Carbs and cancer

This is not one of those “carbs cause cancer” posts. I though “Carbs and cancer” had a better ring to it than for example “Metabolism and cancer”, what with the alliteration and all. Still, it’s important to remember that although carbohydrate restriction is an effective treatment for cancer, this does not mean cancer is caused by consumption of carbs.

Our diet determines our health, even our risk of getting cancer and our risk of surviving it. Her are some reasons macronutrients matter:

The cause

– Humans who live on natural diets seem free of many cancers and also free of metabolic diseases [1]. Metabolic diseases such as obesity, diabetes, insulin resistance and heart disease, also coexist with cancer.

– A high body mass index increases the risk of most cancers [2].

– Cancer cells are normal cells that grow too fast and the cells need both energy and growth factors to grow at an increased pace. A logical theory of treatment would be to take away the energy and growth factors and starve the cancer cells.

– Hanahan and Weinberg suggested that six essential alterations in cell physiology could underlie malignant cell growth [3]. These six alterations were described as the hallmarks of nearly all cancers and included, 1) self-sufficiency in growth signals, 2) insensitivity to growth inhibitory signals, 3) evasion of programmed cell death (apoptosis), 4) limitless replicative potential, 5) sustained vascularity (angiogenesis), and 6) tissue invasion and metastasis.

Cancer cells crave glucose. Aerobic glycolysis, the breaking down of glucose in the presence of oxygen, but with high lactic acid production in the cytoplasm (the Warburg effect), is a metabolic hallmark of most tumors [3]. Almost all cancers express aerobic glycolysis, regardless of their tissue or cellular origin.

Enhanced glycolysis (the breakdown of glucose) is required for the rapid growth and survival of many tumor cells.

– People with type 2 diabetes are at increased risk of getting pancreatic, liver, colorectal, and bladder cancers, and non-Hodgkin lymphoma [4]. But if you have type 1 diabetes you have a reduced risk of lung cancer, Hodgkin’s lymphoma and prostate cancer.

Mitochondrial dysfunction is a key element in most cancers.

– One of the problems if you are insulin resistant is that the mitochondria are bombarded with energy and pushed to the max. This causes them to produce reactive oxygen species (ROS). Increased ROS production can impair genome stability, tumor suppressor gene function and control over cell proliferation [3].

– The glycolytic enzyme «glyceraldehyde-3-phosphate dehydrogenase» potential is upregulated in many common tumors. GAPDH is also a transcription activator and link the metabolic state to gene transcription.

– The integrity of the nuclear genome is largely dependent on the functionality and energy production of the mitochondria.

– Impaired mitochondrial function can also induce abnormalities in tumor suppressor genes and oncogenes.

– Some viruses are associated with certain cancers. Several of these viruses are known to affect the mitochondria.

– While the mutator phenotype of cancer can be linked to impaired mitochondrial function, normal mitochondrial function can suppress tumorigenesis. We can suppress cells capability of causing tumors by fusing cytoplasm from normal cells without a nucleus with tumor cells. This suggests that normal mitochondria can suppress the tumorigenic phenotype [3].

– The function of a tumor suppressor gene called p53 is linked to cellular respiration. Damage to the respiration will gradually reduce p53 function.

– The study of cancer and metabolism involves such fancy words as «the Warburg effect» and «von Hippel-Lindau,» so there’s got to be something to it 🙂

If cancer is a disease of energy metabolism, then a rational approach to cancer management can be found in therapies that target energy metabolism. 
The cure

– Growth and progression of cancers of the mammary, brain, colon, pancreas, lung, and prostate has been reduced following energy restriction.

– Due to accumulated genetic mutations, cancer cells lack metabolic flexibility, so shifting the metabolism makes sense.

– Many tumors have abnormalities in the genes and enzymes needed to metabolize ketone bodies for energy so ketogenic diets are especially potent.

– It is well established that dietary energy restriction protects against cancer in many animal models, but…

– Freedland and coworkers transplanted prostate cancer cells into mice. The mice were then divided into one ketogenic group, one low fat group and one western diet. After 51 days the tumor volume in the low carb mice was 33% smaller than the other two groups, despite similar energy intake [5].

– Zhou and coworkers put mice with malignant brain cancer on a ketogenic diet meant for epilepsy and showed that the diet decreased the intracerebral growth by 65% compared to mice on control diet [6].

– LJ Martin and coworkers randomized women to a low fat diet or a control group, hoping to affect the risk of breast cancer. They did. But not how they wanted. Over an average of 10 years low fat eating led to 118 invasive breast cancers while the control had 102. Carbohydrate intake was found to correlate with cancer risk [7].

– A group of Japanese researchers [8] hypothesized that the increase in colorectal cancer in Japan could be due to increased fat intake. So they told 373 people with previous cancer to restrict their fat energy ratio to 18-22%. After 4 years the researchers were surprised to find that fat restriction had increased the risk of cancer recurrence.

– A group of Italian researchers found direct relations between dietary GI and GL and risk of renal cell carcinoma [9].

– In 1995, two pediatric patients with malignant Astrocytoma tumors were put on a 60% MCT diet to induce ketosis. PET scans indicated a 21.8% average decrease in glucose uptake at the tumor site in both subjects One patient exhibited significant clinical improvements in mood and new skill development during the study- continued the diet and remained free of cancer progression [10].

– An Italian case control study from 1996 found that the risk of breast cancer decreased with increasing total fat intake and that the risk increased with increasing intake of available carbohydrates [11].

Eugene Fine at Albert Einstein College of Medicine of Yeshiva University, have been using a 1 month Atkins diet in cancer patients, hoping to see a reduction in tumor size. Results have not been published yet.

Stephen J. Freedland at Duke Univeristy is currently testing the hypothesis that an Atkins diet will prevent or at least minimize the metabolic consequences of androgen deprivation therapy in prostate cancer treatment.

The University of Würzburg Hospital has recommended a low carb, ketogenic diet for cancer patients since 2007

– Other studies are testing ketogenic diets in relation to cancer treatment. There’s much interesting knowledge to come


Impaired mitochondrial energy metabolism seems to underlie the origin of most cancers. To improve mitochondrial function: avoid toxic foods, read the Perfect Health Diet, avoid foods that induce inflammation, make sure to produce ketones now and then and remember to exercise. 


1. Lindeberg S: Food and western disease: health and nutrition from an evolutionary perspective. Chichester: Wiley-Blackwell; 2010.

2. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M: Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008, 371: 569-578.

3. Seyfried TN, Shelton LM: Cancer as a metabolic disease. Nutr Metab (Lond) 2010, 7: 7.

4. Tabares-Seisdedos R, Dumont N, Baudot A, Valderas JM, Climent J, Valencia A, Crespo-Facorro B, Vieta E, Gomez-Beneyto M, Martinez S, Rubenstein JL: No paradox, no progress: inverse cancer comorbidity in people with other complex diseases. Lancet Oncol 2011, 12: 604-608.

5. Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, Aronson WJ, Cohen P, Hwang D, Peterson B, Fields T, Pizzo SV, Isaacs WB: Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 2008, 68: 11-19.

6. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, Seyfried TN: The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 2007, 4: 5.

7. Martin LJ, Li Q, Melnichouk O, Greenberg C, Minkin S, Hislop G, Boyd NF: A randomized trial of dietary intervention for breast cancer prevention. Cancer Res 2011, 71: 123-133.

8. Nakamura T, Ishikawa H, Takeyama I, Kawano A, Ishiguro S, Otani T, Okuda T, Murakami Y, Sakai T, Matsuura N: Excessive fat restriction might promote the recurrence of colorectal tumors. Nutr Cancer 2010, 62: 154-163.

9. Galeone C, Pelucchi C, Maso LD, Negri E, Talamini R, Montella M, Ramazzotti V, Bellocco R, Franceschi S, La Vecchia C: Glycemic index, glycemic load and renal cell carcinoma risk. Ann Oncol 2009, 20: 1881-1885.

10. Nebeling LC, Miraldi F, Shurin SB, Lerner E: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 1995, 14: 202-208.

11. Franceschi S, Favero A, Decarli A, Negri E, La Vecchia C, Ferraroni M, Russo A, Salvini S, Amadori D, Conti E, Montella M, Giacosa A: Intake of macronutrients and risk of breast cancer. Lancet 1996, 347: 1351-1356.,8599,1662484,00.html

Macronutrients and food reward

If you see one bright red swan, you are not likely to give up a theory that says that all swans are white; you will instead go looking for the person who painted it. 

Imre Lakatos 

Much is being said on this subject. Bet many are getting pretty fed up by now. But I still think this is an interesting discussion and so I will take this opportunity to add some thoughts. After all, the goal here is to find the truth; to find out how the world works. In that respect, I would also like to say that I do not agree with any one side in this discussion. Scientifically speaking, agreeing is not very scientific. That would mean confusing matters of opinion with matters of fact. Things are just what they are.

Chris Kresser is of course right in that there is no single cause of obesity. In animal studies obesity can be induced in a number of ways, just as in humans. The fat tissue is a large part of our body and it has a wide range of receptors and interesting signaling, so it should not come as a surprise that there are many ways to become fat.

If we are to look for a general cause, we could say that western, post agriculture lifestyle is to blame for obesity and our lifestyle diseases. But that does not mean you cannot get fat eating paleolithic foods, although if you did, you should blame your parents for the lousy chromosomes.

Neither carbohydrates nor food reward is able to explain all the observations. They both explain a part of the observations and so are both likely influential factors. Just how big a role each plays is an extremely difficult question to answer. Thus the current discussion.

The key question is: Why is not hunger down-regulated in humans becoming fat?

The Guru Walla
From what I can see, the Cameroonian Guru Walla is a bland food, overeating, fat gaining rite.

In the Guru Walla ritual, young Cameroonian men consume a diet made of red sorghum and cow milk (makes up over 95% of calories). The young men isolate themselves in different houses with a female attendant devoted exclusively to the preparation of Guru Walla meals. The diet and exclusion is supposed to lead to a certain level of purity. The men eat every 3 hour for 60 days, during which time body-weight can increase by an average of 17kg. Only 64-75% of the weight gain is fat [1].

Traditional food amongst these Cameroonians is about 75% CHO, 10% fat and 15% protein. During the Guru Walla it is 70% CHO, 15% fat and 15% protein.

The Guru Walla food is obviously fattening; at least if force fed and combined with minimal physical activity. The question we need to ask is: Would the Cameroonians be overweight if all they consumed was the Guru Walla diet?

It seems that the Cameroonians do not get fat because of the food itself. Rather they become fat because they force feed themselves. The newly gained weight is also lost after the ritual.

The reason I called the Guru Walla food bland, is that it most likely is very bland after the first few days. Try eating any one food exclusively for 2 months, and eat it even though you are not hungry (vomiting is also a part of the Guru Walla). The dopamine reward response should be minimal. Remember the Twinkie Professor who ate nothing but Twinkies, Oreos, donuts and similar crap but who lost 27 pounds in a 10 week experiment. He did consciously under eat, but my point is that we need to ask ourselves how lack of variation affects reward.

Food reward
While food reward might help explain why we overeat at a biochemical level, there is little evidence to indicate that a fat loss diet needs to be unrewarding, if by unrewarding we mean less palatable. We also need to know if it is possible to unconsciously overeat (become fat) on rewarding foods if we have a working metabolism and the rewarding foods do not mess with our metabolism. If not, whatever caused the metabolism to go out of whack is the real problem.

Stephan’s bland food through a straw experiment does not necessarily support a theory claiming that the study participants lost weight because of an inherently unrewarding quality of that particular diet. The finding could easily also support the theory that eating only one food, no matter how rewarding it may be when consumed intermittently, will make people lose weight because the rewarding quality of that food declines with increasing intake.

So we need to know if people could lose similar amounts of weight eating other foods exclusively.

I am still having trouble seeing what’s the big fuzz about leptin. It is a signaling molecule. It signals energy surplus and the lack of leptin signals lack of energy. Leptin also increase fat oxidation. The leptin deficient animal models, that are obese, act and behave as they were starving and administering leptin normalize their behavior and induce weight loss. Either the body just needed to be told that it had stored energy to use, or we just needed to increase fat oxidation. If you increase fat oxidation by other means such as GH, ob/ob mice lose weight just as with leptin.

If for example high insulin levels cause leptin resistance, focusing on leptin does not add anything to obesity treatment. High insulin levels can also be caused (or at least be exacerbated) by factors other than carbohydrates. For example factors that messes with liver function.

“In particular, protein-rich foods such as beef can increase insulin secretion as much as certain starch foods such as pasta, or more.” 

The quote takes the results from trials out of context. It is an unfair statement, just like “proteins are inherently satiating” statement. A few days of beef eating will likely lead to lower insulin than a few days of pasta. I’ve written some about satiating proteins here.

In overweight people, as in overweight animal models, the key issue seems to be a reduced fat oxidation. Reduced fat oxidation with a high energy intake cause fat deposition in most all tissues and also insulin resistance.

Anything that increase fat oxidation in overweight animal or humans, cause weight loss and reduced food intake.

Lessons from insulin resistance
Stephan claims that overweight people have high serum free fatty acids. This is not completely true, at least if we are to listen to Keith Frayn at [2]. The claim may be true in general, but there are lots of overweight people with normal FFA levels. This however does not change Stephan’s argument. Generally the fat tissues of the overweight give out more FFA indicating adipose tissue insulin resistance.

Here is how we imagine insulin resistance to occur (roughly):

The pancreas has a direct route to the liver. The reason for this direct route is that the liver controls blood sugar level through its production of glucose. When blood sugar rises, the pancreas notice and secretes insulin. When the liver receives this insulin, glucose production is reduced. As the cells in the body are utilizing glucose for fuel, blood glucose level drop.

Somehow the liver becomes insulin resistant and keeps sending out glucose despite the insulin being sent from the pancreas. The reason seems to be inflammation and/or buildup of fat (NAFL). In this insulin resistant state, the muscles also fill up with fat. Once glycogen stores are full they become insulin resistant to avoid sugar poisoning, but keep taking up fatty acids. Because of the high carb diet and/or lack of physical activity the muscles do not burn fat and so it builds up. Also, there is some loss of muscle and liver mitochondria function and probably fatty acid transport into mitochondria.

The fat tissue takes up both glucose and fatty acids and expands if it takes up more than it gives out. The expansion of fat tissue eventually cause fat cells to send out stress signals (probably caused by endoplasmatic reticulum stress) and macrophages invade the tissue, gathering around dying fat cells. In this state, the fat tissue secretes a lot of fatty acids that wreak havoc around the body. But if free fatty acids are not burned they need to be re-esterefied. A high FFA level does not mean that we are not gaining weight or that we are losing weight (that more fat is leaving than entering the fat tissue). FFA are measured fasting and although the level might be higher in overweight and insulin resistant in that fasted state, this does not mean that over time more fat is leaving the fat tissue than are entering.

Stephan Guyenet takes the high FFA-level often observed in the overweight to mean that the fat tissue is insulin resistant and that they could not be gaining weight. This might be a wrong assumption. They have definitely been gaining weight and most overweight people are either weight stable or gaining weight. Is it impossible to gain weight while still having high FFA level?

Lean people also get insulin resistant. As do animals and humans with lipodystrophies. Many massively overweight do not become insulin resistant, and it seems that what causes the overflow of free fatty acids from adipose tissue is that it reaches its limit – a limit of course determined by both genetics and lifestyle.

In the insulin resistant state (metabolic syndrome), free fatty acids are usually high and fat builds up everywhere. Anything that increases fat oxidation helps. Pharmacological inhibition of the oxidation of fatty acids in the liver stimulates food intake in both humans and rats and stimulation of hepatic fatty acid oxidation reduces food intake, weight gain and adiposity in rats with diet-induced obesity [3].

FFA’s come from food, the liver or fat tissue. Carbohydrates are largely responsible for the amount secreted by the liver. At a cellular level, insulin resistance/metabolic syndrome seem to come from a high total energy intake. There is a surplus of both glucose (glycogen) and fat and the body can’t handle it all. Reducing the dietary fat load helps (at least if hypocaloric), but reducing dietary carbohydrate is the most efficient treatment to date. The question, though, is still why these people overeat.


“…for insulin to cause fat gain, it must either increase energy intake, decrease energy expenditure, or both.” 

“If calories and protein are kept the same, high-carbohydrate meals cause equal or greater satiety than high-fat meals, and equal or less subsequent food intake, despite a much larger insulin response)” 

Stephan Guyenet

Insulin will reduce hunger as long as there is energy coming from ingested food. Once that flow of energy stops or is reduced, a high insulin level cause hunger. In order for insulin to cause overweight, the level only needs to be high enough for allowing fat oxidation to be less than fat storage in that particular individual over time.

Injecting both glucose and insulin reduce hunger. Injecting insulin alone increase hunger. Long term satiety is better with low carbohydrate diets than high. We need to remember that we adapt to burning different fuels. If we normally eat high carb and suddenly eat high fat we are likely to be poor fat burners and thus more likely to get hungry. This might also explain higher leptin levels after high fat meals in acute feeding studies.

“If blood glucose decreases enough, it activates a system called the «counter-regulatory response», designed to maintain blood glucose at all costs to protect the brain from the effects of hypoglycemia. Part of this response is hunger and increased food intake. However, this system is not activated except in severe hypoglycemia, which is rare except in diabetics, thus it is not relevant to common obesity.” 

This quote seriously needs references. It seems very unlikely.

These are just some thoughts. Nothing more.


1. Pasquet P, Brigant L, Froment A, Koppert GA, Bard D, de G, I, Apfelbaum M: Massive overfeeding and energy balance in men: the Guru Walla model. Am J Clin Nutr 1992, 56: 483-490.

2. Taubes G: Insulin resistance. Prosperity’s plague. Science 2009, 325: 256-260.

3. Ji H, Friedman MI: Reduced capacity for fatty acid oxidation in rats with inherited susceptibility to diet-induced obesity. Metabolism 2007, 56: 1124-1130.

The causality of insulin resistance

There seem to be two large somewhat competing hypotheses trying to explain the causality of insulin resistance (as measured at a whole body level). The lipotoxicity hypothesis, explains to us how insulin sensitivity is reduced in tissues when too much fat builds up in the specific tissue cells; likely caused by high serum levels of free fatty acids and triacylglycerols. The other hypothesis is the inflammation hypothesis, which seeks to explain reductions in insulin sensitivity by high levels of inflammation, possibly caused by stress in general, endoplasmatic stress or dietary fatty acid composition and more.

Both inflammation and cellular lipid overload correlate with insulin resistance and the metabolic syndrome and looking at the literature it seems that both mechanisms have to be a part of a causal chain.

The big unanswered question here is the direction of causality. Overweight, atherogenic dyslipidemia, inflammation and other factors appear in concert with insulin resistance. But what comes first? Does obesity cause insulin resistance or is there some underlying factor causing both insulin resistance and obesity? And which tissues are the first to become insulin resistant? 
Clever scientists have succeeded in creating animal models that are extremely good at storing energy as fat. The funny thing is that this ability seems to protect against insulin resistance. The consequence of this research is the notion that if you are really good at getting fat, you are protected from insulin resistance. The existence of lean insulin resistant individuals would support this notion and would also cast doubt on overweight causing insulin resistance.

There is more to support the above mentioned. It has been proposed that insulin resistance develops because of an imbalance of fat distribution between the tissues. Consistent with this hypothesis is the observation that some obese individuals have few manifestations of the metabolic syndrome. Normoglycemic and normolipidemic obese individuals display improved postprandial fat storage compared with lean subjects. Presumably, the more efficient adipose tissue fat-storing capacity the better the protection against lipotoxicity in nonadipose tissues with reduced risk of insulin resistance.

The pool of FFAs in fat cells is released into the circulation in relation to its size and the greater total fat mass of adipose tissue in obese individuals result in elevated fatty acid flux to nonadipose tissues. Although this is commonly accepted at indisputable, it has proven difficult to find that overweight and obese individuals consistently have higher serum FFA levels. Insulin resistance is not likely caused by overweight in itself. We can conclude this way because there are lean insulin resistant people and as mentioned, many overweight people are also insulin sensitive. There must be some other cause.

Non alcoholic fatty liver also correlates with insulin resistance. Fructose intake has been found to be associated with insulin resistance. Children with non-alcoholic fatty liver disease have been found to have diets high in fructose in addition to low activity patterns.

Fructose is indeed an interesting factor with respect to insulin resistance. It is also a likely candidate for a causal factor
Gross et al examined nutrient consumption in the United States between 1909 and 1997, and found a significant correlation between the prevalence of diabetes and corn syrup. Both high fructose corn syrup and sucrose contribute to high intakes of fructose. The use of HFCS in the US has apparently increased by 1000% between 1970 and 1990.

Fructose is treated and metabolized differently from glucose in the liver. It is extremely lipogenic and makes the liver churn out large amounts of triacylglycerol leading to high levels of VLDL and small dense LDL. This fat producing ability is thought to contribute to cellular lipid overload and insulin resistance.

Chronic fructose consumption also reduces the adipocyte derived hormone, adiponectin, which also seem to contribute to insulin resistance. In addition, despite its low glycemic index chronic ingestion of fructose actually seem to stimulate hyperinsulinemia.

Dietary macronutrients
The metabolic syndrome consists of a cluster of risk factors for diabetes and cardiovascular disease. These are overweight (now commonly measured as waist circumference), hypertriacylglycerolemia, reduced HDL levels, increased blood pressure and increased fasting glucose. Insulin resistance is generally a common feature of the syndrome and a likely causative agent for several of these factors.

Volek and Feinman made a funny observation in 2005. They found that the factors that define the metabolic syndrome are the same factors that are greatly improved by carbohydrate restriction. They proposed that the metabolic syndrome may well be defined by the response to carbohydrate restriction.

Carbohydrate restriction is still not recommended as the standard treatment for the metabolic syndrome despite the fact that improvements in these factors don’t even require weight loss (as it does with low fat/calorie diets) on a low carbohydrate diet.

If carbohydrate intake can improve all the factors of metabolic syndrome and insulin resistance is an important part of this syndrome. And if we know how carbohydrates in general contribute to high levels of triacylglycerols and FFA, especially fructose, then dietary carbohydrate is indeed a very likely causative factor for insulin resistance.

There is a very strong relationship between “central” fat distribution and insulin resistance. Robert Eckel claims that the sum of the evidence indicate that the metabolic syndrome (read insulin resistance) begins with excess central adiposity. By this logic, whatever cause central obesity is then what we should focus on.

A side note to central adiposity is the interesting findings of the Womens Health Initiative. After 7 years of following a diet with more fruit, vegetables and grains and less fat the 19 541 person intervention group had  increased their waist circumference. The depressing findings of what happens when women are advised to follow the national guidelines for dietary intake, lead the authors to the tragicomic conclusion:

A low-fat eating pattern does not result in weight gain in postmenopausal women.

Numerous clinical and experimental studies have linked stress to metabolic disorders. The obvious culprit is cortisol and subsequent hypercortisolemia. Cortisol has particularly strong effects on visceral fat. Giving corticosteroids in the drinking water of mice result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triacylglycerol levels, hyperphagia, and decreased locomotion.

As visceral fat storing is a trademark of the insulin resistance metabolic syndrome, and all the factors of the syndrome are greatly improved by dietary carbohydrate restriction it is also likely that the combination of stress and a high carbohydrate diet sets the stage for insulin resistance.

The causality
No matter the mechanisms, there are likely conclusions to be drawn. Although it seems that carbohydrate intake and composition, physical activity level and stress all contribute to insulin resistance in some manner, one factor seems to stand out. I would be quick to remove low physical activity level from my list, because I believe this is likely an effect of a fat tissue that is reluctant to release stored energy. Its reluctance is likely (for the most part) caused by high insulin levels caused by dietary carbohydrates. Exercising an overweight person on a high carbohydrate diet is like exercising an anorectic person. The energy is not there to be used. Carbohydrate intake must first be manipulated in order to increase fat release and oxidation.

If excessive carbohydrate consumption causes obesity, insulin resistance and metabolic syndrome (and it likely does), and all of these factors are improved or cured by removing dietary carbohydrates, then dietary carbohydrates are a strong, if not the strongest candidate for the causal role. This conclusion is reached by looking at the physiology only, and including evolutionary and epidemiological data, I believe would only serve to strengthen this hypothesis.   

My proposed chain of causality is something like this:

Stress and high levels of FFA and triacylglycerol caused by high carbohydrate intake, stresses and pressures the fat tissue to grow. Inflammation occurs as a consequence, and the liver becomes insulin resistant because the inflammatory substances impair insulin signalling in the liver. The liver then does not decrease its glucose production in response to insulin. Increased glucose levels cause more inflammation by causing fat cells to grow even more. The cells grow due to hyperinsulinemia caused by high liver glucose output. The fat cells then become insulin resistant and do not reduce FFA production in response to insulin. This increases FFA levels which makes tissues fill up with fat (among them the pancreas, which results in abnormal insulin output) and become insulin resistant as well. All this is happening while the individual is getting more overweight and diabetic, and inflamed to the point of near combustion. 

Just a small reminder

”…low carbohydrate diet sets the stage for a significant loss of lean tissue as the body recruits amino acids from muscle to maintain blood glucose via gluconeogenesis.”
                          Exercise Physiology, Mcardle, Katch & Katch 2007
There is one aspect of human metabolism that is too often overlooked in the discussion of human nutrition and exercise metabolism. It is the simple fact that there are two energy sources for our cells. Energy from the food we eat and energy from energy stores in our body (glycogen and fat).
I am often met with the claim that muscles cannot hypertrophy if you are in a negative energy balance. I am willing to agree that the claim does seem plausible, but it is misunderstood. It is misunderstood because we have to view the energy situation from the muscles point of view.
The muscles do seem to require a positive energy balance to grow, but they require a local positive energy balance, not a whole body positive energy balance. Simply put, the muscles may have surplus energy even though we consume less energy than we expend, provided the energy stores give out enough energy.
Local cellular energy availability does not necessarily reflect whole body energy availability. This means that we can loose weight as fat while gaining muscle mass even if our body is in a negative energy balance.
Loss of muscle mass or lean body mass is common in weight reduction studies. The number is often as high as or higher than 30% of total weight lost. This is counterintuitive. The point of loosing weight when you are overweight is to lose fat not muscles.
It seems that in studies of low calorie diets that the muscles often lack the energy to maintain their size. In a recent study by Wycherley et al, 59 overweight persons with diabetes did calorie restricted diets combined with supervised resistance exercise 3 days a week. You would expect to see an increase in muscle mass from all this resistance exercise, but after 16 weeks the participants had lost on average 2kg of fat free mass.
To be fair, several studies have shown maintenance of fat free mass with weight loss from calorie restriction when combined with resistance exercise. But calorie restriction may not be the best way to tap into the body’s energy stores.
A low carbohydrate diet will increase the availability of the energy stored as fat. In addition, ketone bodies prevent a large use of proteins for glucose production. Contrary to what the quote at the start of this post claims.
In 2002 Volek et al  put overweight men on a 6 week diet with only 8% carbohydrate. The study caused an obvious decrease in fat mass, but in combination with a significant increase in lean body mass, without a resistance exercise intervention.
Willy et al put six overweight adolescents on a ketogenic diet and observed an average weight loss of 15.5kg in combination with 1,4kg increase in lean body mass. All in eight weeks.
Individual results in studies show that it is possible to markedly increase muscle mass while reducing fat mass. I’ve personally seen large reductions in fat mass in combination with more large increases in lean body mass from a combination of carbohydrate restriction and resistance exercise.
My point is that if muscles require a positive energy balance to hypertrophy, carbohydrate restricted diets offers an effective way of giving muscles the energy they need while reducing fat mass. Future studies will hopefully elucidate further.

Cancer as a metabolic disease

Is cancer a metabolic disease?
In principle, there are few chronic diseases more easily preventable than cancer.
Seyfried and Shelton 2010

A new and important article in Nutrition and Metabolism makes a case for cancer as predominately a metabolic disease. Research has shown that one of the key features of cancers is an impaired or damaged respiration. In fact, as the authors put it, “Aerobic glycolysis, arising from damaged respiration, is the single most common phenotype found in cancer.” Evidence is reviewed supporting a hypothesis that cancer is a disease of energy metabolism, primarily liked to mitochondrial function.

The hypothesis isn’t new. It was first proposed in the early twentieth century, but was soon displaced with the view of cancer as a genetic disease. Emerging evidence however, questions the genetic origin of cancer and suggests that cancer is primarily a metabolic disease. Damage to cellular respiration may easily precede and underlie the known genome instability associated with tumor development. Once genome instability is established, it increases and furthers respiratory impairment which increases mutation and tumor growth, and we’ve got ourselves a vicious cycle.

The article asks the question “Is it genomic instability or is it impaired energy metabolism that is primarily responsible for the origin of cancer?

The question is of immense importance, as the answer will impact the way we view and treat cancer.

Dietary energy restriction has been used to lower glucose levels, thus reducing growth and progression of several tumor types, like mammary, brain, colon, pancreas, lung, and prostate cancers. Enhanced glycolysis (breakedown of glucose) is required for the rapid growth and survival of many tumor cells, and a treatment targeting cell metabolism will be of great importance.

A shift from glucose to ketone body and fatty acid use would be beneficial because it targets only cancer cells with their reliance on glycolysis, while being benign or even beneficial for normal cells. Not only do cancer cells rely heavily on glucose for fuel, but many do also have abnormalities in the genes and enzymes needed to metabolize ketone bodies for energy.

Despite making a case for a shift in metabolism from glucose to ketone body use, the authors do not make a case for low carbohydrate diets, but rather propose the use of energy restriction to cause a dietary ketosis.
Prostate and gastric cancer are manageable using low carbohydrate ketogenic diets, and these diets are far more efficient and safe for inducing dietary ketosis compared to general energy restriction. Metabolism of ketone bodies for energy can also maintain mitochondrial health and efficiency thus reducing the risk of cancer development.

From the conclusion: 
Two major conclusions emerge from the hypothesis; first that many cancers can regress if energy intake is restricted and, second, that many cancers can be prevented if energy intake is restricted. Consequently, energy restricted diets combined with drugs targeting glucose and glutamine can provide a rational strategy for the longer term management and prevention of most cancers.
Despite beating about the bush when it comes to carbohydrate restriction, this is recommended reading!

A scale model of obesity

Whatever the individual cause of obesity is, in the absolute majority of cases, carbohydrate restriction works effectively at reducing adipose tissue weight. This is a common observation in most human and animal studies. Carbohydrate restriction for the most part works because it influences insulin and glucose. In addition it affects our sensations of hunger and satiety and affects the energy flow to the individual tissues. This might be a simplification, but it’s a fair simplification. The increased fat storage and insufficient fat release apparent in overweight must in most cases be explained by the specific disease or condition’s influence on insulin and glucose metabolism, simply because insulin and glucose are the main regulators of fat metabolism.

I’ve often pictured the adipose tissue as a scale. All the factors that influence energy release from this tissue rest in one cup and all the factors influencing storage of energy rest in the other. Tipping the scale to one side symbolizes fat storage, tipping to the other symbolizes fat release. If the scale is in perfect equilibrium, the storage of energy matches the release of energy and the fat tissue remains roughly the same size.

Most people are more or less weight stable most of the time. The behavior of our fat tissue is, like most other physiological processes, a process seeking equilibrium (although not likely due to a set-point). Imagine any factor that is known to influence fat metabolism. Take dietary carbohydrates. Let us ad an increased intake of dietary carbohydrates as a factor on one side.

The factors contributing to the storage of energy now overpower the factors contributing the release of energy. Increasing carbohydrate intake will cause a decrease in lipolysis (fat release), mainly through the increased insulin release and increased glucose levels. Tipping the scale in this way (provided all other factors remain constant) will cause a net storage and we will gain weight in the form of fat. A larger fat storage in relation to the fat release will cause a more rapid weight gain. Of course, the scale that is our fat tissue goes up and down during the day and night. It does not remain in a fixed position for any amount of time, but the more time spent below horizontal position on one side in relation to the other, the larger the effect.

Adding an increase in exercise level to the scale will once again tip it towards equilibrium. 

Exercise improves the glucose tolerance of our skeletal muscles. Exercise might increase the level of LPL (lipoprotein lipase) in muscles and reduce the level in fat tissue. It might increase glucose uptake in muscles both by reducing glycogen stores, increasing glucose transporters or simply increasing muscle size. The net effect of exercise is that blood glucose and insulin levels are kept at a lower level and the scale is tipped in favor of fat release. Although exercise very often does not make us leaner, it may also do so and the above-mentioned mechanisms are likely explanations.

Exercise and diet are two lifestyle factors with large impact on our imaginary scale. Lifestyle factors do however affect us differently because of our different genetic heritage. Genetic factors may also more easily be understood using a scale model. Looking at fat storage this way, might give us a simple way of explaining many of the often-cited paradoxes of overweight.

Imagine for example that you are overweight while your brother is not, despite having an apparently similar lifestyle. It seems that your scale is tipping in the opposite direction of that of your brother (or sister, friend or whoever). As fat storage most often must be explained through insulin and /or glucose metabolism and not through energy intake or energy expenditure, we can imagine several scenarios that could explain the brotherly differences. Perhaps your brother has been genetically equipped with a more effective glucose uptake in skeletal muscles or that he needs a smaller stimulus (physical activity) in order to improve glucose uptake. A better glucose uptake would mean smaller increase in blood glucose after ingestion of dietary carbohydrate, a smaller insulin release and thus a smaller fat storage with an ensuing better fat release. This small difference would mean that your brother could consume more dietary carbohydrate without tipping the scale too far in direction of fat storage. It might also make your brother more physically active. It is not fair, but it is how it is. We are not all equipped with the same physiology or the same potential for changing our physiology.

I don’t suspect my scale contributes to the knowledge and understanding of health and nutrition, but it has helped me picture how our body works and it reminds me that overweight is about fat tissue size and not body size or body weight. When faced with a non responder (e.g. a person not losing much weight with carbohydrate restriction) we know the factors working against fat storage overpower the factors working for fat release. Knowing the effect of different factors on our physiology we can easily investigate the less common factors like cortisol, thyroid hormones or perhaps myostatin for that matter. The scale may help remind us that we are built differently and respond differently to any external factors.

I am still surprised by the way people often talk about overweight as if we were all physiologically identical. Most people will for example have no difficulty admitting that we tan differently and have different skin complexions from birth, but somehow when it comes to weight it is often expected that we are all created equal. Well, we’re not. Although the underlying cause of overweight and obesity are pretty much the same in all of us, we all have different potential to gain weight both locally and systemic. The scale model may illustrate our genetic differences and answer the poor, but often encountered argument «If carbohydrates make us fat, why isn’t everybody consuming carbohydrates fat?» Our scales are loaded differently from birth. Carbohydrates in a certain amount definitely do have the potential to make most of us fatter, but from a physiological point of view, we are not created equal.

Does it fit the facts?

Explaining overweight through the effect of insulin and glucose metabolism on fat tissue can so far only be termed a hypothesis. It is a hypothesis build primarily on physiological knowledge. The next logical step is to check if the hypothesis fits the observations that have been done and if it can adequately explain these observations. If not, we need a new hypothesis. If it indeed can explain observational data then this serves to strengthen the hypothesis and to increase the likelihood of it being correct.
So does it all fit the facts? 

One way to find out would be to ask overweight people in a controlled environment to consume as much energy as they want and to expend as much energy as they feel, as long as no carbohydrates are consumed. If our hypothesis is correct, we would expect these people to lose weight while on this diet. To further increase the quality of our data, we could include a control group whose energy intake is equal, but with no restriction in carbohydrate intake.

The good thing is that we don’t have to do these studies. They have already been done. In randomized controlled trials (several groups of people who are randomized to different interventions) carbohydrate restriction does usually cause a larger weight loss than fat or calorie restriction. This observation holds true for both sexes and in a wide age range. When total weight loss has been found to be similar in such trials, it is usually because carbohydrates have been reintroduced into the diet of the low carbohydrate group thus reducing the amount of weight lost.
But, remember that this is about fat tissue reduction, not weight reduction. The important question is of course whether carbohydrate restriction is more effective at reducing fat tissue mass than calorie reduced diets of similar energy intake. And indeed they are. I’ve checked. In most randomized controlled trials that has measured the different body tissues, low carbohydrate diets cause larger reductions in fat mass and thus body fat percentage. I’m not the only one who’s checked by the way. In 2006, Krieger et al did a meta-regression of diet trials and concluded that:
Low-carbohydrate, high-protein diets favorably affect body mass and composition independent of energy intake, which in part supports the proposed metabolic advantage of these diets. “   
Weight loss is almost never a loss of just fat mass. Other tissues are reduced as well and mostly skeletal muscles. Even though many trials of low carbohydrate diets have shown a relatively large reduction in fat free mass, there are other findings still, that support the notion that carbohydrate restriction favorably affects non fat tissues. In one trial, Volek et al (2002) demonstrated that carbohydrate restriction for six weeks caused not only a significant loss of fat mass, but also an increase in muscle mass. This same finding has also been reported by Steven M. Willi and colleagues who did a trial on six overweight adolescents. In addition, other trials have shown a larger retention of muscle mass with weight loss with low carbohydrate diets compared to low fat diets. But it seems that a requisite for proper muscle mass retention is an adequate protein consumption.   
Carbohydrate restriction do usually results in larger loss of fat mass and body weight compared to diets higher in carbohydrate. So far our observational data support our hypothesis. There has even been reporting of correlations between insulin levels and the amount of fat lost. It all seems to fit the facts.
A funny “byproduct” of many of the dietary trials that have been made in recent years, is the discussion of thermodynamics in weight loss diets. What sparked the discussion was the finding that carbohydrate restriction has caused up to twice the weight loss as a low fat diet containing just as many calories. Several studies reported a larger weight loss with carbohydrate restriction even though the control group consumed just as many calories but with a higher carbohydrate content. These observations have sparked a debate in the scientific community as to whether any thermodynamic laws have been broken in the process. The common dogma of nutritional science is that a calorie is a calorie, meaning that you should lose just as much weight cutting fat from your diet than from cutting carbohydrates. The thing is that from a physiological point of view this doesn’t make any sense. From a physiological point of view, carbohydrate restriction could easily cause a greater weight reduction than fat restriction despite equal energy intake. Two new expressions are being used to describe this advantage of low carbohydrate diets; decreased caloric efficiency or a metabolic advantage. As it happens none of the laws of thermodynamics have yet been broken, but as Richard Feinman puts it: saying that a calorie is a calorie is a violation of the second law of thermodynamics.
Physiological data tells us that dietary carbohydrates are the main regulator of whether the fat tissue gives up energy or stores energy. If less is given up than what is stored we gradually will increase the size of our fat tissue. In addition to these physiological data, diet trials show us that we’ve most likely got our physiology right. Carbohydrate restriction does indeed cause large reductions in fat mass and is the most effective way to reduce fat tissue size. If we add to this by addressing epidemiological data showing increased intake of refined carbohydrates correlating with increased rates of overweight and obesity, we have ourselves a pretty strong case.
So does it all fit the facts? Well yes, it certainly appears so. In fact it fits so well that any dietary overweight treatment that is not based on a reduction in the intake of carbohydrates could easily be called malpractice. Especially when we know that the most common long term effect of a reduction in fat intake is an increase in body weight (even George Bray with coauthors admitted this much in their Handbook of obesity). If a doctor recommends energy and fat restriction, than this consequently is also a recommendation of a weight loss followed by an increase in weight to a level surpassing the starting weight.