Areas of Research Using a Ketogenic Diet
To sum it up, the classic ketogenic diet is a specific high-fat, adequate protein, very low carbohydrate lifestyle intervention. Current research now investigates different applications for ketogenic diets and there are a lot of studies on the way at the moment.
Epilepsy is the first and the oldest application of the ketogenic diet. Especially in children it can lead to improvements and reduction of seizures when medication doesn’t have the desired effects. It is also being used for diabetes, both type 1 and type 2. At the beginning of 2015, a new research paper was published that clearly states 12 reasons why the ketogenic diet can and should be used as a first protocol in diabetics.
Another emerging area of research for the ketogenic diet is for Parkinson’s, Alzheimer’s and other neurological disease. PCOS, or poly-cystic ovary syndrome, is often treated with metformin, a drug that reduces glucose and therefore insulin levels. The ketogenic diet has very similar mechanism and can therefore be useful in PCOS and also infertility.
Cardiovascular risk parameters can also be targeted with ketogenic diets. Saturated fat and cholesterol were demonized for the wrong reasons for too long. Following a high fat, low carb diet has shown many beneficial effects on cardiovascular health. We also know that acne can be caused by high levels of IGF-1 (insulin-like growth factor), which is lowered on keto.
The other - more obvious condition - is metabolic syndrome and weight management. And very recently more and more endurance athletes have approached me to give them guidance on how to implement the ketogenic diet. I also wrote an e-book about how they can enhance their athletic performance and it’s mainly useful for athletes who do long distance races and very much rely on aerobic performance. It makes sense if we consider the fact that a sugar-burning athlete has access to about 2,000 calories (glucose and glycogen) whereas an athlete that is in fat-burning mode can tap into 100,000 calories and more stored as fat reserves.
There are a lot of other predictable metabolic changes happening and I think it’s important to know what is going on in the body when we started moving towards a ketogenic way of eating.
First of all, food sources of glucose are used up. When we eat carbohydrates and also excess protein, they are converted into glucose, which is being used by the cells. Glucose stored in the liver as glycogen is the next energy source that is starting to be depleted. When glucose and insulin levels are low, the liver is triggered to make glucose from fatty acids, amino acids, lactic acid and also recycled waste. This process is called gluconeogenesis and happens when glucose is required by the body.
Once glucose and insulin levels are consistently low, the liver starts converting both dietary and stored fats into usable energy molecules called ketone bodies. Healthy normal cells operate like hybrid engines and they are metabolically very flexible. This means that they can switch between using glucose or ketone bodies as the main energy source. A metabolic state where ketones are used as the main source of energy is called “ketosis” or “nutritional ketosis”.
Nutritional ketosis has many benefits and there’s more and more research coming out showing what functions ketone bodies have. Research suggests that ketones also may inhibit cancer cell viability. So it’s not just about reducing glucose and insulin, which obviously is a very important step because they are important pathways for cancer, but ketone bodies themselves may have anti-cancer properties. Ketone bodies also reduce inflammation and this is of great importance because inflammation is one of the key drivers in cancer.
There is a lot of research into that, and that’s why I also like to test for systemic inflammation. Ketone bodies are neuroprotective - they help mitigate damage to healthy neurons from cancer treatments such radiation and chemotherapy, for instance.
Neuroscientists are also looking into possible ways to manage conditions like Alzheimer’s, Parkinson’s, MS and others. The other thing that is important to know is the ketones are water-soluble and therefore don’t need any carriers to cross the blood brain barrier. Glucose for instance needs transporters to cross the barrier but that’s not the case for ketone bodies.
Gluconeogenesis, so the production of glucose from fatty acids, amino acids or lactic acid is continuously meets the needs of glucose-dependent cells such as red blood cells. Nobody denies that there are certain cells and processes in the body that require a little bit of glucose like for instance the conversion of certain thyroid hormones. These needs can be met by the process of gluconeogenesis. And the other thing that is important to know is that lowering protein intake both directly and indirectly lowers the levels of cancer-promoting insulin-like growth factor 1 (IGF-1). That’s one of the reasons why we can’t eat limitless amounts of protein. The ketogenic diet and fasting also affects other cancer pathways like for instance AMP-K.
Intermittent Fasting - A Viable Method of Easing into KMP - By Becoming Keto Adapted (more on this method later)...
Is Cancer Really a Genetic Disease?
Recently, more and more researchers have started to question whether it’s a good idea to pour a lot of money into genome projects. Hundreds and thousands of gene mutations in different cancers have been identified and have certainly led to advances in the field of molecular biology, but have they done much to defeat cancer?
Gene-based targeted therapies show a lot of promise against those few cancers that are inherited (5-10%) but what about the rest of them that aren’t? Dr Thomas Seyfried provides plenty of evidence that cancer is a metabolic rather than a genetic disease. Source: “Cancer as a Metabolic Disease”, Thomas Seyfried.
You see on the left that a healthy cell begets two healthy cells and a cancer cell begets two cancer cells. But what is responsible for the unregulated cell growth in the tumour cell? Is it the mutations in the nucleus as mainstream medicine views it or is there a possible connection with abnormalities in the mitochondria? Mitochondria are small organelles sitting in the cytoplasm, the area surrounding the nucleus, and generate the energy in a cell.
We know that they’re also abnormal in the tumour cell because energy metabolism is disrupted. In experiments, when the nucleus of a tumour cell is moved into a healthy cytoplasm, the result is normal cells and sometimes even normal tissue. Although the nucleus is supposed to contain the mutations that drive cancer, we don’t see this happening in these experiments. When the nucleus is taken out of a normal cell and put into a cancer cell cytoplasm, the result is dead or cancerous cells. Could it be that normal mitochondria suppress the formation of tumours? Could this indicate that the gene mutations in the nucleus are NOT the drivers of this disease? Does it make sense to focus the majority of research on finding all the possible mutations?
Mechanisms of the KMP Framework
So why exactly is it that a ketogenic diet compromises cancer cell metabolism - in other words how a cancer cell produces energy? How can a simple reduction of carbohydrates and an increase fat intake make such a difference? So the first thing we need to know is that: - Tumour tissue relies heavily on glucose as a fuel. In cancer diagnostics this has been taken advantage of for quite a good while now with the PET scan. With the help of a PET scan, oncologists aim to detect cells that take up glucose at a much higher rate, i.e. cells that are metabolically more active and “gobble up” glucose. Before the scan, radioactive glucose is injected into the veins. Once the glucose starts to spread, the metabolically active areas light up more than others.
We also know that when insulin levels are low because the glucose is at a consistently low level, there’s a decrease amount of glucose that can reach cancer cells. And this has several consequences: less insulin means that fewer insulin receptors are activated and we know cancer cells have up to 10 times the number of receptors as normal cells both for glucose and insulin. If fewer receptors are present, less glucose is moved across the cell membrane.
As a result, glucose is becoming scarce for healthy cells but they just switch to burning fat as a fuel. The graphic below hopefully helps to illustrate this whole process: On the left side, you see differentiated tissue- which are the healthy cells- and what happens if oxygen is present so (+O2). Glucose enters the cell, it is split into two molecules (by glycolysis) and turned into pyruvate. Pyruvate then enters the so-called mitochondria, small organelles that are the powerhouse of cells. Through oxidative phosphorylation, 36 molecules of ATP are produced. ATP is the energy currency of the cell.
As a by-product, there’s some CO2 and also a little bit of lactate. If no oxygen is present (-O2), for instance when we exercise heavily and go into an anaerobic state as a sprinter, then glucose enters the cell, it is split and we end up with pyruvate again. Also as a by-product, a large amount of lactate is produced. It’s what causes that burning sensation in our muscles.
As you can see, this process is a lot less efficient in terms of energy generation. Through anaerobic glycolysis, we generate 2 molecules of ATP as opposed to 36 when oxidative phosphorylation is used. On the right side, we have proliferative tissue or a tumour cell. It doesn’t matter whether oxygen is present or not - the process of energy generation in a cancer cell is usually the same.
So glucose enters the cell, then glycolysis breaks down glucose and forms pyruvate. Some pyruvate then can go into the mitochondria as well but that’s very much dependent on how damaged the mitochondria are- usually they are severely compromised in cancer cells or even lack completely. The majority of the pyruvate is converted into lactate. Lactate has a few major roles in cancer cells: it makes sure that the immune system has a hard time recognizing that tumour tissue is present and it also makes it easy for a cell to metastasize.
In case anybody is wondering what happens to the 10% here because we have 5% going into the mitochondria and 85% converted into lactate. About 10% of glucose is diverted into so-called bio-synthetic pathways upstream of pyruvate production. These pathways are very necessary for producing new cells for instance and but also just to maintain a certain balance of the cancer cell (called redox balance).
This whole process of energy generation in a cancer cell here is called “aerobic glycolysis” and it’s also called the Warburg effect. Otto Warburg was a Germany scientist carrying out lots of research in the 1920’s 1930’s. He showed that whether oxygen is present or not, cancer cells prefer to use glycolysis (the splitting of glucose) for energy generation. The whole process or effect is also referred to as “fermentation”.
As we have seen, in comparison to oxidative phosphorylation, this process is a lot less effective because it only generates 4 molecules of ATP. You will probably come across the term “Warburg effect” quite a lot when researching the ketogenic diet and I hope you have a clearer idea now what it is.
Did you know… … that Otto Warburg won the Nobel Prize for his research into metabolism of tumours and respiration of cells in 1931?
So is cancer as a metabolic disease really a new discovery? As a summary of what we looked at earlier, cancer cells are “glucose-avid”- this is the scientific terms for cells that require unusually large amounts of glucose. When an oncologist gets the result of the PET scan, he will also know what the rate of glucose efficiency is. By lowering glucose levels and interfering with glucose and insulin transport, cancer cells are deprived of their preferred fuel.