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ISIS Report, 28 February 2002

Diabetes Not in the Genes

Type 2 or late onset diabetes has been reaching epidemic proportions in industrialised countries. Diabetes now costs Britain’s National Health Service nearly a tenth of its budget. Instead of addressing the environmental causes, huge efforts are invested into identifying “susceptibility genes”. Dr. Mae-Wan Ho reviews recent evidence of how ‘lifestyle’ interventions can prevent disease, slow disease progression or reverse disease symptoms, across nations and ethnic groups differing in thousands, if not tens of thousands of genes.

Alarm was raised recently by the diagnosis of the first cases of type 2 (late-onset) diabetes in severely overweight British teenagers, age 13-15. Type 2 diabetes is a disease that normally affects adults over 40 years of age (see Box 1). This increases the pressure on the government “to take a more healthy approach to changing lifestyle”.

Actually, type 2 diabetes is being reported in children from the United States, Canada, Japan, Hong Kong, Australia, New Zealand, Libya and Bangladesh, and represents a growing trend coinciding with the rising prevalence of overweight and physical activity. Among 3 to 4 year old English children, there was a 60% increase in the prevalence of being overweight and a 70% increase in the prevalence of being obese between 1989 and 1998.

“Because the gene pool did not change substantially between 1989 and 1998, the rapid increases in obesity must reflect environmental changes,” according to William Dietz, Director of Division of Nutrition and Physical Activity, Centers for Disease Control and Prevention. He blames the consumption of fast foods, pre-prepared meals and fizzy drinks, reduced exercise due to increased use of cars and increase in watching TV.

Box 1

Glucose metabolism and diabetes

Glucose is the major form in which energy is supplied to the body via the blood stream. The concentration of glucose in the bloodstream is maintained within very narrow limits by two hormones, insulin and glucagon, both released by the pancreas. High blood sugar levels stimulate the release of insulin, which increases the uptake of glucose by the cells of the body to be used as energy, or to be stored as fat or glycogen. Glucagon, on the other hand, is released when blood sugar level is low. It stimulates the breakdown of stored glycogen to glucose, which is released into the bloodstream.

Diabetes is a disease in which glucose levels in the blood becomes abnormally high, either because insufficient insulin is produced, or the insulin produced fails to work. There are two main types of diabetes. Insulin-dependent, type 1 diabetes occurs when there is a severe lack of insulin because most or all of the insulin-producing cells in the pancreas are destroyed. This type of diabetes develops rapidly, usually before the age of 35, and most often between the ages of 10 and 16. These patients require treatment with insulin injections to survive. Non-insulin-dependent, type 2 diabetes occurs when the body does not produce enough insulin and the insulin produced becomes less effective. This type of diabetes usually appears over the age of 40, and tends to have a gradual onset. About 90% of all diabetes are non-insulin dependent, which is also commonly known as late onset diabetes.

Type 1 diabetes is an auto-immune disease in which the body’s immune system, for some unknown reason, destroys its own insulin-producing cells. It is influenced by as yet unknown environmental factors. Two genes have been identified that appear to put individuals ‘at risk’.

Type 2 diabetes is thought to be due both to defects in the insulin-producing cells, and to an inability of the insulin to stimulate the uptake of glucose in muscles and other tissues. The cause of this resistance to insulin is unknown. There is said to be a genetic influence, as it tends to run in families more than type 1 diabetes. But age, obesity and a sedentary lifestyle are also known to increase the risk of type 2 diabetes.

Type 2 diabetes, like asthma and cancer, has increased enormously over the years and is reaching epidemic proportions world-wide (see Box 2). In the United States, type 2 diabetes rose from 4.9% in 1990 to 6.5% in 1998, in both sexes, across all ages, ethnic groups, education levels, and in nearly all states. That should have alerted all rational scientists to look for environmental causes, and many did.

Box 2

Diabetes epidemic worsening

An estimated 1.4 million in the UK have diabetes and up to another million remain undiagnosed. It costs the National Health Service £5.2 billion per year (or 9% of the 2000 budget) in treating the disease and complications.

In the United States, 14 million had diabetes in 1995, by 2025, the figure is expected to rise to 22 million. It cost an estimated $44.1 to $98 billion in direct costs of treatment and $54 billion in indirect costs of disability and mortality.

Diabetes if the fourth leading cause of death in most developed countries. It is also growing rapidly in developing countries. Between 1995 and 2025, the number of adults affected by diabetes in developed countries will increase by 41 percent, from 51 million to 72 million. In developing countries, it is projected to grow by 170 percent, from 84 million to 228 million. The greatest increase is expected in India, from 19 million to 57 million.

But ever since genomics is being foisted on us by the human genome project, it seems obligatory to reduce practically every human condition to the genes. All of the ‘single gene’ diseases that can be attributed to mutations in one or a few genes with major effects have already been identified, most of them in the pre-genomics era. Diagnosing and curing rare single gene defects, however, “did not fit the business model”. So, ‘genetic defects’ and ‘gene therapy’ expanded to include the far more common and potentially highly profitable diseases such as cancer, heart disease, AIDS, Alzheimer’s and Parkinson’s.

Francis Collins, head of the public human genome consortium, is running a laboratory in the US National Institutes of Health, engaged in a “huge and very complicated” search for susceptibility genes for type 2 diabetes. The same approach is strongly promoted by the major UK charity Wellcome Trust, which has donated hundreds of millions to the human genome project, and has since given even more to genomics and related research.

Type 2 diabetes is a good case study to illustrate the poverty of the genetic/ genomics approach. There is now conclusive evidence that modifying risk factors associated with high body weight, lack of exercise and poor diet could substantially prevent disease onset, delay disease progression, and even reverse some of the symptoms.

The Finnish Diabetes Prevention Study Group carried out a study designed to find out if modifying lifestyle could prevent type 2 diabetes developing in people at high risk for the disease.

The study involved 522 middle-aged, overweight subjects 40 to 65 years of age (average 55 years), 172 men and 350 women with ‘body-mass index’ (weight in kilograms divided by the square of the height in meters) of 25 and higher (average 31). All of them had impaired glucose tolerance, ie, slow to clear glucose from the bloodstream after taking glucose.

These subjects were randomly assigned to an ‘intervention’ group or a control group. The intervention group received individual counselling aimed at reducing weight, reducing intake of total fat and saturated fat, and increasing intake of fibre and physical activity. The control group were given general oral and written information about diet in a two-page leaflet, and exercise, but no individualised programs were offered to them. A glucose-tolerance test was given at the end of every year, and the diagnosis of diabetes was confirmed by a second test. The average duration of follow-up was 3.2 years.

By the end of the first year, the intervention group lost on average 4.2 + 5.1 kg while the control group lost 0.8+3.7kg; by the end of year two, the net loss was 3.5+5.5kg in the intervention group and 0.8 + 4.4kg in the control. (The second figure after the average is the standard deviation, which measures how variable the individual measurements are around the average.) The total incidence of diabetes after 4 years was 11 % in the intervention group compared to 23 % in the controls. During the trial, the risk of diabetes was reduced by 58% in the intervention group. It was 63% lower among men and 54% lower among women. The results were highly significant.

There were other improvements in the intervention group: decrease in waistline measurement, decrease in blood glucose and insulin both on fasting and two hours after glucose challenge, decrease in blood triglycerides, decrease in blood pressure. In other words, subjects in the intervention group were generally healthier.

The Fins had pioneered a community-based project in North Karelia almost three decades ago to prevent heart disease. They have now shown that effective lifestyle changes can prevent another major chronic disease of our time, type 2 diabetes.

In the United States, researchers in Harvard School of Public Health followed 84 941 female nurses from 1980 to 1996, initially free of diabetes, cardiovascular disease and cancer. Information about their diet and lifestyle was updated periodically.

A low risk group was defined according to the following criteria: body mass index of less than 25, diet high in cereal fibre and polyunsaturated fat and low in trans fat, low blood glucose, moderate to vigorous physical activity for at least half an hour a day, no current smoking, and consumption of at least half a drink of an alcoholic beverage per day.

A total of 3 300 new cases of type 2 diabetes were diagnosed in 16 years. Obesity was the single most important predictor of diabetes. But lack of exercise, poor diet, current smoking and abstinence from alcohol were all associated with significant risk of diabetes even after adjustment for body-mass index.

Women in low risk group (3.4%) had a relative risk of 0.09. Women in the low risk categories for three factors, body-mass index, diet and exercise, had a relative risk of diabetes of 0.12 compared with all other women.

The reduction in risk was similar for women with a family history of diabetes and for those without such a history, for white and non-white women.

Among overweight women (body-mass index 25 to 29.9) and those with normal weight (<25), approximately half the cases of diabetes could have been prevented by combination of healthy diet, regular exercise, abstinence from smoking, and moderate alcohol consumption. Among obese women (body-mass index 30 and higher), a combination of healthy diet and regular exercise reduced the risk of diabetes by 24%.

The findings suggest that the majority of cases of type 2 diabetes could be prevented by weight loss, regular exercise, modification of diet, abstinence from smoking, and the consumption of limited amounts of alcohol. Weight control appears to be the most important

As in the Finnish study, this group found that adherence to the same guidelines reduced risk of heart disease by 83%.

Results from the first three years of the Diabetes Prevention Program in the US show that regular exercise and the modification of diet reduced the incidence of type 2 diabetes by 58% among patients with impaired glucose tolerance. The study found that diet and exercise were more effective than the drug metformin in preventing the disease. The study was conducted in 27 US medical centres and involved 3234 people. The trial ended a year early because the data had clearly answered the main research questions.

Forty-five percent of the participants were from minority groups in whom type 2 diabetes is disproportionately prevalent, including African Americans, Hispanic Americans, Asians, Pacific Islanders and American Indians. The trial also recruited other high risk groups, including those aged 60 and above, women with a history of gestational diabetes (during pregnancy), and people with a first degree relative with type 2 diabetes.

Similar results came from China. Among 577 patients with impaired glucose tolerance in Da Qing, exercise interventions, dietary interventions, or both resulted in a decrease of 42 to 46% in the rate of progression to diabetes during 6 years of follow-up.

In contrast, The UK Prospective Diabetes Study (UKPDS) started in 1977 was a prospective study of type 2 diabetes. It recruited 5102 newly diagnosed subjects with an average age of 53 years into a randomised trial. Initially, diet alone was used to control symptoms and high glucose levels. This was abandoned after just three months when only 17% responded.

The other 83% were allocated randomly either to a conventional treatment policy of diet with additional therapy for high glucose, or to an intensive policy of immediate treatment with sulphonylurea or insulin. Within twelve years, 32 percent had developed clinical complications, and drug interventions did not diminish the risk of clinically significant diabetic complications. Intensive interventions with insulin or sulfonylureas did not decrease illness or deaths from macrovascular causes associated with the circulatory system, which kill 60% of the diabetics, or vision loss and impotence. Metformin was found to decrease the risk of macrovascular disease, but such patients, treated with a combination of metformin and sulfonylureas, had higher death rates compared to controls receiving conventional therapy.

An editorial in the British Medical Journal commented that translating these findings into effective intervention programmes both at clinical and public health levels may be challenging. “Yet, this challenge pales next to that of sustaining the lifelong implementation of complex, expensive medical and therapeutic regimens to control diabetes and its complications”.

The studies show without a doubt that ‘lifestyle’ interventions can prevent disease, slow disease progression or reverse disease symptoms, across nations and ethnic groups differing in thousands, if not tens of thousands of genes. In other words, environmental factors are so important that they will swamp the influence of any ‘susceptibility genes’ that genomics research aims to identify. Drug interventions based on susceptibility genes may be worse than useless, given all the attendant risks from side-effects.

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