Triggers of Type 1 Diabetes

Inside the pancreas, beta cells make the hormo...

Inside the pancreas, beta cells make the hormone insulin. (Photo credit: jennifertomaloff)

Type 1 diabetes occurs more often at a younger age. Several candidate triggers exist for onset.

Genetics plays a contributory role. No definite proof exists for a specific culprit, despite investigation of many environmental factors and viral infections. A combination of factors needs to occur for disease to manifest.

Early Onset of Type 1
Incidence of childhood type 1 diabetes is rising dramatically, particularly in the very young. In under 5s rates are rising at an alarming rate.

Those developing type 1 get it earlier and earlier, which is a very worrying statistic. This  increases the possibility of more complications starting to occur at age 30 to 40 rather than later in life. A considerable healthcare burden results in terms of costs to both the patient and society.

Looking for a Cause
The biggest barrier to solving this major social and health problem and arresting development in young people is our lack of knowledge about the risk factors for early progression of type 1. The accelerating overall incidence in children is not down to genetics alone. Investigations are ongoing of potential environmental initiating triggers and accelerating factors of onset.

Genetics of Type 1 Diabetes
A lot of evidence exists for a genetic element to type 1. Studies show concordance of identical or monozygotic twins is high at about 30%. and much higher than in dizygotic twin pairs or siblings.

The strongest genetic association is with a specific group of genes called the HLA, which are involved in immune defence. But there is no single gene defect, as type 1 is a complex polygenic disease with about 20 different gene associations identified with pathogenesis.

Role of the Environment
Non-genetic risk factors make a major contribution to the disease. In Caucasians in Europe the incidence of type 1 is worse than for those who live in other areas of the world. Similarly it is higher in migrants who live in areas with higher incidence when compared with areas where it is lower. Seasonal variation of diagnosis of type 1 and the presence of autoantibody populations is also evidence of an environmental influence.

The percentage of new cases with specific high-risk genes is decreasingm which also indicates that the environment may play an important role. About 20% of Caucasians carry the susceptibility genes to type 1 diabetes, but only 5% go on to develop it during their lifetime. Even in monozygotic twins, sharing the whole genome, about one fifth of the pairs both develop type 1 diabetes when one of them has it. So the environmental contribution to pathogenesis is high.

Identifyitng Risk Factors
Identifying a risk factor is important when considering primary prevention strategies for a specific disease. By building up a web of causation it is possible to identify a large number of candidate susceptibility factors that might be implicated as risks. Case-control studies are used to look at genetic factors and incriminating factors at the level of foetal development. But other potential contributing factors include: humoral responsiveness, infections, vaccinations, physical and psychological stress, nutritional factors, and growth and development and social factors.

When the environmental risk factors for a disease are identified, it is important to test that they correlate with the epidemiological mechanisms that have been shown from experimental work.

Evidence for the importance of an initial environmental trigger of abnormal beta-cell dysfunction in type 1 includes the long natural history and the fact that there are people who have susceptibility genes but get no disease.

Auto-Antibody Positivity
The presence of positivity to auto-antibodies – antibodies directed at our own body – is an early sign of disease development. Auto-antibodies can be measured in some people long before manifestation of symptoms. Thus in some patients a long lag time exists between the initiation of the process and detecting symptoms; in others progression is more rapid.

Some people dont develop diabetes despite having autoimmunity or auto-antibodies to beta-cells. In the future it is possible to find the initiating event triggering autoimmunity, then perhaps it might be possible to prevent it.

There are also likely to be accelerating and precipitating risk factors, so there may be potential to arrest this process as much beta cell mass is preserved in many type 1 diabetics. Even if the beta cell mass is reduced by up to 50%, function is not lost.

Risk factors proposed as triggers for autoimmunity of the beta-cell include virus infections early in life or other peri-natal harmful exposures, or perhaps some defect in early nutrition of the foetus or young child.

A Virus Trigger of Type 1 diabetes?
Virus infection was one of the first environmental factors postulated as a possible initiating trigger because of the large number of animal studies showing that different viruses can start autoimmunity or beta-cell destruction.

Enterovirus infection are common, and some evidence has implicated rubella and coxsackie B viruses in type 1 causation. However, despite the fact evidence remains circumstantial for these individual infections it may be that any one of a selection of enterovirus infections may be required as a risk factor. Or perhaps it is the timing of the infection that is crucial and infection needs to occur within a specific window to be a trigger.

There are two proposed mechanisms for the role of virus triggers: antigen mimicry and a pre-tolerance effect. In antigen mimicry, antigens in the capsid of the virus cover are very close or similar in structure to the parts of the beta-cell that make the self-defence direct itself to the beta-cell instead of the virus. The idea of pre-tolerance is that there is a prenatal infection and the virus is not cleared. Thus the foetus doesn’t recognise it as a non-self antigen. The virus survives dormant in or near the beta-cell and it is potentially triggered later on to initiate the disease process.

Other Risk Factors for Type 1 Diabetes
Blood group incompatability between mother and foetus, low birth-weight, foetal nutrition, C-section delivery and recent onset of type 1 diabetes in the mother have all been put forward as potential risk factors for early onset of type 1 diabetes.

Low birth-weight is a potential risk factor in type 2 diabetes but does not seem to be in type 1 diabetes.

Blood group incompatability could cause an early immunological challenge as a trigger and it has been found to be increased in type 1 diabetics. It is known to be associated with beta-cell dysfunction so it remains a potential contributory factor to an autoimmune event early in life.

Nutritional Factors
Early introduction of cow’s milk and cessation of breastfeeding have been found to be associated with early onset type 1 diabetes. This suggests that perhaps breast milk is protective or that cow’s milk provides some sort of antigenic challenge in susceptible babies to trigger early onset.

From animal studies the involvement of Vitamin D has been postulated in human diabetes. Observational studies have shown that vitamin D supplementation in children reduces the incidence of type 1 diabetes, but there as yet no randomised clinical trials.

In Northern Europe, particularly in the winter there is insufficient exposure to sunlight and thus vitamin D deficiency might be present and this seems to correlate with the seasonal increases in incidence of diabetes.

The fact that the winter climate is colder and there is the increased possibility of other infections makes it difficult to be conclusive about the Vitamin D putative association. This is despite the fact that the Eurodiab study showed an independent protective effect of supplementation in children of T1 mothers.
Intrauterine starvation or overfeeding could prime the beta cell sensitivity to local glucose. Perhaps then a different beta cell responsiveness to glucose exposure to normal develops. For example, with overfeeding the baby could be less sensitive to glucose if exposed to large amounts in the womb.

Hygiene Hypothesis
In humans, there is some evidence for the involvement of the gut in autoimmunity, in particular the so-called hygiene hypothesis, and perhaps this is where breast feeding plays an important role in the gut immune system and its response to dietary antigens.

If there is an abnormality in the gut immune system, then the gut will develop a different flora than intended. For example, the gut permeability is changed when there is enterovirus infection. This could change intestinal permeability to all antigens and create a perfect storm for type 1 diabetes and diabetes autoimmunity.

The slow onset typical of the natural history of type 1 diabetes also implicates the importance of certain accelerating factors that differ from the initiating factors. These accelerating factors are thought to act through an insulin overloading effect. Candidate factors that might trigger this overload include cold climate, presence of infection or inflammation, psychological stress and high growth rate.

The incidence of high growth rate is increasing and is very strongly associated with increased wealth and increased feeding. At puberty there is a normal accelerated growth, but diabetics tend to grow at a faster rate than there schoolmates pre-puberty.

If children are exposed to more food than they need, they will grow for longer periods. They can have higher height and higher weight depending on their genetics. In adults there is just increased weight and BMI with over-nutrition. The increased insulin demand will result in the beta cells needing to work harder and more beta cell antigens and this might potentiate autoimmune destruction.

Overnutrition in early childhood leads to higher growth rate and increased body fat. The two may combine to increased insulin overload and accelerated destruction of the beta cell.

There is a period where symptoms are only present at a low level and are not visible.

Some kind of threshold presence of individual risk factors may be required to manifest disease. Different combinations of specific genes may need to occur to contribute susceptibility. Then a combination of environmental risk factors may need to work in concert to produce the same disease in different individuals.
So the prevention of the development of type 1 in those who have susceptible genetics may involve a number of strategies:
• Early vaccination for enterovirus infection.
• Dietary advice to pregnant women.
• Intense nutrition advice for children in schools and health centres.
• Decrease number of c-sections performed.
• Promotion of breast feeding.
• Use of pro or pre-biotics.

Conor Caffrey is a writer on health, science and medicine

Other articles by Conor Caffrey about diabetes



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