After years of research, cancer remains an enigma. It's certainly a label that covers many diseases and one size doesn't fit all, but we also know that obesity and processed foods somehow play a key role-and all the clues are pointing at an unlikely culprit. Insulin, the life-saving hormone released by the pancreas to lower blood sugar (glucose) levels, is evidently an accessory to cancer.
New breakthrough studies, published over the last couple of years, are discovering that insulin helps tumours of all sorts to develop and grow, especially in the case of breast and prostate cancers. The hormone is usually seen as part of a vital process for maintaining a healthy life-just ask any type 1 diabetes sufferer who has to have regular injections of insulin to stay alive-but it can also aid and abet a killer.
Insulin and diet
Cancer specialists are only just beginning to recognize the role that insulin is playing in the develop-ment of cancer, and they believe that it's a characteristic of being overweight and obese. But other evidence suggests that they have it round the wrong way: high insulin production, or hyperinsulinaemia, can lead to obesity, and such a state is a direct result of eating processed foods. If that is so, then this is the strongest evidence yet that our modern Western diet is a major cause of cancer.
Insulin normalizes blood sugar levels, and it also helps body tissues to grow by either signalling growth or increasing levels of hormones that directly affect growth, an essential mechanism involving what are known as 'insulin-like growth factors' (IGF).
But this growth-stimulating process doesn't only aid normal, healthy growth and development; it also appears to be a co-worker with cancer towards the development of tumours when the pancreas produces an excess of insulin. Researchers have noted, for example, that people with cancers of the colon, breast and prostate have high levels of IGF circulating in their blood. Indeed, it has been established that IGF can be found in around 80 per cent of all cases of lung cancer (Neoplasia, 2009; 11: 672-82).
Most oncologists believe that insulin resistance is a direct result of obesity, but researchers are now finding a direct link between it-and hyperinsulinaemia-and carbo-hydrates, the huge food group that includes cereals, vegetables, glu-cose, fructose and sucrose. When carbohydrates were reduced or entirely eliminated from the diet, it was found that tumour growth was either slowed or stopped completely.
But the answer doesn't appear to be that simple. Other researchers have suggested that eliminating an entire food group will, in the long run, cause as many health problems as it solves. One study by the Rowett Research Institute in Aberdeen, Scotland, found that a low-carbo-hydrate diet also reduced levels of the fatty acid butyrate in the gut, which offers protection against colo-rectal cancer (FEMS Microbiol, 2002; 217: 133-9).
As Professor Harry Flint, the research team leader, has said: "In the long run, it's possible that such diets could contribute to colorectal cancer".
One of the best-known examples of the high-fat, low/no-carbohydrate approach is the Atkins diet, and its critics report that those who stay on the diet are also increasing their chances of developing heart disease (J Am Diet Assoc, 2009; 109: 1263-5).
And not all carbohydrates are bad for you. Scientists at the Burnham Institute for Medical Research in La Jolla, California, have recently discovered that complex sugar molecules known as 'glycans', a complex carbohydrate, appear able to suppress tumour growth (Proc Natl Acad Sci U S A, July 8, 2009; doi:10.1073 /pnas.0904515106).
The mistake appears to lie in treating all carbohydrates the same when, in fact, they come in many different varieties-from the single-molecule (monosaccharides) carbo-hydrates, such as glucose, fructose and galactose, and the two-molecule (disaccharides) carbohydrates, such as sucrose, lactose and maltose, to the multichain molecules (polysac-charides), which are the starches found in cereals, potatoes, root vegetables, seeds and pulses.
Most processed carbohydrates, which include white rice, white bread, biscuits and cakes, contain high levels of glucose, as measured by their glycaemic index (GI). The more high-GI carbohydrates we eat, the more insulin the pancreas has to produce to normalize the blood sugar ratio. As a result, most of us who are living on a Westernized, processed diet will suffer to some degree from hyperinsulinaemia. This can be a direct response to a high-GI diet or, because we have become insulin-resistant as a result of our diet-which is often the beginnings of type 2 diabetes-the pancreas will attempt to compensate with an overproduction of insulin. In either case, the excessive production of insulin evidently has two major effects:
- it is a cause of obesity, and
- it increases the risk of cancer.
Researchers in Italy were among the first to make the connection between high-glycaemic carbohydr-ates and breast cancer. In a study of 2569 women with breast cancer, who were compared with 2588 healthy controls, the scientists discovered that the women who regularly ate high-glycaemic carbo-hydrates, such as white bread, doubled their risk of breast cancer, whereas the effect was neutral among those who ate carbohydrates that had a more moderate GI score (Ann Oncol, 2001; 12: 1533-8).
Two years later, the leading oncologist Dr D. Barry Boyd, at the Greenwich Hospital in Connecticut, suggested that insulin and IGF might speed the cellular growth of cancers-especially breast cancer. He also suspected that high levels of IGF might even interfere with chemotherapy, causing it to be less effective (Integr Cancer Ther, 2003; 2: 315-29).
This theory was tested a year later, when researchers from the Brigham and Women's Hospital and Harvard Medical School in Boston profiled the breast cancer risk in a group of 475 women, aged 20 to 75 years, who were living in Mexico. Those who were eating the most carbohydrates were up to three times more likely to develop breast cancer compared with those who ate the lowest amounts in the group.
There were several compelling reasons why the researchers chose to study Mexican women. While carbohydrates have always formed a principal part of the Mexican diet, it's only been in recent years that the levels of obesity in Mexico have increased dramatically.
The main carbohydrates the women were eating were fructose and sucrose. Although fructose is one of the lowest GI foods, sucrose-found in sugar and many other processed foods-is among the highest. The carbohydrates, and not the fats, were apparently the cause of the increased risk of breast cancer, the researchers concluded (Cancer Epidemiol Biomarkers Prev, 2004; 13: 1283-9).
Another piece of the jigsaw was discovered only three years later, when researchers found that a low-carbohydrate diet significantly decreased the growth of brain tumours in mice (so it may not necessarily apply to humans). The research team, from the biology department of Boston College in Massachusetts, used a commercially available powdered food substitute called KetoCal-developed to treat children with epilepsy-that is high in fats (72 g) and low in carbohydrates (3 g). In mice, this diet decreased the growth of brain tumours by between 35 per cent and 65 per cent, and the survival rates in the mice on the special diet were also much higher. The researchers reckoned its success was because the diet "starved the brain tumour cells of the sugary molecules on which they rely for growth and survival" (Medical News Today, 26 February 2007; www.medicalnewstoday.com/ articles/ 63544.php).
These findings have been supported by another study involving laboratory mice this year. This time, the mice had prostate cancer and, again, a high-fat, low-carbohydrate diet slowed the growth of tumours. Lead researcher Stephen Freedland, a urologist at the Duke Prostate Center in Durham, NC, reported that the low- or no-carbohydrate diet significantly lowered serum insulin levels, thereby slowing tumour growth (Cancer Prev Res, 2009; 2: 557-65).
Freedland and his team are currently recruiting human subjects for another trial involving low carbohydrates and prostate cancer. "It's very exciting-this is a potential new mechanism to fight prostate cancer growth and help patients live longer with their disease," he said.
However, perhaps the most compelling evidence has been gathered by the researchers who profiled a subgroup of 1651 post-menopausal women from the US-based Women's Health Initiative Observational Study, half of whom had breast cancer. After taking blood samples, the researchers found that those women who had the highest insulin levels were nearly 50 per cent more likely to have breast cancer compared with those who had the lowest insulin levels.
"Women with the highest insulin levels in their blood were more than two times more likely to develop breast cancer," said lead author Marc Gunter, from the Albert Ein-stein College of Medicine of Yeshiva University, in New York. Although the ovaries stop producing oestro-gen after the menopause, such women can have higher levels of insulin, especially if they are obese (J Natl Cancer Inst, 2009; 101: 48-60).
Researchers have known for years that obesity, or a body mass index (BMI) greater than 30 kg/m2, is somehow related to cancer. In a major report published in 2002, the authors found that people who were obese or seriously overweight had a far higher risk of developing cancers of the colon, breast-especially if the woman was also postmeno-pausal-endometrium (the lining of the uterus), kidney and oesophagus. They also pointed out that there was a highly probable connection between obesity and cancers of the gallbladder, ovaries and pancreas, although the evidence for this was not so clear-cut. Indeed, overall, obesity may be the cause of 25-30 per cent of all colon, breast, endometrial, kidney and oesoph-ageal cancers (Vainio H, Bianchini F. IARC Handbooks of Cancer Prevention. Lyon, France. IARC Press, 2002).
In the US, around 41,000 new cases of cancer each year are considered to be directly related to obesity, representing 3.2 per cent of all new cases (Cancer Detect Prev, 2003; 27: 415-21). Another report reckoned that 14 per cent of all deaths from cancer in men, and 20 per cent of those in women, are due to obesity and being overweight (N Engl J Med, 2003; 348: 1625-38).
If these statistics are correct, then they clearly represent a major health problem, as nearly one-third of adults in the US, for example, are now classified as obese (JAMA, 2002; 288: 1723-7), an increase of 8 per cent in just eight years, while 15 per cent of children and adolescents up to 19 years of age are also obese, numbers which have trebled over the past 20 years (JAMA, 2002; 288: 1728-32).
Nevertheless, such a direct obesity-cancer connection appears to be overly simplistic. If obesity on its own were a major cause of cancer, then more than 41,000 obese people each year would develop the disease. Also, as there are about 218 million adults in the US, this suggests that around 72 million of them are obese, and only 0.06 per cent of these individuals are developing cancer every year.
Most cancer and health information groups agree with the current view that obesity is primarily the result of a sedentary lifestyle coupled with a diet that is high in calories or fat (J Nutr, 2003; 133 [11 Suppl 1]: 3827S-9S; Cancer Epidemiol Biomarkers Prev, 2001; 10: 287-301).
However, nutritional researcher Michel Montignac, who gave his name to his own GI diet, believes that the extent of an individual's hyperinsulinaemia also determines the extent of the obesity.
"What distinguishes the person who is overweight from the person who is slim is that the latter has a pancreas secreting just the right amount of insulin to bring a raised blood-sugar level down to its normal value. The overweight person does not. Instead of releasing the right amount of insulin, the pancreas will secrete more-sometimes much more-than is required to take sugar present in the blood down to its normal level," he says (Montignac M. Eat Yourself Slim. London: Montignac Publishing, 1999).
In its turn, hyperinsulinaemia initiates a metabolic process known as 'lipogenesis', where the body stores abnormally large amounts of fat instead of allowing it to be oxidized and 'burned' for energy. This means that an overweight person will tend to store fat because of hyperinsulinaemia or insulin resistance which, in turn, is caused by either a weak pancreas or a diet that is rich in high-glycaemic carbohydrates (Montignac M. Eat Yourself Slim. London: Montignac Publishing, 1999).
In a small study of 23 women, insulin resistance was reduced when they were put on a diet that was "moderately lower in carbohydrate", suggesting that it is a problem that can be improved just by restricting carbohydrates (Asia Pac J Clin Nutr, 2008; 17: 669-71).
For Montignac and others, hyper-insulinaemia and insulin resistance lead to obesity, and can be a cancer risk, an idea diametrically opposed to the current view that obesity causes insulin resistance.
Warburg's sugar theory
Montignac's approach ties in with another theory of cancer that is finally beginning to gain credence some 80 years since it was first postulated: Otto Warburg's sugar theory. Dr Warburg (1883-1970), an outstanding German biochemist whose work focused on intracellular respiration, photosynthesis and cancer, observed that healthy cells use oxygen to break down glucose from carbohydrates, which releases energy, whereas cancer cells appar-ently obtain energy from a process he referred to as 'fermentation'-better known today as 'glycolysis'-a process of extracting energy from glucose without the use of oxygen.
"The prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar," Warburg said in a lecture to Nobel laureates in 1966, four years before he died.
Despite winning him the Nobel Prize for Medicine, his sugar theory was largely ignored until just recently. A study from the University of Arizona revealed that radiologists can use the extent of glycolysis to determine the stage of development reached by a tumour. According to the researchers, an increased break-down of glucose is a "near-universal property" of cancer (Nat Rev Cancer, 2004; 4: 891-9).
Furthermore, cancer cells are known to have 10 times more insulin receptors than do healthy cells (Cell Commun Signal, 2009; 7: 14), which may explain why it is that insulin helps the growth and development of tumours.
The end in sight
Nutritionists have been telling us that processed, 'white' carbohy-drates are bad for us, but it's never been made clear why that is nor what happens when we eat these foods. However, by piecing together several disparate strands of research, the picture is finally becoming clearer: these processed foods raise our insulin levels, an inevitable reaction in order to reduce the large amounts of blood sugar, or glucose, brought about by carbohydrates that have a high GI score such as white bread, white rice, biscuits, cakes and 'fast foods'.
People who regularly eat pro-cessed foods will eventually go on to develop either hyperinsulinaemia or become insulin-resistant; as a result, the pancreas consistently produces an excessive amount of insulin. This overproduction has two serious consequences: it can make us obese; and it can encourage the growth of cancer cells, which feed off of the insulin.
At this time, oncologists appear to be looking down the wrong end
of the telescope. They believe that obesity causes the insulin resistance or hyperinsulinaemia that, in turn, can cause cancer. Yet, if they were to see it the other way round, the implications for the processed food industry could be devastating-and long overdue.
Insulin therapy and cancer
If naturally produced insulin can boost cancer growth, does the same apply to the insulin therapy that's used by those who have type 1 diabetes?
In fact, four new studies have found that insulin therapy does indeed increase the risk of cancer, and three of these reports implicate Lantus (insulin glargine), an injectable insulin analogue derived from human insulin.
One of the studies, which involved 127,031 German patients with type 1 diabetes, found that the risk increased in relation to the insulin dose. This means that, at the top end, those injecting 50 IU daily have a 1.3 times greater risk of developing cancer than do healthy people who are producing their own insulin (Diabetologia, 2009; doi: 10.1007/s00125-009-1418-4).
A different study, this time involving 114,841 type 1 diabetes sufferers
in Sweden, found that the risk associated with insulin glargine varied according to the cancer: for breast cancer, the therapy nearly doubled the risk whereas it was only marginal for prostate cancer (Diabetologia, 2009; doi: 10.1007/s00125-009-1444-2).
Lantus, manufactured by Sanofi-Aventis, has been used by diabetics ever since it became available in 2000, although concerns over a possible cancer risk were raised in Germany following a survey carried out among the policy holders of a private health-insurance plan. The survey revealed that there was one new case of cancer for every 100 users of Lantus and that the risk was dose-dependent.
Nevertheless, the European Association for the Study of Diabetes (EASD), which commissioned the four studies, is urging diabetics to continue using Lantus until more studies are carried out.
However, the cancer-causing qualities of Lantus may have been known within weeks of its approval. According to Ernst Chantelau, at the Diabetesambulanz MNR-Klinik in Dusseldorf, Germany, the therapy was known to be highly mitogenic-causing cell proliferation-even before it was approved by the European Medicines Evaluation Agency (EMEA). The manufacturer told the EMEA 'orally' about the therapy's mitogenicity, but the EMEA dismissed the comment as 'irrelevant'. However, at around the same time, independent researchers were also discovering that Lantus caused cells to proliferate when tested on human cancer cells. Research team leader Peter Kurtzhals said that the therapy increased insulin growth factors (see main story) by between six- to eightfold (Diabetes, 2000; 49: 999-1005).
And Lantus is not the only insulin therapy that's been associated with cancer risks. In 2008, Pfizer announced that six cases of lung cancer had been associated with its inhaled insulin therapy Exubera. Although the company denied any causal link, the therapy was withdrawn from the market in 2007 (Diabetologia, 2008; 51: 1-5).
The GI scores of some common foods
Only some carbohydrates stimulate excessive insulin production. These are known as the 'high glycaemic-index (GI) foods' as they contain an excess of glucose that has to be normalized by insulin. Glycaemic levels can also be altered by the cooking process. Raw carrots, for example, have a far lower GI score than cooked ones.
High GI foods
Beer (maltose) 110
Roasted potatoes 95
Modified starches 95
Mashed potato 90
Hamburger buns 85
Carrots (cooked) 85
Corn Flakes 85
Easy-cook rice 85
Rice cakes 85
Puffed rice 85
Low GI foods
Green vegetables 15
Apricots (fresh) 15
Dark chocolate 20
Split peas 20
Lentils (green) 22
Sugar-free jams 22
Soy vermicelli 22
French beans 30
Fresh fruit 30
From Montignac M. Eat Yourself Slim. Montignac Publishing, London: 1999
Insulin, the good and the bad
Without insulin, we would die. People with type 1 diabetes-in whom the pancreas is no longer able to produce insulin-are dependent on an injectable form of insulin in order to live. Without a daily injection of an insulin analogue, the diabetic's blood sugar would rise and the body would begin to burn up its fat stores. Within a few days, this leads to the life-threatening condition known as 'diabetic ketoacidosis'.
However, an individual who suffers from hyperinsulinaemia, where the pancreas produces too much insulin, will have too-low levels of blood sugar, a condition known as 'hypoglycaemia'. Its symptoms include pale-ness, shaking, shivering, perspiration, rapid heartbeat, hunger, anxiety and blurred vision. It can also cause convulsions.
People with type 2 diabetes-the stage before type 1, as around a third of all type 2 sufferers will eventually need insulin therapy-often have insulin resistance, where the cells have become resistant to the effects of insulin. Initially, the pancreas attempts to compensate by producing more insulin but, eventually, the pancreas proves unable to cope.
Vol. 20 05 August 2009