Beyond a ketogenic diet for weight loss: Cancer

Recently, I have been posting on the fat-burning ketogenic diet, so called because the body adapts to use ketones (derived from fat), not glucose (from carbohydrate) for fuel. It is a high-fat, adequate-protein, low-carbohydrate eating pattern, and a fairly effortless way to shed weight because the dieter doesn’t go hungry [links at end of post]. This is in contrast to dietary plans that depend on restricting calories and that usually fail in the long term.

While this is an effective and sustainable weight-loss strategy, running the body on ketones rather than glucose might have benefits that go well beyond weight-loss.

For example, there is strong evidence for the benefit of a ketogenic diet in type 2 diabetes, cardiovascular disease and epilepsy. There is emerging evidence in other neurological disorders (including Alzheimer’s disease) and cancer.

It may seem unlikely that a diet could have such wide-ranging ramifications, however, there is science to support these claims. In this post I will look at perhaps one of the least expected – cancer. To understand how ketones might help with such a devastating condition, it is necessary to look a bit closer at how cells in the body generate energy.

Cellular fuels

sugarOur main dietary fuels are glucose (from carbohydrates), fatty acids (from fats) and amino aids (from proteins). There is no dietary source for ketones. Instead, the liver manufactures them when the body has adapted to fat-burning for energy (as with a ketogenic diet). The liver can also manufacture glucose, called gluconeogenesis, or release glucose from glycogen stores.

Fuels from these sources can be transported across a cell membrane to enter the cell and be used to generate energy for the cell. However, transport mechanisms for different fuels compete with each other. Thus, if glucose is plentiful and is being used as the primary fuel, it will oppose fatty acids entering the cell. This means that glucose-fuelled cells will not burn fats, even when there are fatty acids available to burn. Furthermore, glucose-adapted cells do not simply switch to fat burning if glucose availability declines – the transport mechanisms require a period of adaptation that can take weeks (keto-adaptation).

How do cells use these fuel sources?

2000px-Animal_mitochondrion_diagram_en_(edit).svgThe ‘power generators’ of the cell are specialised compartments called mitochondria, which ‘burn’ fuel with oxygen (oxidation) to generate energy and release carbon dioxide and water. The main waste products are free radicals (reactive oxygen species) that the cell neutralises with antioxidants. The energy generated by the mitochondria is packaged in molecules called adenosine triphosphate (ATP), which leave the mitochondria and supply the energy needs of the cell. Any ATP that is not needed by the cell is released into the circulation to fuel other cells that might be experiencing high energy demand.

Cell-diagram-showing-mitochondriaThe mitochondria more or less directly burn fatty acids, ketones and amino acids. However, they cannot directly burn glucose. This requires a preliminary step, performed inside the cell but outside the mitochondria, where glucose is fermented anaerobically to produce pyruvate (a simple 3-carbon molecule). The mitochondria burn the pyruvate. Fermentation produces a little energy, but the mitochondria produce about 20 times more. It is this fermentation step, unique to glucose, that goes wrong in cancer cells.

In comparison to glucose, burning ketones produces more energy per unit than burning pyruvate. Furthermore, ketones produce fewer free radicals, while at the same time up-regulating cellular systems for the manufacture of antioxidants to neutralise free radicals. Ketones are sometimes described as ‘clean fuel’. Perhaps think of ketones as natural gas and glucose as coal.

Cancer

Current thinking is that cancers arise from accumulating mutations that occur over time (perhaps decades) in a cell’s DNA that ultimately lead to damage to cell-growth genes and out of control growth and metastasis. This is the chromosomal hypothesis, because it was first recognised from chromosomal damage in cancer cells.

warburgHowever, there is another model. In 1924, the German scientist Otto Warburg (1883-1970) showed that, despite great diversity in cancer types, cancer cells had one thing in common – hyperactive glucose metabolism. For this, he was awarded the Nobel prize (in 1931). This is the metabolic hypothesis, in which DNA damage is secondary to glucose hyper-metabolism. Conversely, the chromosomal model accepts that glucose metabolism is abnormal in cancer, but attributes it to a secondary effect from DNA damage.

While there does not seem to be agreement on cause-effect, there is agreement that most cancer cells have a much-increased glucose metabolism. Indeed, a gold-standard imaging method for identifying cancer in humans (PET scanning), works by imaging glucose metabolism.

What is happening to glucose inside a cancer cell?

Toshiba-PET-CTIt is fuelling the cell abnormally (the Warburg effect). The fermentation step (glucose to pyruvate) takes over from the mitochondria step (oxidation) as the main source of energy. Cancer cells have high energy needs, however fermentation is not very efficient at generating energy. As a result, the fermentation step gets massively up-regulated (by as much as 200-fold) to meet energy demand. Fermentation is a ‘dirty’ reaction, in that it produces large numbers of damaging free radicals as byproducts. The cancer cell uses these free radicals as weapons. It releases them into surrounding (healthy) tissue, where the free radicals damage and kill healthy cells (the Reverse Warburg Effect). Cancer cells consume the molecular debris released by the death of these healthy cells in order to grow and divide. In this way the cancer consumes, spreads and metastasises. Cancer cells take energy from glucose, and building blocks for growth by killing surrounding cells with the toxic waste.

However, the Achilles’ heel for cancer cells is that they need glucose to survive. Without it they will die. Cancer cells cannot derive energy from any other source – fatty acids, ketones or amino acids. Neither can they adapt to do so. Cancer cells are glucose dependent. That is why a low-carbohydrate ketogenic diet is relevant to cancer.

Insulin

There is one other glucose-related mechanism relevant to cancer – insulin. Insulin does more than manage blood glucose and fat storage, it is also a regulator of cell growth. It does this indirectly through a class of molecules called insulin-like growth factors (IGFs). The combination of high blood glucose and high insulin levels as a result of a high-carbohydrate diet (particularly in insulin resistant individuals) may explain why diabetics have a higher incidence of cancer than the rest of the population.

A ketogenic diet and cancer

images-6It should be obvious by now. By switching from glucose to ketones and fatty acids as fuel, restricting the availability of glucose and suppressing insulin, it seems reasonable to expect that cancer cells might suffer under a ketogenic diet.

There is now convincing evidence for this from laboratory studies (see here for a review). However, there have been no large-scale human studies to date (although they are in the pipeline). In the meantime, case-report studies in human cancer patients have shown that a ketogenic diet in late-stage cancer is safe to administer and can have remarkable results for some people. The diet is usually a calorie restricted ketogenic diet with very low carbohydrates that needs to be managed under medical supervision.

There will always be some circulating glucose with a ketogenic diet, no matter how severe it is, because the liver can manufacture glucose from fat (the glycerol in triglycerides) and protein (9 of the amino acids are glucogenic). It has been suggested that some diabetic medications, such as metformin, could be used to block this. There is evidence that metformin offers protection against some types of cancers (eg, breast cancer) and prolongs the life of diabetic patients with cancer.

Is a nutritional ketogenic diet likely to be protective against cancer in healthy individuals? This is not known, however the same reasoning applies – without regular glucose spikes and excess dietary glucose from carbohydrates, cancer cells may struggle to get established. Clinical trials are required.

Summary

I have provided the scientific rationale behind a (perhaps unexpected) role for a ketonic diet in cancer – it may not matter greatly what has caused a cancer to develop, if the cancer cells depend on glucose for energy then they could be starved, or at least restrained.

However, it remains to be determined whether such a diet will prove to be a useful addition to current cancer treatments. We do not yet have the data.

Likewise, and for the same reasons, a ketogenic diet may confer a protective benefit against cancer in healthy individuals. Again, although plausible, this too is unproven.

Finally, the USDA high-carbohydrate low-fat diet has co-existed with a significant rise in the incidence of cancers, including childhood cancers, over the last 40 years or so. While this association does not prove causality, the level of glucose consumption on a high-carbohydrate diet is something to ponder, given that glucose metabolism is intimately involved in cancer.


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