versus a traditional western diet (WD) on changes in body composition, performance, blood lipids, and hormonal profiles in resistance-trained athletes.

METHODS:

Twenty-five college aged men were divided into a KD or traditional WD from weeks 1-10, with a reintroduction of carbohydrates from weeks 10-11, while participating in a resistance-training program. Body composition, strength, power, and blood lipid profiles were determined at week 0, 10 and 11. A comprehensive metabolic panel and testosterone levels were also measured at weeks 0 and 11.

RESULTS:

Lean body mass (LBM) increased in both KD and WD groups (2.4% and 4.4%, p<0.01) at week 10. However, only the KD group showed an increase in LBM between weeks 10-11 (4.8%, p<0.0001). Finally, fat mass decreased in both the KD group (-2.2 kg ± 1.2 kg) and WD groups (- 1.5 ± 1.6 kg). Strength and power increased to the same extent in the WD and KD conditions from weeks 1-11. No changes in any serum lipid measures occurred from weeks 1-10, however a rapid reintroduction of carbohydrate from weeks 10-11 raised plasma TG levels in the KD group. Total testosterone increased significantly from Weeks 0-11 in the KD diet (118 ng/dl) as compared to the WD (-36 ng/dl) from pre to post while insulin did not change.

CONCLUSIONS:

The KD can be used in combination with resistance training to cause favorable changes in body composition, performance and hormonal profiles in resistance-trained males.

So, for young men on resistance training a ketogenic diet was as good or better than a traditional Western diet for lean body mass gains and hormonal profiles.

Additional Studies On Ketogenic Diets And Epilepsy

More information on ketogenic diets, abstract:

PURPOSE OF REVIEW:High-fat, low-carbohydrate ketogenic diets have been used for almost a century for the treatment of epilepsy. Used traditionally for the treatment of refractory pediatric epilepsies, in recent years the use of ketogenic diets has experienced a revival to include the treatment of adulthood epilepsies as well as conditions ranging from autism to chronic pain and cancer. Despite the ability of ketogenic diet therapy to suppress seizures refractory to antiepileptic drugs and reports of lasting seizure freedom, the underlying mechanisms are poorly understood. This review explores new insights into mechanisms mobilized by ketogenic diet therapies.RECENT FINDINGS:Ketogenic diets act through a combination of mechanisms, which are linked to the effects of ketones and glucose restriction, and to interactions with receptors, channels, and metabolic enzymes. Decanoic acid, a component of medium-chain triclycerides, contributes to seizure control through direct α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition, whereas drugs targeting lactate dehydrogenase reduce seizures through inhibition of a metabolic pathway. Ketogenic diet therapy also affects DNA methylation, a novel epigenetic mechanism of the diet.SUMMARY:Ketogenic diet therapy combines several beneficial mechanisms that provide broad benefits for the treatment of epilepsy with the potential to not only suppress seizures but also to modify the course of the epilepsy.

Epileptic patients may wish to  discuss these findings with their physician to determine whether dietary modifications may be of use in their own case.

Warburg Effect And Some Possible Cancer Treatments

The Warburg effect is important in cancer, since cancer cells rely more heavily than do normal cells on glycolysis for energy production.  This may point at therapies targeting this effect for patient benefit.  A paper is here, abstract:

As stated by Otto Warburg nearly a century ago, cancer is a metabolic disease, a fermentation caused by malfunctioning mitochondria, resulting in increased anabolism and decreased catabolism. Treatment should, therefore, aim at restoring the energy yield. To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models. This treatment, in combination with conventional chemotherapy, has yielded extremely encouraging results in glioblastoma, brain metastasis and lung cancer. Randomized trials are necessary to confirm these preliminary data. The major limitation is the fact that the combination of α-lipoic acid and hydroxycitrate can only be effective if the mitochondria are still present and/or functional. That may not be the case in the most aggressive tumors. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Concomitant correction of this alkalosis may be a very effective treatment in case of mitochondrial failure.

Note that a ketogenic diet is considered one mechanism whereby the Warburg effect can be leveraged for anti-cancer treatment.

Cancer Stem Cells And Lipid Metabolism

Cancer stem cells seem to have an increased reliance on lipid metabolism, which can be a target for anti-cancer therapy.  I wonder if this has any implications for a ketogenic (high-fat) diet for cancer?  On the one hand, most cancer cells seem “glucose-addicted” so a low-carb, high-fat diet may be preferable.  On the other hand, if cancer stem cells rely more on fat, then will increased dietary fat be a problem?  This question needs to be investigated.  Abstract:

BACKGROUND:

Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a small population of cancer cells with self-renewal and tumor-initiating properties. Unlike the bulk of tumor cells, CSCs or TICs are refractory to traditional therapy and are responsible for relapse or disease recurrence in cancer patients. Stem cells have distinct metabolic properties compared to differentiated cells, and metabolic rewiring contributes to self-renewal and stemness maintenance in CSCs.

MAIN BODY:

Recent advances in metabolomic detection, particularly in hyperspectral-stimulated raman scattering microscopy, have expanded our knowledge of the contribution of lipid metabolism to the generation and maintenance of CSCs. Alterations in lipid uptake, de novo lipogenesis, lipid droplets, lipid desaturation, and fatty acid oxidation are all clearly implicated in CSCs regulation. Alterations on lipid metabolism not only satisfies the energy demands and biomass production of CSCs, but also contributes to the activation of several important oncogenic signaling pathways, including Wnt/β-catenin and Hippo/YAP signaling. In this review, we summarize the current progress in this attractive field and describe some recent therapeutic agents specifically targeting CSCs based on their modulation of lipid metabolism.

CONCLUSION:

Increased reliance on lipid metabolism makes it a promising therapeutic strategy to eliminate CSCs. Targeting key players of fatty acids metabolism shows promising to anti-CSCs and tumor prevention effects.

Low Carb Ironman Training?

One possible way to overcome carbohydrate (carb) storage limitations for extreme duration athletic events like Ironman triathlons is for the athlete to train under a low-carb diet, to get the body acclimated to that condition, and then giving carb supplementation during the completion, providing the levels that the now-adjusted body can utilize.  Keep in mind that another study, looking at elite race walkers (somewhat less extreme that the Ironman) found that low carb diets were negative for performance.  So the current finding (abstract below) may apply only to the most extreme events where “carb loading is inefficient?  More study is required.

Ironman triathlons are ultra-endurance events of extreme duration. The performance level of those competing varies dramatically, with elite competitors finishing in ~ 8:00:00, and lower performing amateurs finishing in ~ 14-15:00:00. When applying appropriate values for swimming, cycling and running economies to these performance times, it is demonstrated that the absolute energy cost of these events is high, and the rate of energy expenditure increases in proportion with the athlete's competitive level. Given the finite human capacity for endogenous carbohydrate storage, minimising the endogenous carbohydrate cost associated with performing exercise at competitive intensities should be a goal of Ironman preparation. A range of strategies exist that may help to achieve this goal, including, but not limited to, adoption of a low-carbohydrate diet, exogenous carbohydrate supplementation and periodised training with low carbohydrate availability. Given the diverse metabolic stimuli evoked by Ironman triathlons at different performance levels, it is proposed that the performance level of the Ironman triathlete is considered when adopting metabolic strategies to minimise the endogenous carbohydrate cost associated with exercise at competitive intensities. Specifically, periodised training with low carbohydrate availability combined with exogenous carbohydrate supplementation during competition might be most appropriate for elite and top-amateur Ironman triathletes who elicit very high rates of energy expenditure. Conversely, the adoption of a low-carbohydrate or ketogenic diet might be appropriate for some lower performance amateurs (> 12 h), in whom associated high rates of fat oxidation may be almost completely sufficient to match the energy demands required.

Fad Diets Not Necessary

More support for the ides that “fad” diets – like low carb – are not necessary for weight control and dealing with metabolic syndrome. Take home point: “any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes.”  Abstract:

In the past, different types of diet with a generally low-carbohydrate content (< 50-< 20 g/day) have been promoted, for weight loss and diabetes, and the effectiveness of a very low dietary carbohydrate content has always been a matter of debate. A significant reduction in the amount of carbohydrates in the diet is usually accompanied by an increase in the amount of fat and to a lesser extent, also protein. Accordingly, using the term "low carb-high fat" (LCHF) diet is most appropriate. Low/very low intakes of carbohydrate food sources may impact on overall diet quality and long-term effects of such drastic diet changes remain at present unknown. This narrative review highlights recent metabolic and clinical outcomes of studies as well as practical feasibility of low LCHF diets. A few relevant observations are as follows: (1) any diet type resulting in reduced energy intake will result in weight loss and related favorable metabolic and functional changes; (2) short-term LCHF studies show both favorable and less desirable effects; (3) sustained adherence to a ketogenic LCHF diet appears to be difficult. A non-ketogenic diet supplying 100-150 g carbohydrate/day, under good control, may be more practical. (4) There is lack of data supporting long-term efficacy, safety and health benefits of LCHF diets. Any recommendation should be judged in this light. (5) Lifestyle intervention in people at high risk of developing type 2 diabetes, while maintaining a relative carbohydrate-rich diet, results in long-term prevention of progression to type 2 diabetes and is generally seen as safe.

Body Composition And Diet

Protein shake on left.  By Sandstein - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=6068429

Here’s an article on body composition and diet.  Note that points 4 and 6 are consistent with mainstream bodybuilding advice, which is reassuring because many people have been following that advice (but note that diets very high in protein can be rough on the kidneys over time, so caveat emptor. Points 1-3 are consistent with common sense (also reassuring).  Point 5 should also be common sense, but is a necessary antidote to those who fixate that their particular form of dieting is “best for everyone” rather than just best for them.  Point 7 falls into the same boat; both methods (intermittent vs daily caloric restriction) can be useful for folks who want to lose weight. Point 8 makes sense – dietary success may depend on mitigating the adaption of the body to the diet, and point 9 is that more study is required. Abstract:

Position Statement: The International Society of Sports Nutrition (ISSN) bases the following position stand on a critical analysis of the literature regarding the effects of diet types (macronutrient composition; eating styles) and their influence on body composition. The ISSN has concluded the following. 1) There is a multitude of diet types and eating styles, whereby numerous subtypes fall under each major dietary archetype. 2) All body composition assessment methods have strengths and limitations. 3) Diets primarily focused on fat loss are driven by a sustained caloric deficit. The higher the baseline body fat level, the more aggressively the caloric deficit may be imposed. Slower rates of weight loss can better preserve lean mass (LM) in leaner subjects. 4) Diets focused primarily on accruing LM are driven by a sustained caloric surplus to facilitate anabolic processes and support increasing resistance-training demands. The composition and magnitude of the surplus, as well as training status of the subjects can influence the nature of the gains. 5) A wide range of dietary approaches (low-fat to low-carbohydrate/ketogenic, and all points between) can be similarly effective for improving body composition. 6) Increasing dietary protein to levels significantly beyond current recommendations for athletic populations may result in improved body composition. Higher protein intakes (2.3-3.1 g/kg FFM) may be required to maximize muscle retention in lean, resistance-trained subjects under hypocaloric conditions. Emerging research on very high protein intakes (>3 g/kg) has demonstrated that the known thermic, satiating, and LM-preserving effects of dietary protein might be amplified in resistance-training subjects. 7) The collective body of intermittent caloric restriction research demonstrates no significant advantage over daily caloric restriction for improving body composition. 8) The long-term success of a diet depends upon compliance and suppression or circumvention of mitigating factors such as adaptive thermogenesis. 9) There is a paucity of research on women and older populations, as well as a wide range of untapped permutations of feeding frequency and macronutrient distribution at various energetic balances combined with training. Behavioral and lifestyle modification strategies are still poorly researched areas of weight management.

Travis Christofferson, Mercola, and reductionism

I have recently discussed a troubling trend among scientists and people who pretend to understand science.

This is the trend to make definitive statements about cancer cure that are based upon reductionism.

Reductionism at its extreme has recently focused on the metabolism of cancer cells as the ONLY defining characteristic of this type of cells.

Travis Christofferson, the author of the book Tripping Over the Truth: The Return of the Metabolic Theory of Cancer Illuminates a New and Hopeful Path to a Cure, emphasized on this metabolic feature during his interview with Dr. Mercola.

If you listen carefully to this interview (or read the transcript, as I did), you will hear the revelation of Mr. Christofferson that he looked at The Cancer Genome Atlas and observed that every cancer patient had different mutations; therefore, mutations were NOT the reason for the abnormal behavior of the cancer cells.

It is unfortunate that such a nonsense can be perceived as a nonsense only if you have a Ph.D.  So, everyone else who reads the book or listens to the interview would be impressed by this "discovery".
 
Dear Mr. Christofferson, fortunately, I have a Ph.D. and I would like to tell you that:

1. Not all mutations contribute to the proliferative potential of cancer cells. Only 3 to 5 mutations usually do so. These mutations are called "driver" mutations; whereas, the ones that do not matter are called "passenger" mutations. Passenger mutations may occur at any gene, but remember - they are irrelevant to the malignant development.

2. If you examine the driver gene mutations within specific categories of cancer, you would notice that the same genes are mutated over and over again in different patients. APC for example, is mutated in almost 80% of all colon cancer patients. Is this a coincidence?

3. The mutation diversity that you "discovered" is somewhat deceptive, since several different gene mutations can contribute to the same outcome in the cells. Usually these are genes the products of which participate in the same signaling pathways. Example: EGFR, the RAF genes, and the RAS genes participate in the same downstream signaling pathway. Therefore, seemingly diverse mutations in fact impact very few signaling pathways in the cancer cells.

4. You claim that some cancers did not have a single mutation. Well, did you examine the epigenetic and expression data for such cancers? Do you know that cancer can arise based upon changes at these additional regulation levels of gene activity?

In summary, please do not reduce the complexity of cancer to its metabolism. Yes, the metabolism of cancer cells is different, and every difference between cancer and normal cells should be exploited in cancer treatment. 

However, reductionism has not brought full victory over any disease in the past. 

I do believe that every patient who has been diagnosed with cancer should immediately switch to ketogenic diet. However, this diet should be combined with other cancer treatments. Ketogenic diet alone would not cure anyone from cancer. 

The same stubborn absurdity and reductionism is exemplified by our mainstream oncologists: they hold on to their old tools of chemo and radiation, and at the same time serve juice, doughnuts and ice cream to the patients (I guess to fortify the cancer cells against the chemo/radiation?!). 

Diet and cancer, again

The wording in the video is not quite scientific; however, the message is true. Watch if you or someone around you has cancer:  The Ketogenic Diet and Cancer. 
I have previously written about the benefits of both, ketogenic diet and intermittent fasting.

Mediterranean Diet, Hunger and Cancer

Evolutionary, our ancestors were able to survive on one daily meal, but sometimes went hungry for days.  Today, however, most Americans consume three meals a day with additional snacks. The notion that many small meals a day is healthy is being popularized; however, epidemiological studies have reported that a lesser number of eating episodes is associated with a reduced risk of colon cancer and other types of cancer.  Consistent with these results, rodent studies, controlled for caloric intake, have revealed that longer intervals between meals increase resistance to cancer.

Periods of strictly vegetarian diet and fasting are incorporated in many religious traditions.  For example, throughout the year, the Eastern Orthodox calendar includes 180 days of fasting, during which vegetarian days alternate with periods of complete abstinence from food. Thus, a strict Orthodox Christian observes the following weekly fasting rules: only one vegetarian meal on Wednesdays and no food on Fridays. In addition, there are prolonged periods of fasting during the year: the three main ones being the forty days before Christmas, Lent (40-48 days) and the Assumption (15 days).   According to the rules of these fasts, any meat and meat products, eggs, dairy products, fish, oil, and wine are excluded from the diet, although fish, wine, and oil are allowed on certain days of the week.  Interspersed within the long fasting periods are days or even weeks of complete abstinence from food (e.g., the week before Easter, Holy Week).  

Interestingly, this Orthodox Christian fasting regimen has been proposed as an alternative explanation for the health benefits of the Greek Mediterranean diet. Thus, the Mediterranean diet is not only rich in fiber (grains, vegetables and fruit) and olive oil, but it is accompanied by periods of fasting that might be beneficial by slowing down tumor cell growth and preventing cancer.  

The slowing of abnormal cell growth by fasting could be mediated by the changes in metabolism. What are these changes? Fasting forces the body to switch from one source of energy (carbohydrates, such as glucose), to another – fats.  According to metabolite studies, the glucose from the blood and its storage (glycogen, which is simply a chain of many glucose molecules) is utilized within the first 12 hours of complete fast. On day 2 of the fast, the body already relies on processing of fats (from the adipose tissues) to ketones as a source of energy. Does this major shift in metabolism explain the protective effect of fasting against cancer? Likely, yes. It has been long known that some cancer cells are addicted to sugar (glucose) as a source of energy; now we know that many human cancers exhibit this behavior.  

Such abnormal cells have an excess of glucose receptors on their surface, and therefore, “devour” more glucose from the blood than normal cells. Additional mechanisms also force cancer cells to rely mostly on glucose as their source of energy. Because of this dependence on glucose, the depletion of glucose (as in fasting) can result in the death of the tumor cells. Furthermore, in all cancer cells the depletion of glucose is likely to suppress all signaling pathways that support survival.

In 1921, Dr. Wilder proposed that the effects of fasting on the body could be mimicked by a diet, in which fat was the main component, the ketogenic diet. This diet consists mostly of fat; thus, the ratio of fat : protein : carbohydrate in this diet is close to 90 : 8 : 2. With this diet, the organism uses fat as its main source of energy and forms ketones the same way these compounds are produced during fasting. However, whereas in fasting the body uses its own fat storage to cope with the lack of other energy sources, during the ketogenic diet, exogenous (external) fat from the food is being processed. This difference between fasting and ketogenic diet results in very different levels of LDL cholesterol: fasting individuals compared to controls present with 12.5% lower end-total cholesterol (p < 0.001) and 15.9% lower end-LDL cholesterol (p< 0.001). Therefore, be aware that during ketogenic diet the levels of cholesterol skyrocket, and this is obviously not good for the long-term health outcomes.

Despite the ability of the fasting regimen and ketogenic diet to suppress tumor growth, the cancer therapeutic application of these approaches is limited in the U.S. These modalities are mostly applied as adjuvant (complimentary) modalities to mainstream cancer treatments. One reason to shy away from these approaches is that our medical doctors are not taught about them, and therefore, nor aware of them.

Here I did not discuss the benefits of fasting in reducing obesity and the obesity-related metabolic syndrome with its downstream consequences (e.g., cardiovascular diseases, type 2 diabetes, etc.). I also neglected to discuss the additional benefits of Mediterranean diet to human health. Hopefully, these will be subjects of future posts.

Actionables

It has been proposed that limiting the food and drink intake to 6-10 hours a day may have the same benefits as any longer-term fasting regimen. In practice, this means that one could fast  from early dinner till late breakfast next day, or skip breakfast or dinner. 

PS:
A later post also explores this topic.