What sets the scene for the autoimmune attack of type 1 diabetes?
A new review in Diabetologia looks at the very earliest stages of type 1 diabetes, focusing on the beta cell injury and the inflammatory immune response that set the scene for an autoimmune attack. This recent research will inform strategies for primary prevention, taking us ever closer to a world without type 1 diabetes. Dr Susan Aldridge reports.
The countdown to type 1 diabetes begins with a pre-symptomatic autoimmune attack on the islets, which can be diagnosed through the detection of one or more islet autoantibodies. The presence of more than one of these antibodies is known as stage 1 type 1 diabetes and is associated with a high probability of developing clinical diabetes over the following years.
There are now treatments, such as teplizumab, which can be administered at stage 1 or later to prevent or delay the onset of overt diabetes. However, the more we can learn about the pre-symptomatic stages, the more likely it is that such treatments can be optimised, thereby reducing the burden of type 1 diabetes in the population. Professor Anette-Gabriele Ziegler of the Institute of Diabetes Research, Helmholtz Munich in Germany, has reviewed when, how and why islet autoantibodies arise and how our knowledge to date can be used to plan future strategies to target islet autoimmunity. This review is based on her 2022 EASD-Novo Nordisk Foundation Diabetes Prize for Excellence presentation.
Professor Ziegler draws upon three longitudinal birth cohorts for her findings. The BABYDIAB/BABYDIET study began in 1989 and has over 30 years of prospective follow-up. It included 2441 children with a first-degree relative with type 1 diabetes. The Environmental Determinants of Diabetes in the Young (TEDDY) study, which began in 2004, is an international birth cohort of 8676 children with increased risk for type 1 diabetes defined by their human leukocyte antigen (HLA) status. Finally, the Primary Oral Insulin Trial (POInT), which began recruitment in 2018, has enrolled 1050 children with a high polygenic risk score for type 1 diabetes from Belgium, Germany, Poland, Sweden and the UK. All of these studies are following children for the development of islet autoantibodies and clinical type 1 diabetes.
Islet autoimmunity – when?
Both the BABYDIAB and TEDDY studies showed that incidence of islet autoimmunity peaks between the age of one to 1.5 years, and this is so for both children with a first-degree relative with type 1 diabetes and children from the general population. These data suggest that there is a ‘fertile’ period very early in life in which there is enhanced susceptibility to autoimmune attack on beta cell targets.
The author and her colleagues did a modelling study that showed that the risk of developing islet autoantibodies decreases exponentially with age. This has practical relevance for screening and advising families. For instance, a baby born to a father with type 1 diabetes has an estimated risk of 7% of developing islet autoantibodies by the age of six. However, if they are still negative at this age, the remaining risk of developing them over the next six years falls to just 1%. The age of peak incidence and exponential decay with age also have important implications for the aetiology and pathogenesis of type 1 diabetes, as the genes and/or environmental factors influencing islet autoimmunity must exert maximum impact at, or prior to, the age of peak incidence.
The role of genetics
A type 1 diabetes-associated genotype is the first important component of the fertile environment. Before BABYDIAB, it wasn’t clear whether these genes were responsible for the development of islet autoimmunity or progression to type 1 diabetes. It now appears that genetic susceptibility is important for the initiation of autoimmunity and less so for progression. Both HLA and non-HLA genes are involved in developing islet autoantibodies. The prevalence of multiple islet autoantibodies in children from the general population is around 0.31%, but children with specific HLA genotypes have an average risk of 5% of developing multiple islet antibodies by the age of six.
Adding non-HLA genes to polygenic risk scores can further stratify the risk, thereby identifying newborns in the population with a 10% risk of developing multiple autoantibodies by the age of six. Genetic risk changes with age, suggesting that a substantial component of this risk operates during the fertile period. Most of these genes are associated with immune or cellular responses to infection. Some are associated with altered microbiome compositions or increased birthweight. This is interesting, given that both the microbiome and birthweight are known to be associated with development of islet autoimmunity and type 1 diabetes.
Focus on the fertile period
The genes that predispose for type 1 diabetes are also implicated in other autoimmune diseases, including coeliac disease, pernicious anaemia and thyroid disease. The incidence peaks of autoantibodies differs for each condition – two years of age for coeliac disease and puberty and adolescence for thyroid disease. This does suggest that the affected organ is relevant and its activity, function and maturity may change during its fertile period. The author’s team wanted to know why beta cell autoimmunity occurs so early in life. Therefore, they measured random preprandial non-fasting glucose levels between four months and 3.5 years in children who were enrolled in POInT.
They found substantial changes in glucose concentrations – falling to a nadir at one to 1.5 years of age and increasing thereafter. This not only coincides with the peak incidence of islet autoimmunity, but also follows the adiposity peak that is typically seen at eight to nine months of age, suggesting growth pressure on islets during this susceptible period. Therefore, they propose that age one year might be a period of increased islet cell activity, increased beta cell stress and greater vulnerability to insults.
Respiratory infection is one of these insults, being most frequent during the first two years of life. Indeed, children in the BABYDIAB/BABYDIET studies had an average of 3.7 infection episodes during the peak period of islet autoimmunity. This is not unexpected as the protection afforded by maternal antibodies gradually declines as the child’s own immune system develops. It is thought that some viruses directly infect beta cells, while others indirectly cause beta cell damage and immune activation via systemic inflammation.
A range of studies, taken together, build a picture where there are deviations from a healthy immune response, with propensity to a T helper type 1 (Th) response to insulin and marked inflammation present before the onset of islet autoimmunity.
The role of viruses
Previous research has linked viral infections in the first year of life with type 1 diabetes, particularly among children who have prolonged or multiple respiratory infections. There is evidence to suggest that childhood infections occurring shortly before the onset of autoimmunity play a role in promoting autoreactivity towards islet cells.
Many attempts have been made to identify the viruses responsible for the increased risk of autoimmunity and the candidates with the most convincing evidence to date are the enteroviruses, particularly coxsackie B virus. For instance, a large sequencing study of stool samples from 700 children in the TEDDY study suggests that prolonged shedding of enterovirus B may be involved in islet autoimmunity. However, this was observed in only 11.8% of those with autoimmunity – as opposed to only 6.5% of children without islet autoantibodies – so enterovirus B is clearly only part of the story.
Research has also suggested that other viruses may be involved in islet autoimmunity. For instance, an increased incidence of type 1 diabetes was observed during the COVID-19 pandemic. The receptor for the SARS-CoV-2 virus is expressed on pancreatic ductal, alpha and beta cells, so it is plausible that it may trigger an autoimmune response. Finally, rotavirus and cytomegalovirus have also been implicated in islet autoimmunity. A decrease in type 1 diabetes incidence has been noted with the introduction of rotavirus vaccination in some, but not all, studies. In summary, the available data suggests that viruses, especially those that can infect islet cells, are a co-factor, with genetics, for the development of islet autoimmunity.
Implications for prevention
So what does this recent research mean for prevention of type 1 diabetes? The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) was set up in 2017 to identify infants at higher genetic risk of developing type 1 diabetes and to carry out primary prevention trials. The GPPAD uses a polygenic risk score to screen newborns for risk of type 1 diabetes in five European countries and over 400,000 newborns have joined screening to date. Two randomised controlled trials are underway. POInT, as mentioned above, aims to induce tolerance to insulin by oral insulin therapy and is intended to target the Th 1 propensity to insulin in children with high genetic susceptibility. Results are expected in 2025.
The second trial, Supplementation with Bifidobacterium infantis for Mitigation of Type 1 diabetes Autoimmunity (SINT1A), aims to reduce inflammation and infection by promoting a healthy microbiome through supplementation with B.infantis from the age of six weeks to 12 months. The study has enrolled 600 infants out of a target of 1150, with results expected in 2027. More studies are being planned and one goal of these would be to protect the beta cell from infection or stress to prevent the initiation of autoimmunity.
In summary, there are three factors that contribute to the development of beta cell autoimmunity. There is increased beta cell activity, exposure to infection and a heightened immune response with a propensity for Th 1 immunity. Beta cell injury and activation of an inflammatory immune response therefore sets the scene for autoimmunity. A deeper understanding of these early events in the countdown to type 1 diabetes will aid development of effective primary prevention strategies, bringing us closer to Professor Ziegler’s vision of a world without type 1 diabetes.
To read this paper, go to: Ziegler A-G. The countdown to type 1 diabetes: when, how and why does the clock start? Diabetologia 26 May 2023. https://doi.org/10.1007/s00125-023-05927-2
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Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.
