Pancreatic Islet Autoantibodies as Predictors of Type 1 Diabetes in the Diabetes Prevention Trial–Type 1

Joslin Diabetes Center, Boston, Massachusetts, USA.
Diabetes care (Impact Factor: 8.42). 09/2009; 32(12):2269-74. DOI: 10.2337/dc09-0934
Source: PubMed


There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes.
Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial-Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA(+)). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA(+)).
In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes.
The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Download full-text


Available from: David D Cuthbertson
  • Source
    • "To date, insulitis has been demonstrated in two of three non-diabetic donors with multiple autoantibodies but not in any of the 18 donors with a single autoantibody. Although such donors likely did not have a relative with T1D and rarely were found to carry high-risk HLA types for T1D, these findings are in agreement with the analysis of tissue blocks from pancreata that were processed for islet isolation in Europe [49] and with the well-established low risk of T1D demonstrated by prospective follow-up of patients’ relatives with a single autoantibody [50]. However, a number of studies are discovering evidence for abnormalities affecting the pancreas of donors with autoantibodies, perhaps pointing at some initial stages in the disease pathogenesis that may or may not necessarily progress to overt disease but could be important co-factors in their own right or if more sustained autoimmunity was triggered. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology.
    Full-text · Article · Oct 2014 · Current Diabetes Reports
  • Source
    • "The appearance of diabetes associated autoantibodies in the serum is the first detectable sign of emerging β-cell autoimmunity with over 90% of T1D patients testing positive for at least one at the time of diagnosis. Notable T1D auto-antigens identified include insulin, GAD65 (glutamic acid decarboxylase, 65 kDa isoform), IA2 (insulin auto-antigen 2), and zinc transporter 8 (ZNT8) (Sabbah et al., 1999; Orban et al., 2009). Several reports suggest that insulin is a primary auto-antigen for disease initiation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There is increasing evidence that dysregulated immune responses play key roles in the pathogenesis and complications of type 1 but also type 2 diabetes. Indeed, chronic inflammation and autoimmunity, which are salient features of type 1 diabetes, are now believed to actively contribute to the pathogenesis of type 2 diabetes. The accumulation of activated innate and adaptive immune cells in various metabolic tissues results in the release of inflammatory mediators, which promote insulin resistance and β-cell damage. Moreover, these dysregulated immune responses can also mutually influence the prevalence of both type 1 and 2 diabetes. In this review article, we discuss the central role of immune responses in the patho-physiology and complications of type 1 and 2 diabetes, and provide evidence that regulation of these responses, particularly through the action of regulatory T cells, may be a possible therapeutic avenue for the treatment of these disease and their respective complications.
    Full-text · Article · Jun 2013 · Frontiers in Endocrinology
  • Source
    • "Although it is established that this autoimmune disease stems from a combination of genetic predisposition and environmental factors, the latter remain elusive [1]. During the period preceding T1D clinical onset, autoantibodies (aAbs) directed to islets antigens such as insulin, glutamic acid decarboxylase (GAD65), insulinoma associated protein-2 and zinc transporter 8 (Znt8) may be detectable for months up to years before disease onset [2], and progressively wane after diagnosis [3]. Wenzlau et al. reported that 60–80% of recent-onset T1D harbor antibodies against Znt8 C terminal domain [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our group has recently demonstrated that Mycobacterium avium subspecies paratuberculosis (MAP) infection significantly associates with T1D in Sardinian adult patients. Due to the potential role played by MAP in T1D pathogenesis, it is relevant to better characterize the prevalence of anti-MAP antibodies (Abs) in the Sardinian population, studying newly diagnosed T1D children. Therefore, we investigated the seroreactivity against epitopes derived from the ZnT8 autoantigen involved in children at T1D onset and their homologous sequences of the MAP3865c protein. Moreover, sera from all individuals were tested for the presence of Abs against: the corresponding ZnT8 C-terminal region, the MAP specific protein MptD, the T1D autoantigen GAD65 and the T1D unrelated Acetylcholine Receptor. The novel MAP3865c281-287 epitope emerges here as the major C-terminal epitope recognized. Intriguingly ZnT8186-194 immunodominant peptide was cross-reactive with the homologous sequences MAP3865c133-141, strengthening the hypothesis that MAP could be an environmental trigger of T1D through a molecular mimicry mechanism. All eight epitopes were recognized by circulating Abs in T1D children in comparison to healthy controls, suggesting that these Abs could be biomarkers of T1D. It would be relevant to investigate larger cohorts of children, followed over time, to elucidate whether Ab titers against these MAP/Znt8 epitopes wane after diagnosis.
    Full-text · Article · May 2013 · PLoS ONE
Show more