 William was diagnosed with type 1 diabetes at age 2, following a virus. Viruses are thought to be one of the triggers of type 1 diabetes. Can infections cause type 1 diabetes?A number of viruses have been associated with type 1 diabetes and/or type 1-associated autoantibodies in humans, including enterovirus, rubella, mumps, rotavirus, and cytomegalovirus (CMV). Many viruses have also been shown to affect the development of diabetes in laboratory animals (reviewed in van der Werf et al. 2007).
While viruses can clearly produce diabetes in lab animals, that does not necessarily mean that viruses will produce type 1 diabetes in humans (Gale 2008). Yet a new meta-analysis adds to the evidence that viruses may contribute to type 1 diabetes in humans. It combined data from 24 separate studies, and found a significant association between enterovirus infection and both type 1 and type 1 related autoantibodies (Yeung et al. 2011). There are a number of additional recent studies on viruses and type 1. For example, there is evidence that children may progress from developing autoantibodies to developing type 1 diabetes more after an enterovirus infection involving viral RNA in blood (Stene et al. 2010). Another study from Finland also found that enterovirus RNA in blood was more common in children with type 1 diabetes than those without (Oikarinen et al. 2010). The first study found that measuring enterovirus in stool did not yield an association, and that finding is the same as a third study from Norway (Tapia et al. 2010). All of these studies analyzed children genetically at risk for type 1 diabetes. One study found that babies who experience various infections have higher levels of type 1-associated autoantibodies at age 6 months than those who did not have evidence of infection. This finding was especially significant among those who were formula fed before 3 months of age, showing that diet and the gut (and cow's milk specifically) may play a role in this process (Mäkelä et al. 2006). Hober and Sane (2010) review the evidence linking enteroviruses and type 1 diabetes, and discuss the possible mechanisms involved. Enterovirus RNA has been found in the blood, small intestines, and pancreases of people with type 1 diabetes. Yet despite the significant amount of evidence linking viruses to type 1, it has been difficult to show whether viruses can cause the disease. Why? According to van der Werf et al. (2007), for a number of reasons. For example, genetic susceptibility may be required for a virus to cause diabetes in someone. Other environmental factors may be necessary for a virus to cause diabetes, or perhaps multiple infections throughout life may act together to cause the disease. There also might be a long period of time between infection and disease diagnosis, at which point the viral evidence has long since disappeared. Another reason that it has been so difficult to confirm whether viruses can cause type 1 is that viruses can act via a number of different mechanisms, which are still being defined. Some potential mechanisms have been observed in animal models, and might be applicable to humans as well. For example, viruses may act by directly destroying beta cells, or by making the beta cells a target of the immune system. They may act by increasing inflammation and the secretion of inflammatory cells such as cytokines. These cells may enhance autoimmunity or directly affect beta cells (van der Werf et al. 2007). Infections may also increase the demand for insulin as well as increase insulin resistance, perhaps contributing to beta cell stress (Dahlquist 2006; Ludvigsson 2006).
The curious case of congenital rubellaAn often-cited statistic is that 10-20% of people exposed to rubella in utero will develop type 1 diabetes later in life. Gale (2008) goes back in time, takes another look at the original data, and finds that these figures are misleading. He concludes that while the congenital rubella syndrome "undoubtedly" predisposes people to develop diabetes later in life, whether this is autoimmune (type 1) diabetes is a "definite maybe."
Can infections protect against type 1 diabetes?Some authors argue that infections may also protect against autoimmune disease (and allergies) (e.g., Bach 2005; Tracy et al. 2010). This idea is one of the basic tenets of the "Hygiene Hypothesis" (see the hypotheses page)-- that fewer infections has led to increasing rates of autoimmune diseases, and that people who experienced more infections in childhood are more protected. In some animal strains, fewer infections can increase the risk of autoimmune disease, and infection at an early age can protect against diabetes (yet in other animal strains, infections are not necessarily protective against autoimmune disease) (Bach 2005). Tracy et al. (2010) propose that whether viruses induce or protect against type 1 diabetes depends on an individual's genetics, the type and dose of the virus, the age of exposure (where infections in the first year of life may tend to be protective) and whether the individual has immunity to that virus. Cooke (2009) reviews evidence that certain infections might inhibit the development of type 1 diabetes, and that reduced exposure to infections over the past 60 years might play a role in the increased incidence of the disease. She argues that the type of infection is important, as is timing, and presents evidence that infections with mycobacteria or helminths (parasitic worms) may be able to inhibit type 1 diabetes onset.
Yet these arguments are in part based on the ability of viruses to prevent or delay diabetes in non-obese diabetic (NOD) mice, and researchers are questioning the usefulness of these mice to predict the effects of various environmental factors to prevent or delay type 1 diabetes in humans (see the of mice and men page) (van der Werf et al. 2007; Roep and Atkinson 2004). Also, it is thought that NOD mice raised in germ-free conditions have an increased incidence of diabetes. Yet actual evidence for this is limited, and has been shown not to be the case in female NOD mice. The development of diabetes in female NOD mice was not affected by germ-free conditions. Modulation of gut flora, however, does affect the development of diabetes in these mice (King and Sarvetnick, 2011).
One of the pieces of evidence for the Hygiene Hypothesis is that childhood allergies are preceeded by a dysfunctional immune system, suggesting that the developing immune system requires stimulation by the environment to mature properly (Gale 2002a). Gale proposes a biological mechanism that could explain how this process occurs. Yet he also argues that infectious diseases such as viruses would not be responsible for the development of this mechanism in humans, since the mechanism would have evolved earlier in time, before humans encountered widespread infectious disease. Therefore, other environmental agents that can stimulate the immune system are "more likely candidates for the Hygiene Hypotheses," such as natural gut biota or parasites. (See the diet and the gut page for more information on gut biota and type 1 diabetes). Björkstén (2009) suggests that the term "Hygiene Hypothesis" is misleading, and a better name might be the "Microbial Deprivation Hypothesis." It's not quite as catchy, but perhaps more accurate.
In fact, researchers are not only looking at viruses and gut biota, but all the different environmental factors that constitute the "modern lifestyle." Changes in exposure to not only infections but also pollutants, allergens, antibiotics, and more are thought to lead to a breakdown in the immune system, leading to diseases such as type 1 diabetes (Ehlers and Kaufmann 2010).
Viruses and the rising incidence of diseaseIn the "Booster-Trigger Hypothesis," Knip et al. (2005) propose that enterovirus infections are the most likely "trigger" of autoimmunity in type 1 diabetes. But, how could this be consistent with the increasing incidence of type 1 diabetes in children, since we know that the frequency of these viruses has decreased in developed countries over the past few decades? These authors propose that as certain viruses become less common, there is decreasing immunity to that virus in the general population. When the virus does attack, the results are more severe. Apparently this is what happened when polio was eliminated a century ago. When polio infections began to decrease, the incidence of severe complications from polio infection increased. Similarly, decreasing levels of enteroviruses in a population today could lead to an increased susceptibility to these viruses. Fewer viruses, then, may contribute to increasing type 1 diabetes incidence by increasing the susceptibility of young children to the diabetes-related effects of viruses, and causing more invasive viral infections. Environmental contaminants and virusesBut wait, there are other environmental factors that may be able to increase susceptibility to viruses, and lead to more invasive infections: environmental contaminants. Human studies have clearly shown that people exposed to PCBs, for example, have more infections (Carpenter 2006). PCBs and other persistent organic pollutants (POPs) are suspected to be a culprit in wild animals affected by disease and mass mortalities; these animals carry high levels of these contaminants (Tanabe 2002). An interesting experiment exposed mice to mercury in combination with a bacterial infection. They found that in genetically susceptible mice, autoimmune disease was aggravated by combination of mercury and an infection. Meanwhile the mice that were not genetically susceptible to autoimmunity were made susceptible. Neither mercury or the infection alone led to an autoimmune response. The authors suggest that simultaneous exposure to various environmental factors, such as contaminants and infections, can cause people who are genetically resistant to become susceptible to autoimmune disease (Abedi-Valugerdi et al. 2005). Perhaps not coincidentally, studies are finding that high risk genes are becoming less frequent over time in children with type 1 diabetes, while more children with low to moderate risk genes are developing the disease more now than in years past. These finding imply that environmental factors are now able to trigger type 1 diabetes in people who are less genetically susceptible (Vehik et al. 2008).
Viruses and contaminants may act together in other ways as well. Viruses can alter the uptake of contaminants and change the distribution of contaminants in body tissues. During a coxsackie virus infection (a type of enterovirus), dioxin was redistributed in the bodies of mice: infected mice had higher dioxin levels in the pancreas and thymus as compared to uninfected controls. This finding suggests that viruses can potentially increase the toxicity of contaminants in these organs (Funseth et al. 2000).
Feingold et al. (2010) discuss how current scientific research is lacking on how contaminants and pathogens interact to increase the risk and severity of disease. Exposure to contaminants can affect the immune system such that a host is more susceptible to infection, and the infection is more persistent or severe. Pathogens, meanwhile, can change the body's response to contaminants, and affect the risk for and severity of chronic disease progression. Research should therefore consider contaminants and pathogens together, when either one or both may contribute to disease development.
Just as it has been difficult to show direct evidence that viruses are involved in the development of type 1 diabetes, even after decades of research, it may be difficult to elucidate the involvement of contaminants in this disease. Like viruses, contaminants may act via a variety of mechanisms. Like viruses, the evidence of exposure may be long gone by the time the disease develops. Like viruses, contaminants may act in combination with other factors (or each other) to influence the progression of disease. Like viruses, the effects of exposure in part depend on genetic susceptibility. Like viruses, cumulative exposures over the duration of life, including in utero, may be important. And like viruses, this idea is already generating controversy.
The bottom lineViral infections can clearly contribute to the development of diabetes in animals, and viruses have been associated with the initiation of type 1-related autoimmunity and type 1 diabetes in humans. Direct evidence that viruses can cause type 1 diabetes, however, is still lacking, probably due to the complexities involved (van der Werf et al. 2007). Genetic background, dose, timing, type of virus, and other environmental factors, including contaminants, may play a role in the potential ability of viruses to induce type 1 diabetes. Some infections may also protect against type 1 diabetes, but other agents, such as beneficial gut biota, may be more important protective factors. |