Ketosis is the physiological state where the concentration of ketone bodies in the blood is higher than normal. This is generally agreed to be at beta-hydroxybutyrate (BHB) concentrations greater than 0.5 mM.
Ketosis occurs either as a result of increased fat oxidation, whilst fasting or following a strict ketosis diet plan (ENDOGENOUS ketosis), or after consuming a ketone supplement (EXOGENOUS ketosis). When in a state of ketosis the body can use ketones to provide a fuel for cellular respiration instead of its usual substrates: carbohydrate, fat or protein.
Normally, the body breaks down carbohydrates, fat, and (sometimes) proteins to provide energy. When carbohydrate is consumed in the diet, some is used immediately to maintain blood glucose levels, and the rest is stored. The hormone that signals to cells to store carbohydrate is insulin. The liver stores carbohydrate as glycogen, this is broken down and released between meals to keep blood glucose levels constant. Muscles also store glycogen, when broken down this provides fuel for exercise. Most cells in the body can switch readily between using carbohydrates and fat as fuel. Fuel used depends on substrate availability, on the energy demands of the cell and other neural and hormonal signals.
The brain is different as it is dependent on carbohydrates as a fuel source. This is because fats cannot easily cross the blood-brain barrier. The inability to make use of energy within fat poses a problem during periods where there is limited carbohydrate in the diet. If blood glucose levels fall to low, brain function declines. Relatively little energy is stored as carbohydrate (2,000 kCal) compared to fat (150,000 kCal). The body's store of carbohydrates runs out with a few days of carbohydrate restriction. Once glycogen is depleted, a cascade of hormonal signals causes the body to increase the release of stored fats (from adipose tissue). Signals include the fall in blood insulin, rise in a hormone called glucagon and an increase in cortisol (stress hormone) 1. The increase in blood fatty acids is a key trigger for ketone production (ketogenesis). Unlike fats, ketones are readily used as a fuel in the brain. Fatty acids are converted into ketone bodies in the liver, and ketones can provide up to 60% of the brain's energy requirements during starvation 2. The graph below shows how BHB (black triangles) builds up in the blood over many days until it reaches a level of around 6 mM.
Ketone metabolism evolved to convert fat into energy for the brain when carbohydrate (glycogen) levels are low. This adaptation ensured that prehistoric man could survive periods of fasting and carbohydrate deprivation3.
Some of the benefits of ketosis occur due to the restriction of dietary carbohydrate. Others occur due to the presence of ketones in the blood. Two of the most commonly sought after effects are weight-loss and improved insulin sensitivity. These are conferred by the low carbohydrate content of the diet allowing increased fat burning and the gradual restoration of insulin sensitivity. In this article we discuss the basics of ketone production and metabolism, and some of the many ways that KETONES themselves (endogenous AND exogenous) can benefit health and performance.
Ketogenesis is the pathway that forms ketone bodies from fatty acids. Starvation (specifically low levels of blood insulin and glucose) triggers ketogenesis in the liver cells’ mitochondria. Two molecules of acetyl-CoA from the breakdown of fatty acids are condensed via acetyl-CoA transferase to form acetoacetyl-CoA; a third is added to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) in a reaction catalysed by HMG-CoA synthase. HMG-CoA lyase then splits this to re-generate acetyl-CoA and form one molecule of AcAc. Beta-hydroxybutyrate (BHB) is formed from reduction of AcAc by BHB-dehydrogenase enzyme, and acetone results from spontaneous, non-enzymatic decarboxylation of AcAc. Acetone is a volatile molecule which is primarily excreted in the breath, although some evidence suggests that a small amount can be metabolised and oxidised4.
BHB is the main circulating ketone body, although acetoacetate is also present in the blood at lower amounts. BHB is taken up by cells through a transporter called the monocarboxylate transporter, which is widely expressed throughout the body 5.
Ketolysis is the process of breaking down ketones to ultimately provide energy through the Krebs Cycle and mitochondrial oxidative (using oxygen) phosphorylation. Ketone bodies are broken down in the mitochondria of virtually all tissues in the body. The liver is a notable exception, being unable to utilise ketones as a fuel because liver cells lack acetyl-CoA thiolase, a key enzyme in the ketone oxidative pathway. BHB enters the mitochondria of the cell through a monocarboxylate transporter, undergoes conversion to acetoacetate by BHB dehydrogenase and then addition of a CoA group from succinyl-CoA by 3-oxo-acid transferase. The resulting acetoacetyl-CoA acts a substrate for the formation of two molecules of acetyl-CoA in a reaction catalysed by acetyl-CoA thiolase. Acetyl-CoA is then available to condense with oxaloacetate and enter the Krebs cycle.
Our body is driven by a series of controlled chemical reactions, resulting in the oxidation of carbon fuels (such as ketones, carbohydrate and fat) to water and carbon dioxide. The energy from these reactions is stored in a molecule called ATP.
For a given quantity of fuel, the maximum amount of work that can be obtained from that fuel in a closed system is called ‘the Gibbs free energy’ (G). This takes into account the inherent ‘heat’ (combustion enthalpy (H)) and a property called entropy (a measure of tendency towards ‘disorder’ (S). The change in Gibbs free energy (∆G) is related to the change in combustion enthalpy (∆H), change in entropy (∆S) and the temperature (T):
∆G = ∆H - T∆S
Therefore the combustion enthalpy (∆H) of each fuel is an important factor in the energy it can provide to the cell. When expressed as the energy per 2 carbons in the molecule, ketones (BHB) have a higher combustion enthalpy (∆H) than pyruvate, lactate and glucose (see table). This means that the amount of energy that could possibly be transferred to ATP is higher than for those other substrates:
From Veech et al6.
In order to best investigate the efficiency of different fuels, one needs a closed system, where the substrate conditions can be changed and the oxygen consumption and work done can be accurately measured. Isolated (ex-vivo) animal hearts are the best model to study these variables, as it is easy to manipulate the fuel provided (i.e glucose, ketones), to measure the oxygen use and also the amount of work (how much fluid is pumped).
A 1995 research study compared the energy metabolism in the heart under different conditions aiming to better understand ketone metabolism7:
The results showed that adding insulin (Gl, I) load increased both cardiac output and hydraulic work (although only significant in the case of hydraulic work). Adding ketones (Gl, K) increased both cardiac output and hydraulic work significantly. Combining insulin and ketones with glucose (Gl, I, K) increased neither measure.
Oxygen consumption was significantly reduced in (Gl, I) (G, K) and (Gl, I, K) relative to (G). This means that efficiency was increased in these conditions (by ~28%) because for less oxygen consumption, the hearts delivered greater cardiac output and greater hydraulic work.
The investigators found that this was because ketone metabolism resulted in greater “free energy per ATP molecule” (G). ATP is adenosine triphosphate and is the "energy currency" of biology. The “free energy” (∆G) of ATP represents how much potential energy is stored in each ATP molecule, and this value can shift slightly depending on the conditions inside the cell. The more negative the value of the ‘free energy’ of ATP, the more potential to do work the ATP molecule has.
As an analogy, a tennis ball at the top of Mount Everest has more stored potential energy than the same ball at sea level. Whilst the absolute NUMBER of ATP produced per molecule of ketone oxidised and per oxygen required is fixed, the GREATER FREE ENERGY (potential energy) within the resulting ATP increases the cell’s capacity to do work.
Other factors that mean that ketones are a favourable energy substrate for the cell are:
This method directly measures the amount of blood BHB that is present, either from endogenous production or after consuming exogenous ketones.
The handheld devices that are available for home testing (such as FreeStyle by Abbott, or KetoMojo) require a small droplet of blood (obtained by a finger prick with a lancet) to be placed on a testing strip. A new testing strip must be used each time a reading is taken. The machine delivers a numerical blood BHB measurement in the unit milli molar (mM) after ~8 seconds.
When the kidneys filter blood, metabolic substrates such as glucose and ketones are re-absorbed to prevent energy wastage. If blood levels of a metabolite exceed the capacity of the kidney to reabsorb them, then a ‘spillover’ effect occurs and the metabolite (i.e. glucose or ketones) appear in the urine. However, urine is not a very reliable measure. Firstly, whilst following a ketogenic diet, adaptation occurs over time that means more ketones are reabsorbed in comparison to the early phase of the diet9. Furthermore, at higher levels of ketones, the appearance in the urine does not correlate to levels in the blood10. Similarly, after consumption of exogenous ketones, urine ketone levels were not in proportion to the levels in the blood11 this may be because of the rapid onset of ketosis in comparison to when ketosis is achieved with fasting or diet. Therefore urine test strips are useful as a guide but have several disadvantages to their use to accurately quantify levels of ketosis.
In order to measure urine ketone levels, you urinate onto the strip and wait for a few seconds for the strip to change colour, indicating the levels of ketones (acetic acid) present in the urine. There isn’t an exact reading given. Usually a dark purple colour corresponds to higher levels of ketones present.
Acetone is a molecule that results from the breakdown of acetoacetate. Acetone is commonly referred to as a ‘waste product’ as it is less readily used as energy compared to BHB (although some studies have shown that acetone can be oxidised as a fuel4. That said, some evidence suggests that it is responsible for the antiseizure effects of ketogenic diets so in may not be completely inert. At low levels acetone in the breath corresponds well to levels of ketones in the blood 12,13, however this is not the case as blood BHB levels increase 13 and if the increase is rapid, such as with exogenous ketone consumption11.
Measuring breath acetone requires the one off purchase of a specialised handheld device. The reading is given in parts per million (ppm) of acetone.
Historically, nutrition guidelines for athletes have focussed heavily on ensuring adequate dietary carbohydrate intake to provide a fuel for exercise. This is because:
More recently a community of researchers and athletes have emerged who feel that following a ketogenic diet offers a performance advantage, especially to endurance sports where athletes are more likely to run out of stored carbohydrate during the event. However the evidence remains inconclusive and research is ongoing to provide a definitive answer to as to if a ketogenic diet offers a performance advantage.
The advantages of the ketogenic diet for athletes are:
The disadvantages of the ketogenic diet for athletes are:
Notably, it can take several months to become fully ‘keto-adapted’ and performance can decline in the short term as these adaptations occur. It is also likely that individual responses to the diet vary. These factors make design and interpretation of sports science studies challenging and leave the door open for continued disagreement between scientists on each side of the debate. If you want to find out what each side has to say, we would recommend reading the comprehensive reviews by Louise Burke (who dislikes the use of the ketogenic diet)27 and Volek and Phinney (who promote the use of ketogenic diet)28.
If you are an athlete attempting to follow a ketogenic diet, experienced practitioners make the following recommendations to maximise chances of success29:
A good resource if you are an athlete looking to experiment with the ketogenic diet, The Art and Science of Low Carbohydrate Performance by Volek and Phinney. It is a small book that is a highly readable source of information from the experts in the field.
To conclude, athletes may consider adopting a ketogenic diet in the hope of improving endurance, well being and body composition but unless the diet is well formulated they risk causing fatigue, under fuelling and ultimately compromising performance. There is currently insufficient scientific research to definitively support the use of ketogenic diet for athletes to improve performance, although beneficial effects on fat oxidation, body composition and well-being have been described. However, the anecdotal reports of success and the increasing number of pro and elite athletes claiming to be experimenting with the ketogenic diet is compelling. Furthermore, people who are training and competing at a sub elite level may have a greater net benefit from the effects of the diet on recovery, wellness and body composition that may outweigh the loss of top end power resulting from the diet. Finally, it is unknown if there would be a beneficial effect of following the ketogenic diet but adding in strategic carbohydrate refeeds around more intense training and competition periods. Given the popularity of the ketogenic diet, one hopes these questions will be addressed in the near future.
Many athletes would not consider following a ketogenic diets due to the limited evidence of a performance enhancing effect, the risk of side effects having a negative impact on performance and the difficulty in maintaining the lifestyle changes required to stay in ketosis. Exogenous ketones offer a method to deliver some of the benefits of ketone metabolism without requiring athletes to follow a strict ketogenic diet. Taking exogenous ketones creates a metabolic state that would not normally occur naturally: the state of having full carbohydrate stores as well as elevated ketones.
Studies have revealed manifold potentially beneficial effects of exogenous ketone on exercise physiology:
However, this is still a relatively new field of research and there are many questions to be answered in order to understand how best to use exogenous ketone supplements.
With the recent research findings, and the increasing availability of exogenous ketones, it is unsurprising that some authors have said (with a hint of skepticism) that they “could be the next magic bullet’ for athletes39. More research is required to understand the best use cases, doseage protocols, compounds etc, however it is clear that exogenous ketones are a new ‘tool’ in the athlete’s arsenal that can be used to provide an alternative, energetically favourable fuel source without needing dietary manipulation.
Although glucose is the primary cerebral metabolic substrate for adults under normal conditions, ketone bodies (β-hydroxybutyrate, BHB and acetoacetate, AcAc) are the only other endogenously circulating substrates that can contribute significantly to cerebral metabolism. Ketone metabolism offers these advantages:
Many neurological conditions share a common feature of impaired brain energy metabolism. It isn’t always clear if this impairment is the cause or the effect of the disease, but nonetheless, interventions that even partially restore or improve brain energy metabolism could help to prevent, slow or even reverse some conditions of the brain. Because ketones can: 1) get into the brain; 2) undergo metabolism by a distinct pathway that bypasses glucose metabolism, providing ketones by either following a ketogenic diet or by taking exogenous ketones could impact the natural course of some neurological conditions.
Ketones may also have effects in neurons beyond their use as an energy source. Preliminary work shows ketones can affect neurotransmitter release, reduce inflammation in the brain and reduce damage caused by oxidative stress8. Whilst the strength of the clinical evidence supporting the use of ketosis varies according to the condition, future work should look to explore the efficacy and underlying mechanisms further. Ketosis (by diet or by exogenous ketones) could offer an intervention that has good efficacy, but without the side effects profile of many drugs currently in use. It should be noted that the use of ketogenic diet or exogenous ketones in the conditions discussed below is still classified as ‘experimental’ in the most part and so individuals should not their alter medication or diet without full medical supervision.
The term ‘epilepsy’ covers a broad range of disorders characterised by recurrent seizures. Seizures are physical manifestations of abnormal and chaotic neuronal activity. The cause of most cases of epilepsy are unknown, but are thought to involve:
In some cases epilepsy cannot be treated successfully using anticonvulsant medications. In some cases where drugs have failed, the ketogenic diet has been widely documented to deliver transformative seizure control, reducing frequency by anywhere between 40-90%43. Whilst the exact mechanisms underlying the beneficial effect of the ketogenic diet are unclear, the hypothesised mechanisms include:
Whilst the diet is broadly acknowledged to be safe strategy where medications have failed, side effects such as kidney stones, hyperlipidemia and can occur47. Furthermore, maintaining dietary adherence in young school age children can be very challenging for caregivers. Exogenous ketones may be an alternative or a adjunct to the ketogenic diet in epilepsy. Early work suggests that exogenous ketones could have antiseizure effects. Injection of the ketones acetoacetate and acetone have been found to have anticonvulsant properties in animal models48, and an acetoacetate diester was found to protect against seizures in rats exposed to high levels of oxygen49. Further studies are required to understand specifically how ketone bodies affect seizure control, however for children who experience daily seizures a combination of the ketogenic diet and exogenous ketones could be helpful to manage their condition.
In Alzheimer’s disease (AD), the function of the brain is compromised by the buildup of debris (plaques and tangles) inside the neurons. This mainly occurs in the areas of the brain associated with memory, intelligence, judgement, behaviour and language and impairs the ability to complete normal day to day tasks and to interact socially. Whilst the symptoms of AD usually only begin to appear with age, evidence suggests that damage to the brain begins to accumulate years earlier. This includes the buildup of plaques and tangles and a decreased ability to metabolise glucose (brain insulin insensitivity)50. If an individual has Type 2 Diabetes (systemic insulin insensitivity), the risk of AD is tenfold higher51.
As ketones are the only other metabolic substrate that can fuel the brain, there is a compelling mechanism whereby ketosis could improve brain energy metabolism and therefore improve symptoms of AD. Despite a declining ability of the brain to use glucose, cerebral ketone metabolism is preserved in AD (Castellano2015). This means that ketosis could be used to prevent an energy deficit in the brain. Another possibility is that ketone metabolism decreases mitochondrial damage caused by oxidative stress in the brain52. Individuals with AD tend to have increased mitochondrial oxidative stress, which can worsen brain energy production and increase plaque and tangle formation53.
Clinical trials of various ketogenic agents have shown promising outcomes in AD. Recently, a case report was published describing a dramatic improvement in cognitive function in a patient consuming daily drinks of a ketone ester of beta-hydroxybutyrate-butanediol54. This corroborates evidence from animal studies of AD, which showed behavioural and anatomical improvements in AD mice treated with the same ketone ester55. Also, medical foods containing medium chain triglycerides can give an acute improvement in cognitive scores in AD patients 56 ,57. The effectiveness of this treatment was found to depend on the absence of a gene variant that has been associated to increased chance of AD, called APOE4. Finally, following a ketogenic diet for 6 weeks improved the symptoms of mild cognitive impairment58. It is still early days, but the use of ketogenic diets and exogenous ketones may help to improve the quality of life of patients with dementia and their caregivers.
Parkinson’s disease (PD) is caused by death of neurons in a region of the brain called the ‘substantia nigra.’ As well as loss of neurons, those that survive accumulate misfolded proteins called “Lewy Bodies,” exhibit increased inflammation and impaired mitochondrial function. PD is most common in individuals over the age of 60 and is primarily characterised by poor control of movement (shaking, rigidity etc). Neuronal death leads to decreased levels of a neurotransmitter called dopamine, which is a key factor in the deterioration of motor function. Current treatments for PD centre on replacing dopamine using a drug called L-DOPA, which is a precursor to dopamine. This drug treats the symptoms of PD but not the underlying cause.
One hypothesised contributor to neuronal death is insufficient energy production, secondary to impaired mitochondrial function. However, it is unclear if this is in fact a cause or effect of PD. Whatever the case may be, patients with PD have been shown to have impaired mitochondrial energy production in the brain59 and lower brain glucose utilisation60. Another factor may be neuro-inflammation, which is also common in PD, and is thought to lead to further accumulation of Lewy Bodies and neuronal death.
Ketosis could benefit patients with PD, as ketones provide an alternative energy source to the brain and also have antiinflammatory effects. Several research groups have shown that the ketogenic diet can have manifold beneficial effects in animal models of PD: alleviating motor symptoms, reducing inflammation, decreasing neuronal loss 61 ,62. Also, an in vitro model of PD (neurons in culture treated with a drug called MPTP) was used to demonstrate that addition of 4 mM of BHB was protective against neurodegeneration52. An early study of the ketogenic diet in PD patients reported very promising results: patients improved their clinical PD ‘score,’ as classified by factors including tremor, balance and mood 63. Whilst there are promising results, further clinical studies are required to demonstrate if the ketogenic diet or exogenous ketones (either alone or in combination) are a tolerable and efficacious intervention for PD.
Concussion (a mild form of TBI), is defined as a short term impairment of brain function caused by impact. Symptoms include dizziness, confusion and headache. When the brain suffers a concussive impact this triggers an acute cascade of cellular events that can eventually cause chronic problems. Firstly, immediately after impact there are changes to the concentrations of ions and neurotransmitters in and outside of the neurones. For example, the cells release potassium and glutamate (excitatory neurotransmitter); this can cause neuronal damage instantly64. The disruption to the equilibrium of substances within the brain must be corrected, which requires the action of the ATP dependant ion pumps in the cell membranes. In order to produce enough ATP the brain has a transient period of high glucose metabolism (within 30 minutes of impact), which is followed by a period of glucose metabolic depression that can last anywhere from 5 days to several months, depending on severity65. In this time the brain is starved of energy when it is unable to metabolise glucose, which can cause long term damage. Severe or repeated impacts can lead to development of conditions such as chronic traumatic encephalopathy (CTE).
Theoretically, supplying ketones during this period of compromised glucose metabolism could prevent the energy deficit and reduce the likelihood of long-term brain damage. This could be because ketones can act as an alternative, highly energy efficient substrate7. Additionally, the antioxidant, antiinflammatory33 and anti-apoptosis properties of ketones (i.e ketones prevent the opening of the mitochondrial permeability transition pore, which causes cell death66) could protect against neuronal loss and damage.
Practically speaking, because it takes several days to raise blood ketone levels by following the ketogenic diet it has been virtually impossible to study the effects of ketosis on brain injury in humans. It is also complicated by the difficulty in quantifying the extent of the damage without repeated imaging and there is a lack of reliable biomarkers for concussion. Furthermore, concussions can’t be ‘administered’ to humans experimentally, making it impossible to study in a controlled setting. Therefore much of the proof of concept research looking a ketosis for concussion has been done in animals. Nevertheless, the results are promising: rats who were given a ketogenic diet or ketone precursors before67 and after68 a controlled concussive injury have were found to have improved brain energy metabolism, and improved cognitive and motor function post injury. Also, giving exogenous ketones as an injection post-injury protected the brain against glutamate induced excitotoxicity69 and alleviated the decrease in brain ATP that occurs due to the depression of glucose metabolism70. Therefore, as scientists’ ability to quantify concussion in humans improves, ketosis could be an interesting intervention to attempt to reduce the harmful after-effects.
Research looking at the applications of ketosis in other neurological conditions is at its very early stages, but already interesting results are emerging in the areas of mood, migraine and autism amongst others.
Recent studies indicate that mood disorders such as depression and anxiety can be linked to a range of physical changes in the brain, such as inflammation or change in gene expression71. Early results from animal studies have shown that ketosis could improve mood disorders, although the mechanism is still unclear. Rats fed exogenous ketones for several weeks showed reduced anxiety behaviours72. Similarly, endogenous and exogenous BHB alleviated depressive behaviour in mice subjected to stress73. This was found to be linked to altered epigenetic markers (modifications to DNA that affect the degree of gene expression) and an increased amount of brain derived neurotrophic factor (BDNF) in the brain. At this time, there are no trials investigating the effects of ketosis in human patients with mood disorders.
Recurrent migraines are highly prevalent and sometimes debilitating. They manifest as throbbing, one-sided headaches and can also involve visual disturbances (aura). Many of the processes involved in migraine are shared with those implicated in epilepsy, especially an abnormally high glutamate (excitatory) activity. In fact, medical professionals sometimes prescribe anti seizure medications that block glutamate activity to migraine patients. The ketogenic diet has been associated with improved migraine control both anecdotally and in a small number of case studies 74 ,75 ,76 ,77. Researchers are currently undertaking further investigations to confirm if the ketogenic diet or exogenous ketones are viable and effective treatment options for migraine patients.
Some investigators feel that mitochondrial dysfunction and compromised brain glucose metabolism may play a role in the development of autism. As autism is sometimes accompanied by seizures such as those seen in epilepsy (which could be improved by the ketogenic diet), the diet has been trialled in a small number of case studies. These cases have shown that the ketogenic diet can lead to improvements in the childhood autism rating scale score 78 ,79, however dietary adherence may prove even more of a challenge with these children, decreasing the viability of the ketogenic diet as an intervention.
Given the prevalence of this category of illness, and the insidious nature of the conditions, an intervention with minimal side effects (vs. drugs) such as ketosis could be used as a first line intervention before attempting treatment with medication in some cases. However, there is still some way to go before research can conclusively address this possibility, individuals considering the diet should do so with full medical supervision.
In recent times there has been an exponential increase in the rates of obesity and diabetes. Popular opinion has blamed (in turn) overconsumption of fat, overconsumption of carbs and sugar and overconsumption of calories. Whilst the overall calorie balance is a crucial factor that cannot be overlooked, it is also the case that different macronutrients in the diet (especially carbs and fat) have different effects on the body when consumed.
The macronutrient profile of a ketogenic diet itself (low carbohydrate, high fat, restricted protein) causes several beneficial changes to hormone levels and metabolism that lead to either a voluntary decrease in calories consumed or an inherent increase in the body’s metabolic rate. This may explain why the diet is effective for weight loss.
Decreasing dietary carbohydrate consumption results in:
Higher fat consumption results in:
Although protein content of a LCHF diet is restricted, a relative increase in dietary protein leads to:
However, it is possible that ketosis alone may also help weight loss (i.e an effect caused by BHB rather than by the nutrients in the diet).
Lately anecdotal evidence has been building that a ketogenic diet can yield transformative results with respect to weight loss: with people taking to social media to share ‘before and after keto’ photos and to stories of ‘how keto changed my life.’ Despite this, concrete clinical evidence confirming that a ketogenic diet is superior to any other diet that creates a calorie deficit is lacking. At the moment the most accurate statement is that ‘the best diet for you is one you can stick to,” a pattern of eating that maintains a small calorie deficit should, over time, lead to weight loss.
Cancer is a broad term that refers to the presence of abnormal cells in the body that have the potential to grow and spread to other sites in the body. Cancer develops over time as cells acquire defects that affect their function, growth, proliferation and metabolism. Recently a list of ‘Hallmarks of Cancer’ was proposed by some of the leading investigators, Hannahan and Weinburg90 . These hallmarks include:
Sustained growth and proliferation
Evasion of growth suppression signals
Avoiding immune destruction
Enabling replicative immortality
Tumor promoting inflammation
Activating invasion and metastasis (spread to other parts of the body)
Genome instability and mutation
Resisting cell death
Deregulating cellular energetics
It is still unclear what is the very first step that occurs in a normal cell becoming cancerous. Two theories that explain the development of cancer are the ‘somatic mutation’ theory, and the ‘metabolic theory.’ The somatic mutation theory states that the first event in cancer is a gene mutation due to environmental damage or a mistake in the DNA replication and repair processes. This gene mutation initiates a cascade of events that subsequently leads to tumour growth. Popular opinion favoured the somatic mutation theory for many years, leading to a large body of research describing the different genetic mutations of cancer cells, and ambitious projects to sequence the ‘Cancer Genome.’ From the compelling simplicity of the somatic mutation theory, an increasingly complicated picture has emerged as more than 100 oncogenes and 30 tumor suppressor genes have been identified, leading researchers to look for alternative explanations.
The metabolic theory states that the root cause of cancer is a defect in mitochondrial energy production or ‘an irreversible injuring in respiration’91. Once the cells ability to produce energy is compromised, this is hypothesised to lead to the subsequent accumulation of changes that make the cell cancerous92. A key change is decreased mitochondrial glucose metabolism in cancer cells. Cancer cells ferment glucose to lactate (which happens outside of the mitochondria) at a much higher rate than normal cells93, in a change called ‘The Warburg Effect.’ This implicates damage to the mitochondria and failure in energy production as a central process of cancer progression.
As both gene mutations and de-regulated metabolism are both present in cancer, it is unclear which is the ‘chicken’ and which is the ‘egg.’ However taking a metabolic view of cancer leads to the possibility of changing the course of the disease by altering the whole body metabolism through nutritional interventions. such as the ketogenic diet.
Recently several ‘metabolic therapies for cancer’ have been proposed. These include:
Ultimately, cancer is highly complex, whereas some tumors may be highly responsive to carbohydrate restriction, others may become adapted to utilise fats or ketones. Cancer, and the treatments currently in use cause unpleasant systemic effects such as muscle wasting and compromise of the immune system, therefore any interventions should be undertaken under the guidance of a doctor. There are limited treatment options available for some types of cancer, many drugs have toxic side effects and many types of cancer have a poor prognosis. In these cases, considering metabolism as an adjunct to conventional treatments is interesting, and offers the potential of another avenue of attack on cancer.
The hallmark of diabetes is abnormally high concentrations of blood glucose. Blood glucose is usually regulated by the hormone insulin. Following a carbohydrate rich meal, blood glucose rises. Insulin is then released by the pancreas and binds to receptors around the body and causes the cells to take up glucose from the blood.
There are two main types of diabetes. In Type I diabetes, the insulin producing cells in the pancreas are destroyed by an immune response resulting in insulin deficiency. In Type II diabetes insulin is still secreted, but the cells in the body no longer respond adequately and so glucose uptake is not triggered. Sometimes pregnancy can trigger a period of diabetes (gestational diabetes), which resolves after giving birth.
Type I diabetes is usually treated by insulin injections, that replace the body’s own insulin production. In Type I diabetics, lowering dietary carbohydrate consumption can reduce the need to inject insulin to lower blood sugar101. However, because they do not release any insulin Type I diabetics can be at risk of developing a complication called “Diabetic Ketoacidosis” (DKA). DKA occurs because, alongside its effects on glucose, insulin has other effects in the body. Insulin normally inhibits the release of fat (lipolysis) from adipose tissue. In Type I diabetics, the lack of insulin can lead to high levels of lypolysis, high levels of fatty acids in the blood, this then drives rapid and uncontrolled liver ketone production. The symptoms of DKA are weakness, confusion and deep gasping breathing. In order to avoid developing DKA while following a ketogenic diet, Type I diabetics should seek medical supervision and closely monitor their glucose and ketone levels if reducing their dietary carbohydrate intake.
The situation for Type II diabetics is different because some insulin production remains and some cells of the body can still respond to insulin. It is worth noting that insulin sensitivity can be different between the different tissues of the body such as liver, adipose tissue and muscle. A small amount of insulin release can help to prevent development of DKA unless the body is totally insulin resistant. Insulin resistance is a term used to indicate that for a given amount of insulin, the cells of the body are less responsive and take up less glucose. This means that blood glucose levels remain higher for longer when insulin resistant Type II diabetics eat a carbohydrate rich meal. Over time, the pancreas secretes more insulin to compensate for reduced insulin sensitivity, which can damage the insulin producing (beta) cells. Furthermore, having high blood glucose can lead to a number of side effects:
Type II diabetics can reduce their risk of developing these complications by keeping blood glucose levels within a healthy range (4.5 - 6.5 mM). This can be achieved using insulin injections, but using insulin is not without side effects (i.e hypoglycemia requiring assistance and weight gain)101. Therefore dietary carbohydrate restriction is likely to be a good lifestyle change to help with diabetes management,. Companies such as Virta Health are popularising this approach to diabetes management and pioneering the use of technology to improve compliance. The benefits of carbohydrate restriction include:
Most of these benefits occur due to the decrease in dietary carbohydrate intake; it is largely unknown what role ketones themselves play in the efficacy of the diet. Because of this, it is unclear how exogenous ketones could be used to help treat diabetes. One effect that is consistently reported is that ketone ester and ketone salt drinks and infusions lower blood glucose and lipid levels 11,106 ,107. It is also possible that exogenous ketones have a positive effect on insulin sensitivity; ketone ester supplementation increased insulin sensitivity in rodents by 73%108. It is possible that exogenous ketones could be used alongside diet and lifestyle changes to help control blood in diabetes, but further research must be done before this can be realised.
Finally, an important consideration is the effect of the ketogenic diet on blood lipids. This is because the levels of various lipids in the blood have been shown to predict the likelihood of cardiovascular disease. Lipids and cholesterol are carried through the blood in biochemical assemblies called ‘lipoproteins,’ because they do not dissolve in water. There are two broad classes of lipoproteins in the blood: high density lipoprotein (HDL) and low density lipoprotein (LDL). HDL is thought of as more ‘healthy’ (H = ‘Healthy’) because it responsible for moving cholesterol and lipids from the peripheral tissues into the liver for metabolism. LDL is demonised as bad cholesterol (L = ‘Lethal’), levels are elevated after a fatty meal and elevated LDL is associated with cholesterol build up in the arteries.
Blood tests often report the level of total cholesterol (HDL + LDL) as well as the levels of each type independently. It is possible that the relative abundance (ratio) of HDL: LDL is more important to predict the occurrence of cardiovascular disease that the total cholesterol level109. Whilst the ketogenic diet can cause an increase in total cholesterol, the ratio of healthy HDL : less healthy LDL generally increases (i.e more HDL)110 whilst following a ketogenic diet. In contrast, whilst total cholesterol tends to be lower whilst following a low fat diet, the ratio of HDL:LDL tends to be lower (i.e more LDL)21.
Another lipid marker of interest is blood triglyceride levels. Blood triglycerides are frequently elevated in the metabolic syndrome, and are a risk factor for cardiovascular disease111. A common misconception is that consuming high levels of fat leads to persistently high levels of blood triglycerides. However, there is data that suggests that a high fat diet does not affect blood triglyceride levels, and may even lower them21 ,112, especially following a period of adaptation113.
The effects of a ketogenic diet on cholesterol and triglycerides is complex. It is dependant on the exact composition of the diet, the genetic and physical characteristics of the individuals studied and other hormonal and environmental factors. Therefore, blood lipid changes whilst on the ketogenic diet can vary between individuals. This means that it is advisable to track your personal levels by having a blood test before starting the ketogenic diet and to follow this with regular testing to monitor any changes.
Finally, exogenous ketones have been shown to decrease the levels of triglycerides and free fatty acids in the blood after one drink 107 ,106 ,11. There is also early data showing that ketone ester consumption decreases cholesterol biosynthesis in rodents, an effect which appeared to be conserved in humans114. It is unclear at this stage what the long term effects of exogenous ketone consumption on blood lipids and cholesterol would be, but this is an area of promising research.
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