Viruses and other infectious agents are associated with both an increased and a decreased risk of type 1 diabetes. One hypothesis argues that viruses can cause type 1 diabetes by damaging insulin producing beta cells. Another hypothesis (the hygiene hypothesis) argues that exposures in early childhood stimulate the immune system to control autoimmune reactions (Kondrashova and Hyöty, 2014). We'll look at both hypotheses below.
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). Viruses have even been associated with type 1-related autoimmunity in wild animals (Warvsten et al. 2017).
In addition to causing diabetes in animals, enteroviruses are associated with an increased risk of type 1 diabetes in human studies, and have been detected in the pancreas of people with type 1 diabetes (Busse et al. 2017; Kondrashova and Hyöty, 2014; Krogvold et al. 2014). A meta-analysis that combined data from 24 separate studies 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, children who developed autoimmunity had signs of enteroviruses in their stool many months earlier (Honkanen et al. 2017). There is also evidence that children may progress from developing these 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. 2011). All of these studies analyzed children genetically at risk for type 1 diabetes. In Germany, a population-wide study found that recurrent viral respiratory tract infections in the first 6 months of life were associated with an increased risk of type 1 diabetes by age 8 (Beyerlein et al. 2016).
Yet other studies have not found evidence of viral infections before type 1 development. For example, a large, prospective study of children around the world who are at genetic risk of type 1 did not find evidence of viruses in the children who developed a rapid-onset type 1 as compared to controls who tested negative for autoimmunity (Lee et al. 2013). A study from Norway did not find that enterovirus predicted later development of type 1-related autoantibodies, however, signs of the virus were somewhat more common at the time of the first positive test for antibodies than in controls (Cinek et al. 2014).
Older types of infections linked to type 1 include mumps; however a recent review and meta-analysis found only a weak association between mumps and type 1 diabetes, with a lot of variation between studies (Saad et al. 2016).
Newer types of infections may also play a role in type 1 diabetes development. For example, a study from Chile found that more children were diagnosed with type 1 diabetes during 2009-2010, just following the influenza H1N1 virus outbreak of 2009. However, when the researchers took a closer look at the individuals diagnosed with diabetes, only one boy had a confirmed case of H1N1. This looks like a good potential research project to pursue... (Valdés et al. 2013).
Putting aside discussions of genetic engineering, researchers put human pancreatic islet cells into mice and then infected the mice with a Coxsackie B virus (CBV), to see if they would get diabetes. They did-- almost half of the infected mice developed high blood sugar, with signs of the virus and reduced insulin secretion in the islets as well (Gallagher et al. 2014). Viruses may trigger type 1 via inflammatory processes in the beta cells. Researchers have found that Coxsackie virus changes the epigenetic processes with beta cells that would normally suppress inflammation (Kim et al. 2015).
Does maternal exposure to viruses increase the risk of type 1 diabetes in the offspring? Well, maybe. One study found that signs of maternal virus infection were present in 19% of mothers with a child who developed type 1, compared to 12% of mothers with unaffected children. These authors suggest that that "an enterovirus infection during pregnancy is not a major risk factor for type 1 diabetes in childhood but may play a role in some susceptible subjects" (Viskari et al. 2012). A similar study found that the boys of mothers who tested positive for enterovirus antibodies during pregnancy had a 5 times higher risk of developing type 1 diabetes in adolescence/early adulthood (Elfving et al. 2008). On the other hand, another study found that children (specifically girls) whose mothers had infections during pregnancy had a lower risk of type 1-related autoantibodies than those who did not, suggesting that infections were protective (Stene et al. 2003). Other studies have found no association between early-life virus exposure and islet autoimmunity or type 1 diabetes one way or another (Cardwell et al. 2008; Füchtenbusch et al. 2001).
There is evidence, from human studies, that various infections can increase the risk of type 1-related autoimmunity and autoantibodies. For example, studies have found that babies who experience various infections have higher levels of type 1-associated autoantibodies in infancy/early childhood 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 viruses and cow's milk may interact to play a role in this process (Lempainen et al. 2012; Mäkelä et al. 2006; Vaarala et al. 2002). Another study also found that a higher number of gastrointestinal illnesses were associated with a higher risk type 1-related autoimmunity, but only in children who had been first exposed to gluten before 4 months of age or after 7 months of age. The authors suggest that a virus may increase the risk of autoimmunity when there is already existing inflammation (Snell-Bergeon et al. 2012). And, respiratory infections during the first year of life (but not the second year of life) were associated with the development of islet autoimmunity in German children (Beyerlein et al. 2013).
In adults, a Swedish study found that pregnant women who had signs of a virus in early pregnancy, and a certain genetic risk, had a higher risk of developing islet autoantibodies during pregnancy (Rešić Lindehammer et al. 2012).
Not all studies show a link, however. A study of Finnish children at genetic risk of type 1 did not find a link between influenza A virus and the development of islet autoimmunity (Kondrashova et al. 2015). Nor did a Norwegian study of Saffold virus (Tapia et al. 2015).
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. (One study did look to see if persistent evidence of viruses could be found in the gut of people with type 1 and celiac, and did not find any (Mercalli et al. 2012).)
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). 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. Note that new techniques may make the process of studying viruses in type 1 diabetes easier, and earlier in the disease process, which could lead to a possibility of prevention (Bergamin and Dib, 2015).
An 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."
Two related studies from Europe have looked into the role of Coxsackie virus B and type 1 diabetes risk in children. Oikarinen et al. (2014) found that European children with diabetes more frequently had antibodies against Coxsackie virus B-1 (CVB1) than children without diabetes. (Dr. Oikarinen's doctoral thesis on this topic found that children with type 1 diabetes in Finland, Sweden, the UK, France and Greece, more often have CBV1 infections than those without diabetes Oikarinen 2016). Laitinen et al. (2014) found something even more interesting-- that Finnish children with antibodies to CVB1 had an increased risk of beta-cell autoimmunity, which precedes type 1 diabetes development. The risk was especially high when infection occurred a few months before autoantibodies appeared. And yet, there were some protective factors as well. One, if the children's mothers had antibodies to this virus, it reduced the child's risk of autoimmunity. Two, two other Coxsackie viruses, B3 and B6, were associated with a reduced risk of autoimmunity in these children. It may be that prior exposure to closely related B3 and B6 Coxsackie viruses provide an immune response that later protects against diabetes-producing B1 Coxsackie virus. For an article explaining these studies, see Enteroviral Infections and Development of Type 1 Diabetes: The Brothers Karamazov Within the CVBs (Dotta and Sebastiani 2014). These studies may also help explain why infections may protect against type 1 diabetes, as discussed in the following section.
In addition, other authors have found that there is a difference in the immune response of children who develop certain autoantibodies as a result of a Coxsackie virus infection (Ashton et al. 2016). A case study from Japan describes a 65 year old man who developed fulminant type 1 diabetes (a fast-acting type) along with a Coxsackie virus type A2 infection (Ohara et al. 2016).
Sardinia, Italy, is an island in the Mediterranean Sea that has a high incidence of type 1 diabetes. One study found that Sardinians with type 1 have high rates of infection with Mycobacterium avium paratuberculosis (MAP), which is transmitted from dairy herds through food to people (Masala et al. 2011). Scientists are now pursuing this topic further (e.g., Masala et al. 2013; Masala 2014; Naser et al. 2013; Niegowska et al. 2016a). People at-risk of type 1 diabetes tested positive to MAP-related markers more often than healthy controls. MAP is easily transmitted to humans with infected cow's milk and found in retail infant formulas, and possibly MAP could stimulate beta cell autoimmunity (Niegowska et al. 2016b). Signs of MAP have been found in a significant number of people with type 1 diabetes in Iran, as compared to a group without diabetes (Hesam Shariati et al. 2016).
Certain viruses are also associated with type 2 diabetes and insulin resistance-- hepatitis C for example (Antonelli et al. 2014; Desbois and Cacoub 2017; Gastaldi et al. 2017). In animals, toxic shock syndrome toxin can develop impaired glucose tolerance, inflammation, and insulin resistance (Vu et al. 2015). Some propose that Herpes virus may be related to type 2 diabetes as well (Pompei 2015). Others have looked at HIV, but a systematic review and meta-analysis of (albeit limited) data from Africa did not find an association (Prioreschi et al. 2017). Endotoxins (also known as lipopolysaccarides, LPS) can induce inflammation and may be also linked to type 2 diabetes and metabolic and cardiovascular disease (Min and Min 2015). (LPS levels are also associated with fat mass and inflammation in the fatty tissue of people with type 1 diabetes (Lassenius et al. 2016).)
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 why is diabetes increasing? 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).
Certain microbes (e.g. hepatitis A virus and Helicobacter pylori) and the gut microbiome (see the diet and the gut page) are associated with lower risk of type 1 diabetes (Kondrashova and Hyöty, 2014).
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. One study, however, found evidence of the opposite-- it found that living in crowded houses (as a proxy approximation of exposure to infectious agents) in very early life was associated with an increased risk of type 1 diabetes (and was not associated in later life) (Bruno et al. 2013). And, a study of all babies born in Southeast Sweden could not find any link between type 1 diabetes and a variety of hygiene-related parameters (Ludvigsson et al. 2013). A Finish study of various microbial measurements did not find any links between type 1 diabetes and exposure to microbes in the first year of life-- except exposure to dogs may have been protective (Virtanen et al. 2014).
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. Before we take action, however, note that some studies have found that "worm infestations" are not associated with the development of type 1 diabetes or other autoimmune diseases in children (Ludvigsson et al. 2017). Phew.
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, dogs 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 preceded 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 et al. 2010).
Despite all the publicity, there are many aspects of immune system diseases that the hygiene hypothesis does not explain (Matricardi 2010). For example, incidence is increasing in areas that are becoming industrialized, but still have high levels of infectious disease. And those of us in industrialized countries are not, in fact, living in a "clean" environment-- kids still get sick all the time, and the number of chemicals we are exposed to -- chemicals known to affect the immune system -- has increased dramatically.
In 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.
But wait, there are other environmental factors that may be able to increase susceptibility to viruses, and lead to more invasive infections: environmental chemicals.
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 chemicals (Tanabe 2002). Dioxin is another persistent organic pollutant that makes individuals more susceptible to viruses (Fiorito et al. 2016).
In humans, exposure to BPA has been associated with higher levels of cytomegalovirus antibodies in adults, a sign of altered immune system function. In youth, BPA exposure was associated with lower cytomegalovirus antibody levels. It is unclear what could account for these differences. The authors of this study suggest that perhaps the consequences of BPA exposure may vary depending on the timing, quantity, and duration of exposure. Perhaps short exposures stimulate the immune system, and longer exposures result in immune dysfunction (Clayton et al. 2011). In rats, early life exposure to BPA made them more susceptible to intestinal infection than those unexposed, and impaired their ability to respond to food antigens (Ménard et al. 2014). Intestinal infections (e.g., enteroviruses) and food antigens are both linked to type 1 diabetes (see the diet and the gut page).
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 chemicals 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).
Other studies also show that mercury heightens the immune response to infection, promoting autoimmunity in mice (Penta et al. 2014).
Viruses and chemicals may act together in other ways as well. Viruses can alter the uptake of chemicals and change the distribution of chemicals 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 chemicals in these organs (Funseth et al. 2000).
Feingold et al. (2010) discuss how current scientific research is lacking on how chemicals and pathogens interact to increase the risk and severity of disease. Exposure to chemicals 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 chemicals, and affect the risk for and severity of chronic disease progression. Research should therefore consider chemicals and pathogens together, when either one or both may contribute to disease development.Bougnères et al. 2017).
Viral 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 chemicals, 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.
To see or download the references cited on this page, see the collection Viruses and hygiene and diabetes/obesity in Pubmed.