Type 1 diabetes-early life origins and changing epidemiology

Abstract

Type 1 diabetes is a chronic, immune-mediated disease characterised by the destruction of insulin-producing cells. Standardised registry data show that type 1 diabetes incidence has increased 3-4% over the past three decades, supporting the role of environmental factors. Although several factors have been associated with type 1 diabetes, none of the associations are of a magnitude that could explain the rapid increase in incidence alone. Moreover, evidence of changing prevalence of these exposures over time is insufficient. Multiple factors could simultaneously explain the changing type 1 diabetes incidence, or the magnitude of observed associations could have been underestimated because of exposure measurement error, or the mismodelling of complex exposure-time-response relationships. The identification of environmental factors influencing the risk of type 1 diabetes and increased understanding of the cause at the individual level, regardless of the ability to explain the changing incidence at the population level, is important because of the implications for prevention.

Figure 1:. Time trends in incidence of type 1 diabetes

Published data taken from references listed in the appendix pp 1,5–6. GDR=German Democratic Republic (former Eastern Germany). BW=Baden-Württemberg.

Figure 2:. Increasing type 1 diabetes incidence explained by single risk factor under different hypothetical scenarios

(A) and (C) show prevalence of exposure over time with constant annual increase of 3% or 6% (from a baseline of 5%). (B) and (D) show the expected corresponding incidence trends in type 1 diabetes and annual percentage change caused by an exposure under simulated scenarios, where it confers a constant incidence rate ratio, or relative risk (ie, the incidence rate in the exposed group relative to the unexposed group) between 1∙2 and 5∙0. Baseline type 1 diabetes incidence was arbitrarily set to 10 per 100 000 person-years, and the incidence assumed constant at this rate for unexposed people. More details about the methods and additional results are shown in the appendix pp 1–5. APC=annual percentage change. RR= rate ratio.

Figure 3:. Differentiating factors influencing transitions in the natural history of type 1 diabetes

(A) Natural history of type 1 diabetes can be divided into two major transitions: first, from autoantibody negative to persistently positive (green, usually for multiple islet autoantibodies), and the second from islet autoimmunity to clinical type 1 diabetes. (B) Analysing samples to disentangle factors influencing the first or second transition is complex. We observe snapshots of longitudinal development and made useful simplifications. For assessment of factors modifying the incidence islet autoantibody seroconversion, exposures in the (light grey) period before seroconversion in islet autoimmunity cases (child 1 and 2) are compared with the corresponding period in children who do not seroconvert during the same follow-up time (child 3)—eg, vertical arrow 1. For assessment of factors modifying the rate of progression from islet autoimmunity to clinical type 1 diabetes, exposure must be studied in the (darker grey) period after seroconversion, but before type 1 diabetes. Exposure in children developing type 1 diabetes is compared with the same period for children who do not develop type 1 diabetes during the same follow-up period—eg, vertical arrow 2. This principle applies to cohort studies and nested case-control studies. Any difference in exposure between child 2 and 3 in the (dark grey) period after seroconversion eg, vertical arrow 3—could be influenced by reverse causation if involving biomarkers or other measures of exposure that could conceivably be influenced by autoimmunity. The true time of seroconversion is normally not observed, but occurs in the seroconversion interval, between the last negative and the first positive serial blood sample.