Diabetologia

, Volume 60, Issue 7, pp 1284–1293

Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

  • Petra M. Pöllänen
  • Johanna Lempainen
  • Antti-Pekka Laine
  • Jorma Toppari
  • Riitta Veijola
  • Paula Vähäsalo
  • Jorma Ilonen
  • Heli Siljander
  • Mikael Knip
Article

DOI: 10.1007/s00125-017-4258-7

Cite this article as:
Pöllänen, P.M., Lempainen, J., Laine, AP. et al. Diabetologia (2017) 60: 1284. doi:10.1007/s00125-017-4258-7

Abstract

Aims/hypothesis

In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility.

Methods

We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9–21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes.

Results

Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (>7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion.

Conclusions/interpretation

At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.

Keywords

Children Diabetes-associated autoantibodies GAD antibodies HLA IA-2 antibodies Insulin autoantibodies Islet cell antibodies Prediction Prevention Type 1 diabetes 

Abbreviations

DIPP

Type 1 Diabetes Prediction and Prevention

FUT2

1,2-α-Fucosyltransferase

GADA

GAD autoantibodies

IA-2

Islet antigen 2

IA-2A

IA-2 autoantibodies

IAA

Insulin autoantibodies

ICA

Islet cell antibodies

JDFU

JDF units

RU

Relative units

Supplementary material

125_2017_4258_MOESM1_ESM.pdf (6 mb)
ESM(PDF 6177 kb)

Funding information

Funder NameGrant NumberFunding Note
Suomen Akatemia
  • 250114
Sigrid Juséliuksen Säätiö
    Diabetes Research Foundation Finland
      Fifth Framework Programme
      • BMH4-CT98-3314
      Novo Nordisk Foundation
        Juvenile Diabetes Research Foundation International
        • 4-1998-274, 4-1999-731, 4-2001-435

        Copyright information

        © Springer-Verlag Berlin Heidelberg 2017

        Authors and Affiliations

        • Petra M. Pöllänen
          • 1
          • 2
        • Johanna Lempainen
          • 3
        • Antti-Pekka Laine
          • 3
        • Jorma Toppari
          • 4
        • Riitta Veijola
          • 5
        • Paula Vähäsalo
          • 5
        • Jorma Ilonen
          • 3
        • Heli Siljander
          • 1
          • 2
        • Mikael Knip
          • 1
          • 2
          • 6
          • 7
        1. 1.Children’s HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
        2. 2.Research Programs Unit, Diabetes and ObesityUniversity of HelsinkiHelsinkiFinland
        3. 3.Immunogenetics LaboratoryUniversity of Turku and Turku University HospitalTurkuFinland
        4. 4.Department of PediatricsUniversity of Turku and Turku University HospitalTurkuFinland
        5. 5.Department of Pediatrics, PEDEGO Research Group, Medical Research CenterOulu University Hospital and University of OuluOuluFinland
        6. 6.Tampere Center for Child Health ResearchTampere University HospitalTampereFinland
        7. 7.Folkhälsan Research CenterHelsinkiFinland

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