Elsevier

The Lancet

Volume 387, Issue 10035, 4–10 June 2016, Pages 2340-2348
The Lancet

Series
Environmental risk factors for type 1 diabetes

https://doi.org/10.1016/S0140-6736(16)30507-4Get rights and content

Summary

The incidence of type 1 diabetes has risen considerably in the past 30 years due to changes in the environment that have been only partially identified. In this Series paper, we critically discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes. We revisit previously proposed hypotheses to explain the growth in the incidence of type 1 diabetes in light of current data. Finally, we suggest a unified model in which immune tolerance to β cells can be broken by several environmental exposures that induce generation of hybrid peptides acting as neoautoantigens.

Introduction

The incidence of type 1 diabetes has increased by several times over the past 30 years.1 This increase can only be explained by changes in environment or lifestyle. Supporting the impact of environment or lifestyle on risk, migrants tend to acquire the same risk of type 1 diabetes as the population in their new area of residence.2, 3 In Europe, the risk of type 1 diabetes differs substantially in people who are genetically close but separated by socioeconomic borders.4 This risk has become more homogeneous within populations with free movement of people and trade.5 Improved understanding for the environmental determinants of type 1 diabetes could make it possible to prevent or delay the disease.

Type 1 diabetes is diagnosed after onset of overt hyperglycaemia;6 however, evidence is mounting that islet autoimmunity is the first stage of the disease.7 Islet autoimmunity is defined by the persistent presence of autoantibodies to pancreatic islet antigens. Islet immunity usually starts in early childhood, with incidence peaking in the second year of life,8, 9, 10 and can have a remitting-relapsing course before onset of diabetes.11 Development of two or more islet autoantibodies (to insulin, glutamic acid decarboxylase [GAD], insulinoma-associated antigen 2, or zinc transporter-8 [ZnT8]) marks a point of no return from which 70% of children progress to diabetes over the next 10 years.12 Prospective birth cohorts9, 10, 13, 14, 15 have helped to identify potential triggers of islet autoimmunity and the natural history of progression to diabetes. Candidate triggers include infections, diet, and toxins that affect children in utero, perinatally, or during early childhood. These triggers need to be recorded prospectively in studies rather than recalled retrospectively at the time of diabetes diagnosis, several years later.

In paper one of this Series on development of type 1 diabetes, Pociot and Lernmark16 summarise factors for genetic susceptibility and resistance to type 1 diabetes. In this paper, we discuss candidate triggers of islet autoimmunity and factors thought to promote progression from autoimmunity to overt type 1 diabetes (figure 1). These factors seem to have their effect mainly in the genetically predisposed individuals. We also review data for candidate environmental factors that have not yet been confirmed to predict islet autoimmunity or type 1 diabetes or might have weak or confounding effect.

Section snippets

Infections

Early ecological reports,17 seroepidemiological studies,18 and case reports19 have drawn attention to viral infections as a potential cause of type 1 diabetes. Bacterial infections are rarely discussed, although bacteria as a cause of pancreatic lesions cannot be excluded. Several viruses have been implicated, with enteroviruses having the strongest evidence from studies in animal models20 and in human beings.21 These viruses have a tropism to human pancreatic islets in vivo and in vitro,19, 22

Intestinal microbiota

Some of the candidate environmental factors for type 1 diabetes (eg, caesarean delivery, early childhood diet, and use of antibiotics) are intertwined with the development and function of the human microbiome. Gut microbes influence lipid and glucose metabolism, as well as immunity and systemic inflammation outside of the intestine.39, 40, 41 Commensal microbiota might modulate the risk of type 1 diabetes,39, 42, 43, 44, 45, 46, 47, 48 but studies so far have been underpowered and focused on

Vaccines

There has been speculation that vaccines might trigger autoimmunity, but no association has been detected with islet autoimmunity49, 50 or type 1 diabetes.51, 52 A recent meta-analysis of 23 studies investigating 16 vaccinations53 concluded that childhood vaccines do not increase the risk of type 1 diabetes. The BCG vaccine has attracted some interest as a potential immune-modulator that could theoretically reduce the incidence of autoimmunity. Clinical data have shown no association between

Hygiene hypothesis

The hygiene hypothesis posits that incidence of autoimmune diseases might be rising because of a decreasing frequency of childhood infections due to improved hygiene.60, 61, 62 However, a UK population-based study showed that infections in early life, routinely recorded by family doctors, were not associated with subsequent childhood type 1 diabetes.63 On the other hand, prospective studies have reported a significant increase in the risk of islet autoimmunity with more frequent respiratory

Breastfeeding

Although some retrospective studies showed a small reduction in the risk of type 1 diabetes with breastfeeding, all but one, ABIS in Sweden,68 of the prospective birth cohort studies failed to find a protective effect.13, 14, 69, 70 Nevertheless, children who were still breastfed at the time of introduction to cereals had a reduced risk of islet autoimmunity,13 and type 1 diabetes.71 These findings suggest that breastfeeding might play a protective role in the relationship between dietary

Toxins and chemical compounds

Toxins in foods or water might activate autoimmune mechanisms in genetically susceptible individuals, and exposure to toxins might result in pancreatic islet cell death. The list of elements, man-made chemicals, and naturally occurring mycotoxins associated with type 1 diabetes is long and the evidence too preliminary to review here. Some circumstantial and ecological95 evidence suggests a connection between type 1 diabetes and water containing nitrates, nitrites, or nitrosamines, although

Birthweight and infant growth

Higher birthweight102, 103 and rapid weight gain during age 12–18 months104, 105 have been linked to type 1 diabetes. The magnitude of effect is modest and the associations have been noted in Scandinavian countries, but not in the USA or Germany.106, 107 The accelerator hypothesis proposes that excess weight gain leads to insulin resistance in early childhood and could initiate islet autoimmunity, eventually leading to type 1 diabetes.108 Although there is little evidence for the hypothesis,109

β-cell stress

Although the accelerator hypothesis mainly relates to rapid growth, the β-cell stress hypothesis proposes that factors causing increased insulin demand, such as rapid growth, overweight, puberty, low physical activity, trauma, infections, and glucose overload,110 might play an important role in development of type 1 diabetes.111 Serious life events (eg, divorce or death in the family) as shown in the ABIS study, might increase the risk of islet autoimmunity112, 113 and type 1 diabetes.15

Post-translational modification and neoautoantigens

Physiological states related to oversecretion of insulin might promote generation of neoautoantigens via post-translational modification of islet proteins (eg, proinsulin, chromogranin A, islet amyloid polypeptide [IAPP], and GAD; figure 2). Although post-translational modification plays a role in other autoimmune diseases, such as coeliac disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, or berylliosis,117 it has only recently become the subject of systematic

Heterogeneity of type 1 diabetes

The patterns of insulitis (ie, infiltration of the islets by CD8, CD4, and CD20 lymphocytes) in people with type 1 diabetes seem to differ by age at diagnosis. Insulitis shows high proportion of CD20 B cells in patients diagnosed before the age of 7 years, mixed pattern at age 7–13 years, and low CD20 content after age 13 years.127, 128 Importantly, patients diagnosed when older than 13 years retain about 40% of residual insulin-containing islets at diagnosis, consistent with the observed

Discussion

There is no shortage of hypotheses to explain the rise in the incidence of type 1 diabetes in most of the world. The accelerator and β-cell stress hypotheses propose that several unspecific environmental factors, for example, overweight, fast growth, infections, dietary deficiencies or psychological stress, alone or in combination, might make pancreatic β cells exhausted and eventually fail due to a secondary autoimmune destruction. For a long time, these models lacked a convincing biological

Search strategy and selection criteria

We identified papers through searches of PubMed with search terms “type 1 diabetes”, “autoimmunity”, “environmental”, “trigger”, and “promoter” and also from references from relevant articles. We did not include abstracts and reports from meetings. We included only articles published in English between 1960 and Jan 31, 2016.

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