Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk.

Department of Pediatrics, Turku University Hospital, Kiinamyllynkatu 4-8, PO Box 52, 20521 Turku, Finland.
Diabetologia (Impact Factor: 6.88). 03/2012; 55(7):1926-36. DOI: 10.1007/s00125-012-2523-3
Source: PubMed

ABSTRACT The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to clinical diabetes.
Children were recruited to the Type 1 Diabetes Prediction and Prevention Project, an ongoing study based on HLA-conferred genetic risk. Autoantibodies against islet cells, insulin, GAD65 and islet antigen 2 were analysed at 3-12 month intervals, starting from birth.
During the follow-up, 1,320 children (18.4% of the cohort of 7,165 children) were autoantibody positive in at least one sample. Altogether, 184 autoantibody-positive children progressed to type 1 diabetes. Seroconversion occurred at an early age in the progressors (median 1.5 years), among whom 118 (64%) and 150 (82%) seroconverted to autoantibody positivity before the age of 2 and 3 years, respectively. The incidence of seroconversion peaked at 1 year of age. Compared with other autoantibody-positive children, the median autoantibody levels were already markedly higher 3 to 6 months after the seroconversion in children who later progressed to diabetes.
Early initiation of autoimmunity and rapid increases in autoantibody titres strongly predict progression to overt diabetes before puberty, emphasising the importance of early life events in the development of type 1 diabetes.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of the autoimmune disease, type 1 diabetes (T1D), has increased dramatically over the last half century in many developed countries and is particularly high in Finland and other Nordic countries. Along with genetic predisposition, environmental factors are thought to play a critical role in this increase. As with other autoimmune diseases, the gut microbiome is thought to play a potential role in controlling progression to T1D in children with high genetic risk, but we know little about how the gut microbiome develops in children with high genetic risk for T1D. In this study, the early development of the gut microbiomes of 76 children at high genetic risk for T1D was determined using high-throughput 16S rRNA gene sequencing. Stool samples from children born in the same hospital in Turku, Finland were collected at monthly intervals beginning at 4-6 months after birth until 2.2 years of age. Of those 76 children, 29 seroconverted to T1D-related autoimmunity (cases) including 22 who later developed T1D, the remaining 47 subjects remained healthy (controls). While several significant compositional differences in low abundant species prior to seroconversion were found, one highly abundant group composed of two closely related species, Bacteroides dorei and Bacteroides vulgatus, was significantly higher in cases compared to controls prior to seroconversion. Metagenomic sequencing of samples high in the abundance of the B. dorei/vulgatus group before seroconversion, as well as longer 16S rRNA sequencing identified this group as Bacteroides dorei. The abundance of B. dorei peaked at 7.6 months in cases, over 8 months prior to the appearance of the first islet autoantibody, suggesting that early changes in the microbiome may be useful for predicting T1D autoimmunity in genetically susceptible infants. The cause of increased B. dorei abundance in cases is not known but its timing appears to coincide with the introduction of solid food.
  • Diabetes Technology &amp Therapeutics 06/2013; 15(S2):S2-8-S2-12. DOI:10.1089/dia.2013.0114 · 2.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AIMS: Non-diabetic children with multiple islet autoantibodies were recruited to a secondary prevention trial. The objective was to determine the predictive value of baseline (1) HbA1c and metabolic variables derived from intravenous (IvGTT) and oral glucose tolerance tests (OGTT), (2) insulin resistance and (3) number, type and levels of islet autoantibodies, for progression to type 1 diabetes. METHODS: Children [n = 50, median 5.1 (4-17.9) years] with autoantibodies to glutamate decarboxylase (GAD65A) and at least one of insulinoma-associated protein 2 (IA-2A), insulin or ZnT8 transporter (ZnT8RA, ZnT8WA, ZnT8QA) were screened with IvGTT and OGTT and followed for a minimum of 2 years. RESULTS: Baseline first phase insulin response (sum of serum-insulin at 1 and 3 min during IvGTT; FPIR) ≤3 μU/mL [HR 4.42 (CI 1.40-14.0) p = 0.011] and maximal plasma glucose ≥11.1 mmol/L measured at 30, 60 and/or 90 min during OGTT [HR 6.13 (CI 1.79-21.0) p = 0.0039] were predictors for progression to diabetes. The combination of FPIR from IvGTT and maximal plasma glucose during OGTT predicted diabetes in 10/12 children [HR 9.17 (CI 2.0-42.0) p = 0.0043]. High-level IA-2A, but not number of autoantibodies, correlated to dysglycemia during OGTT (p = 0.008) and to progression to type 1 diabetes [HR 4.98 (CI 1.09-22.0) p = 0.039]. CONCLUSIONS: Baseline FPIR, maximal plasma glucose ≥11.1 at 30, 60 or 90 min during OGTT and high-level IA-2A need to be taken into account when randomizing islet autoantibody positive non-diabetic children to secondary prevention.
    Acta Diabetologica 11/2014; DOI:10.1007/s00592-014-0680-1 · 3.68 Impact Factor

Full-text (2 Sources)

Available from
Jun 3, 2014