Diabetes onset: nature vs nurture

Catherine Hanrahan looks at some of the possible environmental factors associated with diabetes. Could they hold the key to prevention?

TWENTY-FIRST century children live in spotlessly clean houses with carefully controlled exposure to the sun. They spend little time outside, and lots of time watching TV and using computers. Eating fatty and sugary foods is the daily norm.

This lifestyle characterises what researchers call the "modern diabetogenic environment".

But while it’s accepted that junk food and little exercise contribute to rocketing rates of type 2 diabetes, other environmental factors may also be involved.

And the further researchers delve into how environmental factors cause diabetes, the more it becomes clear that type 1 dia­betes is not just unavoidably a result of an individual’s genes.

The incidence of type 1 diabetes has been rising over the past four decades in Australia. It doubled from 11.3 per 100,000 person years in 1985 to 23.2 per 100,000 in 2002. 1

But according to Professor Len Harrison, head of the Autoimmunity and Transplant division at Melbourne’s Walter and Eliza Hall Institute of Medical Research, there is no evidence our genes have changed in that time.

"All the increase in type 1 diabetes has been due to children with lower risk genes becoming affected," he says.

"Several decades ago, those people would never have developed type 1 diabetes.

"The only plausible explanation is that on a genetic background of lower-risk genes than ever before, these people are being pulled into type 1 diabetes by the environment."

Martin Silink, professor of paediatric endocrinology at the University of Sydney and The Children’s Hospital at Westmead, says studies in countries with low rates of type 1 diabetes show “Westernisation” is causing the incidence to rise.

"Places like Kuwait, where in the 1980s childhood type 1 diabetes was between four to five children per 100,000 under 15, now the incidence rate is close to Australia, which is over 20," Professor Silink says.

Professor Harrison says if we could discover what is different about the environment in 1950 compared to now, in theory more than half of the cases of type 1 diabetes could be prevented.

He explains that in both type 1 and type 2 diabetes, there is evidence the innate immune system is activated, creating a general inflammatory background.

Activated non-specific, primitive immune cells such as macro­phages and neutrophils, are the “smoke before the fire” of diabetes development.

This inflammatory response can cause beta cell dysfunction in type 2 diabetes, drive adaptive immunity to beta cells in type 1 diabetes and initiate insulin resistance in both diseases.

"We know that a number of environmental factors can promote an increase in this background innate immunity, ranging from diet, particularly foods high in saturated fat, even [to] glucose itself," Professor Harrison says.

"We think that activation it­self, of macrophages and even T cells, mediates insulin resistance."

His group has shown that children at risk of type 1 dia­betes who are also insulin resistant have a much higher risk of developing the disease.

And he says insulin resistance could develop soon after birth. "The paper we published… last year shows clearly that weight gain in the first two to three years of life is a risk factor for developing type 1 diabetes in children who are genetically at risk." 2

Professor Silink says the incidence of type 1 diabetes is moving down the age range – with greater increases in the under-five age group – but the reasons for the change are unclear.

According to Professor Harrison, a variety of environmental factors, including sleep quality, vitamin D levels and pathogen exposure, can promote immunoinflammatory diseases. 3

CONTROVERSIAL ROLE

Dr Jenny Gunton, head of the Diabetes and Transcription Fac­tors group at Sydney’s Garvan Institute, says the role of vitamin D in diabetes is controversial.

In type 1 diabetes, "vitamin D seems to play an important role in helping the immune system control itself", she says.

"So when there isn’t enough vitamin D, the immune system is more prone to confusion, attacking the wrong things, including beta cells."

Dr Gunton says several studies show that if vitamin D is supplemented in the first six months of life, an individual is less likely to develop type 1 diabetes.

But the role of vitamin D in the development of type 2 diabetes is uncertain.

"It’s pretty clear there’s a strong association between low vitamin D and type 2 diabetes," Dr Gunton says.

"Where it gets murky is whether it’s cause or effect or just an association.

"My personal belief is it’s probably causal. I think low vitamin D probably actually… gives you insulin resistance."

Western Sydney Area Health is undertaking a randomised, controlled study to give pregnant women vitamin D supplements to see if they prevent gestational diabetes, or lessen blood glucose levels in those women who do develop it.

Dr Gunton warns that even in this country, where there is abundant sunshine, vitamin D deficiency is a public health issue.

At Sydney’s Westmead Hos­pital, where Dr Gunton is a staff specialist in endocrinology, a study in 100 normal volunteers revealed 25% were vitamin D deficient.

A yet-to-be-published study shows the rates are even higher in diabetes patients, she says.

SLEEP QUALITY FACTOR

Another lifestyle determinant contributing to the modern diabetogenic environment is sleep quality.

Average sleep duration in US adults decreased from nine hours in 1910 to seven hours in 2003. 4

And in children, less sleep is an independent risk factor for becoming overweight. 5

Associate Professor Peter Liu, head of the Endocrine and Metabolic Group at the Woolcock Institute of Medical Research at the University of Sydney, says several epidemiological studies link sleep duration with diabetes development.

"In one interventional study, normal people were forced to sleep less, which increased their insulin resistance," Associate Professor Liu says.

"Another study took people and disrupted their deep sleep. What they showed was that it was slow wave, or the deep sleep, that was responsible for insulin resistance.

"With better-designed studies we may actually in future be making recommendations about how long people should sleep
to reduce their diabetes risk, which is plausible but we are not there yet."

Professor Silink believes type 1 diabetes may be more readily prevented than type 2 diabetes.

He cites modulation of the immune system to prevent type 1 diabetes in children at risk as one possible preventive strategy.

This is being tested in the Intranasal Insulin Trial II (INIT II) being conducted by Professor Harrison (see box above right).

Professor Silink says there is hope for preventing type 1 diabetes if the sequence of environmental factors and how they interact can be worked out.

"In that disease, we should be able to create some sort of strategy," he says.

Reversing type 1 diabetes by regenerating beta cells and islet cell transplantation in recent onset cases remains largely experimental, so tackling environmental triggers in those at risk may be more successful.

THE DETERMINING FACTORS: THE INIT II TRIAL

• A randomised, controlled trial in Australia and New Zealand to show whether an intranasal insulin vaccine can prevent or slow the progression of type 1 diabetes in children and young adults at high risk.
• "Negative" vaccination with insulin in the mucosa generates regulatory T cells that suppress the autoimmune attack on beta cells.
• At least 12,000 relatives of patients with type 1 diabetes will need to be screened for autoantibodies to enroll 102 participants in the trial.

Trial registration is at Stop Diabetes.

REFERENCES

1. Haynes A et al. Continued increase in the incidence of childhood type 1 diabetes in a population-based Australian sample (1985-2002). Diabetologia 2004; 47:866-70.
2. Couper JJ et al. Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes. Diabetes Care 2009; 32:94-9.
3. Wentworth JM et al. Reappraising the stereotypes of diabetes in the modern diabetogenic environment. Nat Rev Endocrinol 2009; 5:483-89.
4. Gangwisch JE et al. Sleep duration as a risk factor for diabetes incidence in a large US sample. Sleep 2007; 30:1667-73.
5. Agas WS et al. Risk factors for childhood overweight: a prospective study from birth to 9.5 years. J Pediatrics 2004; 145:20-25.