Preventing the Predictable. Type 1 diabetes in children: Risk factors and impact of participation in prospective follow-up

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Aim: The aim of this thesis was to identify risk factors for type 1 diabetes in children, evaluate the effects of participation in prospective follow-up and the safety of immune tolerance treatment with GAD-Alum in children with islet autoimmunity.Methods: Subjects from the Swedish DiPiS cohort were studied regarding risk factors, cord blood islet autoantibodies and the effects of early severe life events. We further evaluated morbidity at diagnosis and glycemic control during the first two years of diabetes, comparing the DiPiS follow-up cohort to non-enrolled children. The TEDDY cohort was used to analyze prevalence and effect of analgesic antipyretics before 2.5 years of age on islet autoimmunity at 6 years of age and patterns of analgesic antipyretic use at the study sites. The safety and efficacy of immune tolerance treatment with GAD-Alum were analyzed in a five-year follow-up of at-risk children. Results: IA-2A autoantibodies in cord blood predicted an increased hazard for type 1 diabetes (HR 6.88; 95% CI 1.46, 32.4; p=0.003.). Parental severe life events after pregnancy predicted type 1 diabetes risk for both the total cohort (HR 1.66; 955 CI 1.02, 2.70; p=0.043) and the DQ2/8 cohort (HR 2.21; 95%CI 1.08, 4.51; p=0.03). The use of analgesic antipyretics did not predict islet autoimmunity at age six years (HR 1.02; 95% CI 0.99, 1.09; p=0.27) but weakly predicted islet autoimmunity at age 3 years. The use of analgesic antipyretics differed between study sites, with a higher prevalence in the US (95.7%) and Sweden (94.8%) than in Finland (78.1%) and Germany (80.2%). Use in the absence of fever was common, especially in the US in comparison to the other sites. Subjects enrolled in DiPiS follow-up were diagnosed with diabetes with less morbidity (p=0.014) and lower prevalence of ketoacidosis (p=0.005). Among subjects enrolled in DiPiS follow-up, HbA1c at diagnosis was lower (9 mmol/mol; p=0.006) and glycemic control was better after diagnosis (12 months, 4 mmol/mol; p=0.009, 24 months, 9 mmol/mol; p <0.001). Immune tolerance treatment with GAD-Alum is safe but does not affect the time to diabetes diagnosis in this cohort.Conclusion: Early severe life events and IA-2A cord blood antibodies but not early use of analgesic antipyretics may increase type 1 diabetes risk. Severe life events and cord blood autoantibodies are both rare events, and care must be taken in interpreting these results. Participants in prospective follow-up are diagnosed at an early stage, with low morbidity and improved glycemic control, which may be an important factor for recruitment and ethical approval. Immune tolerance with GAD-Alum is safe, but larger, stratified studies are needed to ascertain the possible effects.

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Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
  • Pediatrics
Original languageSwedish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2017 Nov 24
Place of PublicationLund
Publisher
  • Lund University: Faculty of Medicine
Print ISBNs978-91-7619-547-5
Publication statusPublished - 2017
Publication categoryResearch

Bibliographic note

Defence details Date: 2017-11-24 Time: 13:00 Place: Kvinnoklinikens aula, SUS Malmö External reviewer(s) Name: Stene, Larc C Title: PhD Affiliation:Oslo diabetes research center, Oslo, Norway --- ISSN: 1652-8220 Lund University, Faculty of Medicine Doctoral Dissertation Series 2017:165

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