The TrialNet Natural History Study of the Development of Type 1 Diabetes: objectives, design, and initial results

Division of Endocrinology and Metabolism, University of Western Ontario, London, ON, Canada.
Pediatric Diabetes (Impact Factor: 2.57). 10/2008; 10(2):97-104. DOI: 10.1111/j.1399-5448.2008.00464.x
Source: PubMed


TrialNet's goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials.
The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset.
Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), > or =25% (n = 36), and > or =50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, > or =25%; 3 or more, > or =50%) and/or an abnormal OGTT (> or =50%).
The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers.

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    • "Subjects with at least two positive tests for any one of the five islet-specific autoAbs (GADA, ICA512A, ICA, mIAA, and ZnT8) were defined as autoAb positive (autoAbPOS); subjects with negative or unconfirmed results for all autoAb tests (i.e., one positive test never confirmed in subsequent analyses) were defined as autoAb negative (autoAbNEG). AutoAbPOS subjects have a higher risk of developing T1D than do autoAbNEG subjects (7). The individuals enrolled in the TN01 Trial and included in our ancillary study were classified further as relatives at low risk (i.e., subjects positive for one autoAb and with a normal oral glucose tolerance test, n = 15), who have a 2.5% 5-year risk of developing diabetes, and relatives at high risk (i.e., subjects positive for ≥2 autoAb or a history of at least one abnormal oral glucose tolerance test, n = 10), who have a 32% 5-year risk of diabetes (9). "
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    ABSTRACT: Human type 1 diabetes (T1D) is an autoimmune disease associated with MHC polymorphisms, β-cell autoantibodies and autoreactive T-cells. However, there is increasing evidence that innate cells may also play critical roles in T1D. We aimed at monitoring peripheral immune cells in early stages of T1D (i.e., in healthy autoantibody positive subjects) and in more advanced phases of the disease (i.e., at disease onset and years after diagnosis). We found a mild, but significant and reproducible, peripheral neutropenia that both precedes and accompanies T1D onset. This reduction was not due to peripheral neutrophil cell-death, impaired differentiation or the presence of anti-neutrophil antibodies. Neutrophils were observed by electron microscopy and immunohistochemical analysis in the exocrine pancreas of multi-organ donors with T1D (both at onset and at later stages of the disease) and not in that of donors with T2D or non-diabetic donors. These pancreas-infiltrating neutrophils mainly localized at the level of very small blood vessels. Our findings suggest the existence of a hitherto unrecognized clinical phenotype that might reflect yet unexplored pathogenic pathways underlying T1D.
    Diabetes 01/2013; 62(6). DOI:10.2337/db12-1345 · 8.10 Impact Factor
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    • "If diabetes can be predicted earlier, it may be possible to prevent disease progression while an adequate islet mass remains to maintain euglycemia throughout the patient's lifetime. Several data revealed that, individuals must lose 50–90% of their islet mass before onset of hyperglycemia.[20] At hand, the most highly predictive model for identifying people—not yet manifesting diabetes—depends on recognition of abnormal insulin secretion, and glucose intolerance. "
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    ABSTRACT: An increased incidence of Type 1 diabetes mellitus (T1DM) is expected worldwide. Eventually, T1DM is fatal unless treated with insulin. The expansion of interventions to prevent diabetes and the use of alternative treatments to insulin is a dream to be fulfilled. The pathophysiology in T1DM is basically a destruction of beta cells in the pancreas, regardless of which risk factors or causative entities have been present. Individual risk factors can have separate patho-physiological processes to, in turn, cause this beta cell destruction. Currently, autoimmunity is considered the major factor in the pathophysiology of T1DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules. Many components of the immune system have been implicated in autoimmunity leading to β-cell destruction, including cytotoxic and helper T-cells, B-cells, macrophages, and dendritic cells. The inflammatory process in early diabetes is thought to be initiated and propagated by the effect of Th1-secreted cytokines (e.g. g interferon) and suppressed by Th2-secreted antiinflammatory cytokines (interleukins). Structure and function of β-cell may be modulated by using Th1/Th2-secreted cytokines. Several experimental and clinical trials of applying GAD65, Hsp60, peptide-MHC, pepetide-277 immunization, anti-CD3 infusion, and interleukins to modulate immune response in T1DM were done. Applying such trials in patients with prediabetes, will most likely be the future key in preventing Type 1 autoimmune diabetes.
    11/2012; 16(6):904-9. DOI:10.4103/2230-8210.102989
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    • "Blood samples were drawn from islet autoantibody-positive and -negative subjects enrolled in the Type 1 Diabetes TrialNet Natural History (12) and DAISY (13) studies during their routine study visits. Both are prospective studies conducted in first-degree relatives of patients with T1D with the goal of better understanding the natural history of the disease (12,13). "
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    ABSTRACT: We tested the hypothesis that altered Toll-like receptor (TLR) signaling may be involved in early stages of type 1 diabetes (T1D). To do so, we analyzed TLR-induced interleukin (IL)-1β and IL-6 responses in freshly isolated peripheral blood mononuclear cells (PBMNCs) from seropositive compared with seronegative subjects. Similar frequencies of myeloid dendritic cells (mDCs), plasmacytoid DCs (pDCs), and monocytes were observed in seropositive and seronegative subjects. Subjects with autoantibodies had increased proportions of monocytes expressing IL-1β ex vivo. Activating PBMNCs with TLR3, TLR4, or TLR7/8 agonists in vitro led to increased percentages of IL-1β-expressing monocytes and mDCs from seropositive versus seronegative subjects. TLR ligation also resulted in a diminished IL-6 response in seropositive individuals as lower frequencies of IL-6-expressing monocytes and mDCs were induced. The dysregulated TLR-induced IL-1β and IL-6 pathways were more readily detectable in children aged <11 years and from 11 to <21 years, respectively, and did not involve altered HbA(1c) or the presence of one or more autoantibodies. Finally, subjects with autoantibodies had lower amounts of serum chemokine (C-X-C motif) ligand 10 compared with autoantibody-negative subjects. Our data may imply that alterations in innate immune pathways are detectable in genetically susceptible individuals and could be linked with the early course of T1D.
    Diabetes 06/2012; 61(10):2525-33. DOI:10.2337/db12-0099 · 8.10 Impact Factor
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