Guest post: Dr. Eugene J. Fine
Last time I discussed our pilot study showing the effects of carbohydrate (CHO) restriction & insulin inhibition (INSINH) in patients with advanced cancers. We described how the molecular effects of INSINH plus systemic (total body) effects like ketosis might inhibit cancer growth. My goal now is to present the underlying hypothesis behind the idea with the goal of understanding how patients with cancers might respond if we inhibited insulin’s actions? Should all patients respond? If not, why not? Might some patients get worse? These ideas were described briefly in our publication describing our pilot protocol.
The hypothesis hinges on understanding how natural selection works, and how it works on two levels. The first is based on our evolutionary heritage and how humans evolved biochemically. The second level addresses how cancers evolve within people. In sum, we’re considering an intersection of human evolution over our long prehistory vs. cancer evolution over several years within human beings. Let me explain:
Human evolution: We’ll arbitrarily date the first humans from the evolution of Homo erectus about 1 million years ago, or from Homo sapiens, approximately 200,000 years ago. Since agriculture emerged about 10,000 years ago we can conclude that our ancestors were hunter-gatherers for at least 95% of our existence. According to paleontological evidence dietary CHO of hunter-gathers was in the range of 20-35% of total caloric intake. For most of human evolution we had no bread on the table, nor cakes, puddings, pies or chips. Wild fruits gathered during hunter-gather days don’t measure up to the huge domesticated fruits now abundantly available all year round. It’s difficult to imagine how humans didn’t starve during the winters in northern Europe or on the Asian steppes. Even in Africa, the cooling climate beginning around 100,000 years ago forced migrations of people toward more hospitable (and food abundant) climes. At the very least, there’s little doubt that our forebears did not consume excess dietary sugar and starch resulting in obesity and metabolic syndrome. In short, for 95% of human existence, the paleontological record shows that we were very tolerant of minimal CHO intake.
But the best evidence is in our biochemistry: under well fed modern conditions our brain uses about 130 grams of glucose/day (for most of us in the developed world). During a fast our brain continues to use glucose derived from the breakdown of glycogen in our liver as well as from glucose synthesis (gluconeogenesis) largely from body proteins. However, the continued consumption of our own proteins for a fast lasting longer than a few days isn’t a good evolutionary survival strategy as the protein would be stolen from our muscles, killing us rapidly from heart and diaphragm failure.
A key survival strategy that allowed conservation of body protein — the ability to generate ketone bodies as an alternative fuel source — is what actually survived. Under conditions of fasting—total reduction in nutrients (including carbohydrate) — glucose concentration will fall in the bloodstream thereby causing less pancreatic insulin secretion. Breakdown of fat in fat cells (lipolysis) is ordinarily inhibited by high levels of insulin. Conversely, fat breakdown accelerates under conditions of fasting (low insulin signaling), causing release of fatty acids (FA) into the blood. FA’s circulate to the liver where they then get metabolized into circulating ketone bodies (KB). That’s why fasting results in ketosis, as does strict low carbohydrate dieting (e.g. less than 50 grams of CHO/day). The brain uses 130 grams of glucose/day under our ordinary modern dietary conditions. But during starvation/fasting, over a 6 week period, the brain switches to ketone bodies to supply more than 2/3 of its fuel. This masterful metabolic switch spares protein breakdown and permits humans to tolerate starvation as long as fat stores hold out. That’s why people can survive without food sometimes for months, whereas absolute water deprivation can kill in just a few days.
One way to describe the evolution of our metabolism is that, over millennia, environmental conditions selected those individuals for survival who a) stored up enough fat during the more plentiful months to provide an energy source for their body and b) had the enzyme capacity to make ketone bodies (KB) from the stored fat and could utilize these KB as brain fuel to reduce the brain’s need for glucose derived from protein.. These individuals survived over the long lean winters to reproduce, and they passed on the genes that enabled this capacity.
Anyway, civilization and agriculture changed the availability of many foods, but especially grains. Bread became the ‘staff of life.’ In recent years, excessive, cheap CHO, coupled with the Food Pyramid’s recommendations to consume CHO to the tune of 55-70% of total caloric intake have likely contributed to widespread metabolic syndrome, obesity, type 2 diabetes, dyslipidemias and hypertension. Finally, obesity and high insulin concentrations in the blood (both linked to dietary CHO excess) have now been associated with an increased risk for a variety of different cancers. Obesity has in fact surpassed smoking as the greatest behavioral risk factor for cancers in the U.S. Reducing cancer risk by CHO restriction would seem to be a meaningful preventive cultural dietary goal. The idea appears to resemble our study where we treated cancers with a VLC/INSINH diet, but it’s not quite the same thing. Cancer cells behave differently from normal cells, so, metabolically, treatment isn’t quite the same as prevention.
Figure 1: The American Institute for Cancer Research links more than 100,000 new cases of cancer per year to obesity.
Cancer evolution: Cancer initiation is a subject of intense research interest. I share the prevailing view that cancers start with a mutation that changes a normal cell into a slightly abnormal but not yet malignant cell. A total of four to six critical mutations over a period of 30 to 70 generational doublings taking 3 or more years result in unregulated cell growth, proliferation, invasion, metastasis, in other words cancer-like behavior (or ‘phenotype’) ().
Regardless of the initial insult, each one of these abnormal but not yet malignant cells must evolve over time within a human organism. We must remember that mutations in normal cells happen all the time and they are usually maladaptive or destructive to the cells; healthy cells have mechanisms to protect the organism by a kind of cell suicide or apoptosis, best thought of as self-pruning of maladaptive cells. So most mutations within these aberrant cells will cause cell death and will not result in a cancer. But there are mutations, seen in many types of cancers, which can cause resistance to apoptosis and therefore permit abnormal cell growth to continue.
This is where the evolution of humans and the evolution of cancers within humans collide. In the modern developed world most cancers evolve within individuals under conditions of substrate/nutrient abundance, and especially CHO abundance. And while famine continues to plague people during wars and in underdeveloped regions, it’s nevertheless reasonable to suggest that sustained ketosis and INSINH are not prevalent in the modern developed world. Therefore in the developed world, cancers in many people are unlikely to have experienced a microenvironment due to the metabolic effects of insulin inhibition (INSINH) or ketosis (a limiting state of INSINH).
In summary, INSINH would represent a new metabolic selective pressure for many cancers to which they would reasonably be vulnerable.
Hypothesis: Humans are adapted to starvation and the metabolically related low CHO diet/INSINH state. On the other hand, cancers in large cohorts of people in developed countries are under high chronic insulin stimulation and are largely unexposed to the unfamiliar INSINH state. These cancers will sensibly express a wide range of molecular and metabolic vulnerabilities to INSINH. However, they may express an equally wide range of adaptive mutations. Investigators have confirmed both vulnerability of some cancer types to inhibition by added ketone bodies as well as continued uninhibited cancer growth with added KBs in other cancers.
Two important corollaries about cancers in hunter-gatherers and modern ‘low carbers’:
First, there’s no a priori reason that cancers can’t arise in individuals on INSINH/VLC diets in the modern world, or in modern (or prehistoric) hunter-gathers. Cancers initiate from a series of mutations due to causes that may be intrinsic to cell metabolism or to the external environment. Even for hunter-gatherers, heavy metals in ground water (even without civilization), background radiation all around us, smoke from smoking tobacco or herbs, campfires and cooking (hunter gatherers had controlled fire for close to 1 million years) and chronic inflammation are some of the factors that have existed for millennia, even if more pervasive since the onset of civilization. Although anecdotal and paleontological evidence is all that we have, cancers have been reported in ancient bones. Nothing would prevent cancers from forming, even in the likely reduced insulin signaling state of early hunter-gatherers (or in modern people on VLC/INSINH diets).
Second, while fewer cancers might be expected to develop, those hunter-gatherers (or modern low-carbers) who do develop cancers would not experience a VLC diet as a new selective pressure. Our pilot study, in fact, excluded patients who had been on a VLC diet within 3 years of the diagnosis of their cancer because a VLC/INSINH diet would not be expected to have any positive effect on their cancers.
To sum up: For people on high CHO diets who develop cancer, a low carbohydrate diet targeting insulin (VLC/INSINH) may be therapeutic. The rationale is that control of insulin and the presence of ketone bodies provides a new selective evolutionary pressure to which the cancers may not be adapted. On the other hand, those cancers that develop in people who are already on low-carbohydrate diets (already in a state of dietary insulin inhibition) will not be expected to be vulnerable to the VLC/INSINH diet.