Environmental Factors, Not Just Genes, Cause Type 1 Disease

For a long time, type 1 diabetes mellitus (T1DM) was considered a genetic autoimmune disease. Yet, correlations have been found between T1DM and environmental triggers such as viruses, with the seasonal onset within populations being the cue. But so far, the evidence has been largely circumstantial. Rotavirus, rubella, and mumps infection have been studied and disregarded¹; studies in a Finnish population disproved the rotavirus connection,² while successful vaccination campaigns that largely eliminated the 2 viruses could not curb T1DM.^3,4 However, there is validity to claims of an association between enteroviral infections and acceleration of islet autoimmunity, as was shown in a recent report from Taiwan.

A national population-based retrospective study compared the incidence of T1DM in children diagnosed with the enterovirus (EV) with that in age- and gender-matched children without EV infection in Taiwan. The study found increased susceptibility in the EV-infected children.⁵ The study utilized claims data from Taiwan’s National Health Insurance program between the years 2000 and 2008, with a study population that included children 18 years and younger.

With an adjusted hazard ratio of 1.48, the incidence rate was 5.73 for the infected children compared with 3.89 in the uninfected cohort, per 100,000 person-years. Additionally, when the authors examined the influence of atopic disease status in the children as a variable that could influence susceptibility to T1DM, they found that children in the EV group had significantly higher rates of atopic dermatitis, allergic rhinitis, and bronchial asthma. Age was another variable that determined incidence, with younger children (5 to 7 years old) and those over 10 years of age showing increased incidence of T1DM independent of their EV status. Based on previous studies, the authors concluded that increased incidence in the younger age group may correspond with the children starting school, while the second spike in older children may correspond with hormonal upheaval as the children entered puberty.⁵

The authors argued that while genetics are a factor, genes alone cannot explain the rapid rise in the number of cases of T1DM across ethnicities and geographic locations. The DiaMond Project, for instance, evaluated T1DM incidence between 1990 and 1999, and identified a steep rise among European children, especially in Sardinia, Sweden, Finland, Norway, Portugal, and the United Kingdom, as well as in Canada and New Zealand. Quite surprisingly, incidence increased with age, with 10-to-14-year-olds being the most susceptible.⁶ This and similar studies provide evidence for environmental factors, such as chemical exposure and infections, being possible triggers of disease.

Enteroviruses Detected in the Pancreas in T1DM

Better technology has improved the sensitivity of tests for viral detection. In 2009, a paper published in Diabetologia described the results of reexamining paraffin-embedded samples from 72 recent-onset T1DM patients and 161 controls. In addition to several immune response proteins that are produced in the pancreatic islets following a viral infection (PKR, class I MHC), expression of the EV capsid protein VP1 was examined.⁷

Multiple VP1-immunopositive cells were identified in multiple islets of more than 60% of the 72 samples of young, recent-onset T1DM patients, compared with only 6% of the 50 neonatal and pediatric normal controls. Of note, the VP1 expression was restricted to insulin-containing β cells, implicating the virus in cellular destruction. The authors conclude that genetic predisposition to T1DM, coupled with an EV infection of the β cells, can precipitate autoimmunity in young children.⁷

Despite this and similar studies, pinpointing a specific viral strain has proved challenging. Why would that be? Clinical disease onset, measured as the development of clinical hyperglycemia, likely happens months or years after the initial infection(s) that lead to the autoimmune loss of the islets. So when patient samples are analyzed, traces of the trigger may be long gone. Additionally, even if an individual is positive for the virus, confirming whether the virus is diabetogenic can be difficult.

So can immunization against EV or other suspect viruses help curb the current worldwide epidemic of T1DM? A global consortium of scientists—from research institutes to vaccine companies—says perhaps, and are working toward developing an EV vaccine to prevent the occurrence of T1DM. This effort would identify the diabetogenic serotype of the virus in different populations. Prototype vaccines are also being evaluated in mouse models.⁸References

1. Coppieters KT, Boettler T, von Herrath M. Virus infections in type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2(1):a007682.

2. Mäkelä M, Oling V, Marttila J, et al. Rotavirus-specific T cell responses and cytokine mRNA expression in children with diabetes-associated autoantibodies and type 1 diabetes. Clin Exp Immunol. 2006;145(2):261-270.

3. Gale EA. Congenital rubella: citation virus or viral cause of type 1 diabetes? Diabetologia. 2008 Sep;51(9):1559-1566.

4. Honeyman M. How robust is the evidence for viruses in the induction of type 1 diabetes? Curr Opin Immunol. 2005;17(6):616-623.

5. Lin HC, Wang CH, Tsai FJ, et al. Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study [published online October 22, 2014]. Diabetologia. doi:10.1007/s00125-014-3400-z.

6. Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J, Diabetes Mondiale (DiaMond) Project Group. Incidence of childhood type 1 diabetes worldwide. Diabetes Care. 2000;23(10):1516-1526.

7. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes. Diabetologia. 2009;52(6):1143-1151.

8. Nurminen N, Oikarinen S, Hyöty H. Virus infections as potential targets of preventive treatments for type 1 diabetes. Rev Diabet Stud. 2012;9(4):260-271.