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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Available from: Clinton Thompson
    • "By analyzing a large cohort of pediatric patients affected by T1D, we have demonstrated that the circulating levels of TRAIL are significantly decreased in T1D with respect to control subjects. On the other hand, in autoantibodypositive individuals (AutoAb POS /T1D NEG ), who have a higher risk of developing T1D than do autoantibody-negative individuals[26], circulating TRAIL levels were not significantly different from healthy control subjects. Diabetic ketoacidosis at the diagnosis of T1D is a lifethreatening situation that represents the main cause of morbidity and mortality in pediatric patients with T1D[3]. "
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    ABSTRACT: Experimental evidence in animal models suggests that TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, might play an important role in type 1 diabetes (T1D). We have performed a retrospective study by analyzing the sera of a cohort of pediatric subjects (age ≤18 years; n = 507) consisting of (1) patients diagnosed with T1D (n = 387), (2) healthy individuals (n = 98, considered as controls), and (3) healthy autoantibody-positive subjects (n = 22). Patients with T1D exhibited significantly decreased levels of circulating TRAIL with respect to the control healthy subjects, as well as to the healthy autoantibody-positive subjects. Within the T1D group, no differences in the levels of circulating TRAIL were observed between patients with or without other concomitant autoimmune pathologies. Of note, the levels of TRAIL were significantly lower in the T1D patients analyzed at onset, although reduction in TRAIL levels persisted also in patients analyzed after disease onset (>1 year from diagnosis). In particular, T1D patients who exhibited ketoacidosis at onset showed significantly lower levels of circulating TRAIL with respect to patients without ketoacidosis at onset. Moreover, the levels of TRAIL at diagnosis correlated inversely with the insulin requirement up to 21 months of follow-up. This is the first study demonstrating that the levels of circulating TRAIL are significantly decreased in T1D, with the lowest levels of TRAIL being observed in patients with ketoacidosis at the onset and with the highest insulin requirement.
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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.
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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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