Viruses and Bacteria
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.
Links Between Viruses and Diabetes
Historically, viruses have been the main suspected trigger of type 1 diabetes, with research spanning many decades (e.g., Gamble et al. 1969). Yet the subject is still controversial. New evidence from COVID-19 may help show whether or not viruses can trigger diabetes.
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 (e.g., see this review Isaacs et al. 2021). The "hygiene hypothesis," however, posits that infections in early childhood stimulate the immune system to control autoimmune reactions (Kondrashova and Hyöty, 2014). We'll look at both hypotheses below. Genetic background, dose, timing, type of virus, gut microbes, and other environmental factors, including chemicals, may play a role in the potential ability of viruses to induce or protect against type 1 diabetes.
Some viruses are also linked to the development of type 2 diabetes.
Can Viruses Contribute to the Development of 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 (reviews of viruses in type 1 include Kondrashova and Hyöty, 2014; Principi et al. 2017; Toniolo et al. 2019; van der Werf et al. 2007). Viruses have even been associated with type 1-related autoimmunity in wild animals (Warvsten et al. 2017). Most studies that have evaluated the association between viruses and type 1 have found that it is highly likely that some viruses do play a role in type 1 diabetes development (Principi et al. 2017).
In addition to causing diabetes in animals, enteroviruses are associated with an increased risk of type 1 diabetes in human studies (e.g., Abdel-Latif et al. 2017; Boussaid et al. 2017; Geravandi et al. 2020; Geravandi et al. 2021; Karaoglan and Eksi 2018; Sane et al. 2020), and have been detected in the pancreases of people with type 1 diabetes (Busse et al. 2017; Kondrashova and Hyöty, 2014; Krogvold et al. 2015). 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). Another meta-analysis of 10 studies of viruses in early life an autoimmunity found a statistically significant increased risk of islet autoimmunity and enterovirus levels (Faulkner et al. 2020). Cytomegalovirus has also been found in the pancreas of someone with type 1 diabetes, and not in controls. The infection was found in the islets of the patient, in addition to immune cells, showing that the immune response to the virus could have triggered beta cell injury (Yoneda et al. 2017). Gut viruses in general have been shown to precede the development of type 1-related autoimmunity (Park and Zhao, 2018; Zhao et al. 2017); enteroviruses have been found in the gut of children with type-1 related autoimmunity at a higher rate than in other children (Kim et al. 2019). An enterovirus found in the stool of a child who developed type 1-related autoantibodies affected beta cells in the lab and reduced insulin secretion (Wernersson et al. 2020).
Infections and the Environment
Infections may interact with other factors, including individual susceptibility factors and environmental chemicals to influence disease.
The Diabetes Virus Detection (DiViD) study is the first study to laparoscopically collect pancreatic tissue and pancreatic islets with other samples from people with newly diagnosed type 1 diabetes. They have found enterovirus RNA in various tissues including islets (Oikarinen et al. 2021).
There are a number of additional recent studies on viruses and type 1. For example, Finnish 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). Also in Finland, Coxsackievirus is also associated with the development of type 1-related autoimmunity (Sioofy-Khojine et al. 2018a). However, while the incidence of type 1 diabetes in Finland is the highest in the world, it is interesting that signs of enteroviruses are relatively low in Finland as compared to other countries (Sioofy-Khojine et al. 2018b).
Timing may also make a difference; children had a higher risk of autoimmunity and type 1 diabetes if they had more infections in their first years of life, and if these infections occurred earlier in life (Mustonen et al. 2018). The large, international TEDDY study found an increased risk of type 1 diabetes in children who had had a respiratory infection early in life (Krischer et al. 2017). This group also found that more respiratory infections in the 9 months prior to diagnosis was linked to an increased risk of type 1-related autoimmunity, primarily infections in the winter (Lönnrot et al. 2017). The TEDDY study also found that prolonged enterovirus infections rather than short-duration enterovirus infections may be involved in the development of islet autoimmunity (but not subsequent type 1 diabetes) in some young children. They also found that fewer early-life human mastadenovirus C infections were present in the children who developed autoimmunity (Vehik et al. 2019). 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).
There are other related findings as well. The TEDDY study 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). A large, population-based study from Norway found that general early life infections and infection frequency were not associated with the development of childhood type 1. Hospital admission for gastroenteritis was associated with type 1 risk, but there were very few cases (Tapia et al. 2018). In Taiwan, children diagnosed with type 1 had higher rates of enterovirus infection than healthy people, but only up to age 6, not at higher ages (Shih et al. 2021).
Additional viruses linked to type 1 diabetes include rotavirus (Ataei-Pirkooh et al. 2019) and mumps. 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). As for rotavirus, a review finds that research into associations of rotavirus infections with type 1 diabetes development in humans have yielded mixed findings and, that there are interactions with age and diet (Burke et al. 2020). There is some (but also not entirely consistent) evidence that the rotavirus vaccine may help reduce the risk of type 1 diabetes (discussed on the Vaccines page), thus supporting the possibility that rotavirus may contribute to type 1 diabetes (Harrison et al. 2019).
Additional 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. (Valdés et al. 2013). A population-wide study from Norway did not find a clear association between flu infection and type 1 diabetes incidence. However, it did find a twofold higher incidence of type 1 in those with laboratory-confirmed H1N1 (Ruiz et al. 2018). Other researchers have since found links between H1N1 and type 1 diabetes in animal studies as well (Qi et al. 2018). However, analysis of actual human pancreases of people with diabetes found that signs of H1N1 were not only found in those with autoimmunity, and that animal studies show that while the virus can be found in the pancreas of animals, it doesn't cause effects linked to diabetes (Capua et al. 2018). Retroviruses are also being investigated in relation to type 1 diabetes (Levet et al. 2019), as is human herpesvirus-6 (Sabouri et al. 2019), and norovirus (Pearson et al. 2019).
There aren't many studies of viruses and type 1 from non-Western countries. One study of children in Africa and Asia did not find links between viruses and type 1, but there isn't a lot of research on this yet (Cinek et al. 2021).
A picornavirus named Ljungan virus, which is related to enterovirus, may also be linked to type 1. Some researchers noticed that there was an association between the abundance of rodents in the wild and the onset of type 1 diabetes in humans. They then isolated this virus from wild voles, and found that it infects islets (in both voles and humans) (Klitz and Niklasson, 2020). Interesting.
Putting aside discussions of genetic engineering, researchers put human pancreatic islets 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. 2015). 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. 2016). Beta cells exposed to this virus contain less insulin (Nyalwidhe et al. 2017). scientists are actually using these finding to see if a CBV vaccine could help prevent type 1 diabetes (Hyöty et al. 2018).
Viruses may interact with other factors related to type 1 diabetes as well. For example, an Italian study found that those with type 1 diabetes had higher rates of enterovirus infection, as well as lower levels of vitamin D. Interestingly, of those with diabetes, people who had signs of infection also had lower vitamin D levels. So maybe there is some interaction between these factors (Federico et al. 2018). Also, enterovirus infection appears also to be associated with higher intestinal permeability (in people with type 2 diabetes) (Pedersen et al. 2018). Genetic background may also be able to influence the risk of diabetes in relation to viruses (Blanter et al. 2019).
What About COVID-19?
Well here we go. Finally we may get some strong evidence that viruses can indeed cause type 1 diabetes in humans.
Diagnoses of type 1 diabetes among children in a small UK study almost doubled during the peak of Britain's COVID-19 epidemic (Unsworth et al. 2020). For an article on this study, see Study Links COVID-19 to Rise in Childhood Type 1 Diabetes Diagnoses, published in Medscape. Additional evidence from Germany, however, finds that type 1 diabetes incidence in 2020 was not higher than expected (Tittel et al. 2020). In Colorado, while not published yet, it appears that the Barbara Davis Center "saw a 40% increase in new-onset pediatric cases in May and June compared with the same time period in 2019" (see this article re the Barbara Davis Center, 2020). (Note that overall U.S. hospital admissions for children declined significantly in 2020 compared to earlier years, including for diabetes, probably because people were avoiding hospitals (Pelletier et al. 2021).)
In Finland, the type 1 incidence was higher in 2020 as compared to previous years, BUT all the children diagnosed with type 1 tested negative for COVID-19 antibodies (Salmi et al. 2021). In 2020, researchers in Colorado tested everyone with new-onset type 1 at the Barbara Davis Center for Childhood Diabetes for COVID-related antibodies. They found that fewer than 1% of new-onset patients had them, which was statistically the same (and an even lower number) as the general population. They thus "found no evidence for increased prevalence of COVID-19 infections among youth with newly diagnosed type 1 diabetes." (Jia et al. 2021). In Belgium there were similar results, with the prevalence of anti-SARS-CoV-2 antibodies in children with newly diagnosed type 1 diabetes (20%) similar to that found in children without diabetes (although higher overall than Colorado) (Messaioui et al. 2021).
In Romania, the number of children diagnosed with type 1 diabetes at one center was 30% higher during the pandemic than in prior years (Boboc et al. 2021), and a center in Turkey also saw an increase in the number of children diagnosed with type 1 than in the prior year (Dilek et al. 2021).
A meta-analysis of eight studies (from the USA, Italy, and China) found that of 3711 hospitalized COVID-19 patients, there were 492 cases of newly diagnosed diabetes, which is a rate of 14.4% (Sathish et al. 2020). That seems pretty high! This same analysis also found that newly diagnosed diabetes was just as common as preexisting diabetes in hospitalized COVID-19 patients (Sathish and Cao 2020). However data seem to differ in the different places around the world. In France, only 2.8% of people hospitalized for COVID with diabetes had new-onset diabetes, compared with 5% in Italy and 16-21% in China (Cariou et al. 2021). In India, the rate was about 20% (Sathish et al. 2021). In Italy, type 1 diabetes incidence in children was a little higher in 2020 than in prior years, although not statistically significantly higher than in 2019 (Mameli et al. 2021).
A group of researchers has started a COVIDIAB registry to better analyze diabetes triggered by COVID-19. It aims to answer a variety of questions, for example, How frequent is the phenomenon of new-onset diabetes? Is it classic type 1 or type 2 diabetes or a new type of diabetes? Does it resolve on its own? Do these patients remain at higher risk for diabetes or diabetic ketoacidosis? And, in patients with preexisting diabetes, does Covid-19 change the underlying progression of the disease? (Rubino et al. 2020).
So figuring out what happened with diabetes will be a little complicated.
COVID-19 is definitely linked to diabetic ketoacidosis (DKA). In New York City, despite a decrease in ER visits during the pandemic, cases of DKA rose drastically as compared to the year before (Ditkowski et al. 2021). There are a lot of published individual case studies as well. For example, Chee et al. (2020) report a case of DKA caused by COVID-19 in a 37 year old male patient with newly diagnosed diabetes. Diabetes type is not specified, but DKA is usually associated with type 1 diabetes. However, another study found that COVID-19 caused ketosis and ketoacidosis in people with or without diabetes, and induced DKA in people with diabetes (only one person had type 1) (Li et al. 2020). Another case report describes a 54 year old man who developed DKA a week after a COVID-19 diagnosis (Heaney et al. 2020). Additional studies also describe people who developed DKA from COVID-19 (Akbarizadeh et al. 2021; Alsadhan et al. 2020; Domínguez Rojas et al. 2021; Gianniosis et al. 2020; José Concepción Zavaleta et al. 2020; Omotosho et al. 2021; Patel et al. 2021; Rabizadeh et al. 2020; Reddy et al. 2020; Singh et al. 2021), including an 8 month old infant (Soliman et al. 2020) and someone who had normal blood glucose levels but ketoacidosis (high ketone levels) (Morrison et al. 2020). Studies also show that people hospitalized with COVID-19 (without diabetes) tend to have higher blood glucose levels than other hospitalized patients without COVID-19, and those critically ill had higher insulin resistance and compromised insulin secretion (Ilias et al. 2021).
An interesting study looked at people without diabetes, who developed COVID-19 and were given continuous glucose monitors to wear. It turns out that COVID-19 resulted in higher blood sugar levels and more blood sugar fluctuations (Shen et al. 2021). COVID-19 also can increase insulin resistance in people without diabetes (Chen et al. 2021).
Type 1 Diabetes
As for type 1 diabetes, A study describes a 29 year old woman who developed type 1 diabetes (with GAD autoantibodies) a month after having COVID-19 (Marchand et al. 2020). Some case studies describe people who have developed autoantibody-negative type 1 diabetes following COVID-19 (Hollstein et al. 2020; Venkatesh et al. 2021). It appears that COVID-19 can attack beta cells directly, and worsening existing diabetes cases. If that is true, then I would expect it could cause diabetes as well-- of any type. In a commentary, Caruso et al. (2020) state, "...future studies are warranted to investigate the existence of a pathogenetic role of COVID-19 pandemic on T1DM onset. In the meantime, clinical practitioners should be aware of this contingency, giving more attention to individuals predisposed to autoimmunity." Additional case studies also describe people who may have developed type 1 diabetes as a result of COVID-19 (Aabdi et al. 2021; Albuali and AlGhamdi 2021; Alfishawy et al. 2021; Alshamam et al. 2021; Benyakhlef et al. 2021; Chekhlabi et al. 2021; Derrick et al. 2020; Firouzabadi et al. 2021; Kästner and Harsch, 2021; Naguib et al. 2020; Nielsen-Saines et al. 2021; Sarwani et al. 2021). But there are also case studies of people who developed non-autoimmune (sometimes called type 1B diabetes) following or during COVID-19 infection as well (Hoyos-Martinez et al. 2021; Seow et al. 2020). And, "Long Covid" may also increase the risk of developing new-onset diabetes (Sathish et al. 2021). In people without diabetes who developed COVID-19, follow up found that many developed higher glucose levels and some diabetes (Mistry et al. 2021).
A Comment in the Lancet Diabetes and Endocrinology by Mark Atkinson (a long-time, really good type 1 researcher) notes that we do know that SARS-CoV-2 infection can induce high blood glucose levels in people without diabetes, and that there are case reports of diabetes onset simultaneously or shortly after SARS-CoV-2 infection (as noted above). However, findings from epidemiological studies have been conflicting. There is also conflicting evidence regarding which cells within the pancreas—and particularly the beta cells—express the key viral receptor for SARS-CoV-2, ACE2, and additional factors necessary for effective SARS-CoV-2 entry (Atkinson and Powers, 2021). However, other cells involved in metabolism do express these receptors (Mahrooz et al. 2021).
Beta Cells and the Pancreas
Evidence does suggest that the COVID-19 virus might enter islets, and cause acute beta cell dysfunction, followed by hyperglycemia and diabetes (Mukherjee et al. 2020). A news item in the scientific journal Nature notes that the virus can damage beta cells and trigger diabetes (Mallapaty 2020). A review finds there is a chance that the virus can directly infect the islets, although the evidence so far is somewhat contradictory (Somasundaram et al. 2020). Reviews also describe various mechanisms by which COVID-19 might trigger diabetes (Ibrahim et al. 2021; Kloc et al. 2020; Sathish et al. 2020). Two studies have found that the receptors that COVID-19 targets are in the pancreas but are not "enriched" in the beta cells specifically (Coate et al. 2020; Kusmartseva et al. 2020). Another found that the receptors are "preferentially expressed" in the beta cells (Fignani et al. 2020). And ongoing research shows that the virus can infect and replicate in the beta cells in the test tube, leading to impaired insulin secretion. In the lab, In human cadavers, the pancreas seems to be targeted by the virus as well (Müller et al. 2021; Morris 2021). SARS-CoV-2, it turns out, can impair and kill beta cells (Wu et al. 2021). New evidence from autopsies finds signs of the virus in the beta cells of people who died from COVID-19 (Steenblock et al. 2021; Tang et al. 2021). It appears that there is now evidence that the SARS-CoV-2 virus can indeed infect beta cells, and that this can contribute to the high blood sugar seen in people with COVID-19 (Clark and Mirmira, 2021). Research finds that "SARS-CoV-2 infection induces beta cell stress that may compromise beta-cell function beyond the duration of the disease course" (Millette et al. 2021). So evidence is growing.
According to a review (free full text, which includes both type 1 and type 2 diabetes), COVID-19 "can precipitate acute metabolic complications through direct negative effects on β-cell function. These effects on β-cell function might also cause diabetic ketoacidosis in individuals with diabetes, hyperglycaemia at hospital admission in individuals with unknown history of diabetes, and potentially new-onset diabetes." (Apicella et al. 2020).
COVID-19 appears to have other effects on the pancreas as well, not just on the beta cells (Bacaksiz et al. 2021).
Type 2 or Type 1?
A study that provides some follow-up of people who developed diabetes and DKA from COVID-19 found that while the diabetes appeared to resemble type 1 at first, after 4-6 weeks the people were able to move to oral drugs instead of insulin, suggested it is more like type 2 diabetes (Kuchay et al. 2020). A case study identifies one patient as developing "ketosis-prone type 2 diabetes" but note the patient tested "weakly positive" for GAD autoantibodies (Siddiqui et al. 2020). In Germany, an analysis of those newly diagnosed with type 1 diabetes before and during the pandemic finds that the pandemic did not lead to any change in the rate of diagnosis of "auto-antibody negative type 1 diabetes" in children or young adults. There wasn't an increase in type 2 diabetes or MODY either (or type 1, as reported by the Tittel article above). These authors do note that just because they didn't find a population-wide trend yet does not mean that in some people there could have been a link, and that the trends may change as the pandemic continues (Kamrath et al. 2021). A study from the Veterans Affairs health system found a 39% higher likelihood of a new diabetes diagnosis among COVID-19 survivors within six months following infection, compared with people who had not had COVID-19 (Al-Aly et al. 2021). A review focuses on how COVID-19 may be responsible for the "accelerated development of type 2 diabetes as one of its acute and suspected long-term complications." (Hayden, 2020).
One commentary, however, points out that we need more data. Sometimes COVID-19 could cause transient hyperglycemia, but whether that is permanent or not requires long-term follow-up. COVID-19 also might be revealing pre-existing diabetes-- a lot of people have type 2 but don't know it. When they show up at a hospital for another reason they find out. In any case, it seems the jury is still out (Accili 2021). There is at least one documented case study of someone who developed type 2 diabetes (presumably) following a mild case of COVID-19 (most people who develop high blood sugar or ketosis have severe COVID) (Ghosh and Misra, 2020). Research from Italy, however, finds that a high percentage of people who had COVID-19 and who did not have prior diabetes had higher blood glucose levels which can persist long after recovery (Molinari et al. 2021; Montefusco et al. 2021).
In Egypt, a study found that of 570 people with COVID-19, 1.2% had new-onset type 1, and 10.2% had new-onset type 2, and the diabetes persisted for at least 3 months in 73% of these cases (Farag et al. 2021).
Autoimmunity, the Gut
SARS CoV-2/COVID-19 may also be able to trigger autoimmunity (Cappello et al. 2020; Marino Gammazza et al. 2020) as well as affect the gut microbiome (Villapol 2020). SARS-CoV-2 interacts with genes that are linked to autoimmune disease, type 2 diabetes, coronary artery diseases, and asthma (Bellucci et al. 2020).
Note also that exposure to environmental chemicals may weaken our immune systems, perhaps making us all more susceptible to COVID-19 (Tsatsakis et al. 2020).
See also the article, 'We have more to learn': Data inconclusive on COVID-19 driving form of type 1 diabetes. Also see additional reviews or articles on how COVID-19 might trigger diabetes (Al-Kuraishy et al. 2021; Lima-Martínez et al. 2020; Papachristou et al. 2020).
More on Viruses and Type 1
Exposure During Development
Does maternal exposure to viruses increase the risk of type 1 diabetes in the offspring? Well, maybe. A meta-analysis of ten studies found that virus infection during pregnancy was associated with type 1 diabetes during childhood, but not with islet autoimmunity (Allen et al. 2018). Another meta-analysis, of 18 studies, also found that maternal infection during pregnancy was associated with type 1 in the offspring (Yue et al. 2018).
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). A Scandinavian study found that concomitant enterovirus antibodies and beta cell autoantibodies tended to be more common among mothers of children with type 1 or autoimmunity (by age 7) compared to control mothers, although the frequency of maternal enterovirus antibodies did not differ (Lind et al. 2018). 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). The TEDDY study found that a mother's respiratory infections during pregnancy were associated with a lower risk of the child developing certain autoantibodies, although this depended on genetic background (Lynch et al. 2018). And a large, population-based Swedish study found that urinary tract infection during pregnancy was associated with an increased risk of type 1 diabetes in offspring, but infections around the time of birth or in infancy were not (Waernbaum et al. 2019). Also in Sweden, a mother's respiratory infection in the first trimester and gastroenteritis during pregnancy were associated with an increased risk of type 1 diabetes in offspring (Bélteky et al. 2020). 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).
Experimental data support the idea that viruses might infect the fetal thymus-- an organ involved in immune system development-- and increase the development of diabetes-related autoimmunity (Geenen and Hober, 2019).
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).
Exposure to stomach viruses early in life is associated with an increased risk of celiac disease, an autoimmune disease common in people with type 1 diabetes (Beyerlein et al. 2017; Oikarinen et al. 2021). This exposure is also linked to celiac disease autoimmunity development, especially in combination with a diet higher in gluten (Lindfors et al. 2019).
Why Is It Hard to Show a Link Between Viruses and 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. (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).) Some authors propose that folate levels might affect people's response to a virus and thereby the risk of type 1 (Bayer and Fraker 2017).
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).
The Curious Case of Congenital Rubella
An often-cited statistic is that 10-20% of people exposed to rubella (German measles) 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."
A recent case study, however, describes a case of type 1 diabetes that might be due to congenital rubella, and the patient, a 13 year old Turkish boy, tested positive for the autoantibodies associated with type 1 diabetes. The boy also had other health issues associated with congenital rubella, including hearing loss, microcephaly, behavior issues, and heart and eye problems (Korkmaz and Ermiş, 2019).
Rubella/German measles is not the same virus as measles, but since they have a similar name and the same vaccine (MMR) I'll put this here. Historically, outbreaks of type 1 diabetes have occurred following measles outbreaks, for example in Philadelphia in 1993, where an "epidemic" of type 1 occurred two years after a measles outbreak (Lipman et al. 2002). It will be interesting to see if the current measles outbreak in the U.S. will lead to an increase in type 1 diabetes incidence. (Please note that vaccines are not linked to an increased risk of type 1 diabetes! See the Vaccines page for more information).
The Curiouser Case of Coxsackie Virus
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 section below, Can Infections Protect Against Type 1 Diabetes?
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). In the laboratory, Coxsackie virus affects human beta cells and targets genes related to autoimmunity and type 1 diabetes risk (Engelmann et al. 2017); scientists are working on figuring out the mechanisms by which Coxsackie viruses affect beta cells (Colli et al. 2019; Nekoua et al. 2021), how Coxsackie viruses affect the immune system (Alhazmi et al. 2021), and how the immune system interacts with virus-affected beta cells (Nekoua et al. 2019).
Coxsackie virus can be spread through water pollution. In Egypt, evidence suggests that contaminated drinking water or untreated sewage may play a role in type 1 diabetes development in children, via spreading this virus (El-Senousy et al. 2018).
A case study describes how a Japanese woman developed fast-onset (fulminant) type 1 diabetes during pregnancy possibly as a result of a Coxsackie virus infection (Hayakawa et al. 2019). Another case study from Japan describes a 65 year old man who developed fulminant type 1 diabetes along with a Coxsackie virus type A2 infection (Ohara et al. 2016).
One group of researchers used mapping data from France to look at the infectious environment and type 1 diabetes development over time. They found that flu-like infections and "summer diarrhea" were associated with an increased risk of type 1 diabetes, while varicella (chickenpox) seemed protective. Genetic background also played a role in these associations. The authors note that, "the infectious associations found should be taken as possible markers of patients' environment, not as direct causative factors of type 1 diabetes" (Bougnères et al. 2017).
Other authors have recognized that in theory, vaccines against disease linked to type 1 diabetes may protect against the development of type 1. This may have happened with mumps in the past, for example. However a new study on rotavirus, one of the viruses linked to type 1, found that rotavirus vaccination had no effect on type 1 diabetes (or celiac disease) rates (Vaarala et al. 2017).
Some people want to test antiviral medications in humans to see if they can treat type 1; they seem to work in animals (Niklasson et al. 2020).
Bacterial infections have been linked to a higher incidence of severe diabetic retinopathy, a complication of diabetes, in people with type 1 diabetes (Simonsen et al. 2020).
Mycobacterium Avium Paratuberculosis (MAP)
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). Another study found adults with LADA (Latent Autoimmune Diabetes in Adults) have higher levels of MAP infection as well (Niegowska et al. 2017). Scientists are now pursuing this topic further (e.g., Garvey 2018; 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).
In addition, just regular tuberculosis is associated with type 1 diabetes, as well as type 2 (Cadena et al. 2019), which brings us to...
Viruses and Type 2 Diabetes
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), and with gestational diabetes-- hepatitis B for example (Giles et al. 2020) (As an interesting tidbit, ducks with "duck hepatitis B" have higher blood glucose and impaired glucose tolerance (Tan et al. 2021)). In animals, hepatitis C infection can impair beta cell function and insulin secretion (Chen et al. 2020). Toxic shock syndrome toxin can cause impaired glucose tolerance, inflammation, and insulin resistance in animals as well (Vu et al. 2015). Some propose that Herpes virus may be related to type 2 diabetes (Pompei 2016). 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).)
Note that people with type 2 diabetes are more susceptible to viruses (as we've seen with COVID-19) (Lontchi-Yimagou et al. 2021).
Helicobacter pylori (H. pylori) is one of the most common human infections and has been associated with the development of type 2 diabetes (Bener et al. 2020; Hosseininasab Nodoushan and Nabavi, 2019; Mansouri et al. 2020), but not necessarily type 1 (Esmaeili Dooki et al. 2020; Li et al. 2017). (Although among people who already have type 1 or 2 diabetes, H. pylori is associated with higher long-term blood glucose levels (HbA1c) (Chen et al. 2019).) For example, H. pylori infection was associated with and increased risk of diabetes in people with a lower BMI, and peptic disease (ulcers) were also associated with diabetes. It may be that gastric inflammation and damage to the gut microbiota might play a role in these associations (Haj et al. 2017). H. pylori is also associated with increased insulin resistance (Cherkas et al. 2018) and type 2 diabetes (Kato et al. 2019). A large longitudinal study from Taiwan found that H. pylori was associated with an increased risk of developing type 2 diabetes and metabolic syndrome in men but not women (Chen et al. 2019). Note also that people with higher levels of lead in their blood may have a higher risk of H. pylori infection (Park et al. 2019). However, not all studies find links; a large Korean study found no association between H. pylori and diabetes (Pyo et al. 2019). And, a prospective study that followed people for 10 years found that H. pylori infection was associated with a lower risk of diabetes in Chinese adults (Zhou et al. 2018), which brings us to our next topic...
Can Viruses Protect Against Type 1 Diabetes?
Some authors argue that infections may also protect against autoimmune disease (and allergies) (e.g., Bach 2021; 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).
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). A Finish study also found that early childhood CMV infection may decelerate the progression from islet autoimmunity to clinical type 1 diabetes in at-risk children, but did not affect the appearance of type 1-associated autoantibodies, showing that CMV in early childhood may be protective overall (Ekman et al 2018). And, a Finnish study found that while there was no association between between Ljungan virus or human parechovirus and islet autoimmunity, there was a trend for significantly higher prevalence of human parechovirus antibodies in control children, suggesting a possible protective effect (Jääskeläinen et al. 2018).
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. Others are also looking into this possibility (e.g., Tang et al. 2019; Mughal et al. 2021). Before we start eating worms, 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 2002). 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. Additional authors argue that infections also have to be analyzed in combination with the microbiome, in relation to autoimmune diseases (Bogdanos and Sakkas 2017). Others argue that the focus should not be on hygiene in the sense of washing your hands ("hygiene habits"), but a theory combining diverse elements, including the microbiome (Alexandre-Silva et al. 2018). Other authors also point out the inter-relationships between things like the microbiome, diet, vitamin D, lifestyle, and pollution, and that just "hygiene" is too simplified (Murdaca et al. 2021).
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.
Viruses and the Rising Incidence of Disease
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.
Viruses and Environmental Chemicals
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. 2017). Arsenic can increase susceptibility to infection during pregnancy and in early life (Attreed et al. 2017).
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).
Prenatal exposure to perfluoroalkyl substances (PFASs) are associated with markers of infections in early childhood (Dalsager et al. 2016; Goudarzi et al. 2017) and with more common and more severe reactions to respiratory (but less common gastrointestinal) viruses (Dalsager et al. 2021).
Mice exposed to dioxin in early life and then viruses in later life had different T cell reactions and different epigenetic changes due to the virus than mice unexposed to dioxin. These changes are linked to autoimmune diseases (Burke et al. 2021). For an explanation of this study, see, Developmental Origins of Delayed Adult Immune Response: The AhR Connection, published in Environmental Health Perspectives (Pascual et al. 2021).
An interesting experiment exposed mice to the heavy metal 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). Other studies also show that mercury heightens the immune response to infection, promoting autoimmunity in mice (Penta et al. 2015). The heavy metal cadmium appears to increase inflammation in response to the H1N1 infection in mice (Chandler et al. 2019).
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 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.
How Chemicals and Infections Can Interact
Four potential scenarios showing potential interactions between infections and toxicants. (A) A toxicant and a pathogen may both act together to cause a disease. (B) Either a pathogen or a toxicant alone is sufficient to cause the disease. (C) A chemical toxicant can modify the association between a pathogen and a disease. (D) A pathogen can modify the association between a chemical toxicant and a disease.