This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.OBJECTIVE: The overall objective of this study is to perform baseline and repeat assessments over time of the metabolic and immunologic status of individuals at risk for Type 1 Diabetes (T1D) in order to a) characterize their risk for developing T1D; b) describe the pathogenic evolution of T1D; and c) to increase the understanding of the pathogenetics factors involved in the development of T1D. Specific objectives are:1. To determine the risk for the occurrence of T1D according to oral glucose tolerance tests (OGTT), C-Peptide levels, biochemical autoantibodies (anti-GAD65, anti ICA52 and IAA), islet cell autoantibodies (ICA) markers of cell-mediated immunity, intravenous glucose tolerance tests (IVGTT), and HLA genetic markers that are associated with risk for T1D.2. To examine the accuracy of TrialNet risk assessment procedures for predicting future T1D.3. To determine the prevalence of impaired glucose tolerance and ICA posivity in individuals with at least one positive biochemical autoantibody test.4. To characterize the progression of immunologic abnormalities in the development of the T1D by serially studying biochemical autoantibodies, ICA and markers of cell-mediated immunity.5. To characterize the progression of metabolic decompensation in the development of T1D by serially studying insulin, C-peptide and glucose levels, and to identify immunologic and other factors associated with this decompensation.6. To determine the incidence of severe acute metabolic decompensation as the initial clinical presentation in individuals who have been identified as being at increased risk for T1D.7. To identify individuals who qualify for TrialNet prevention trials to T1D.8. To accrue additional information about immunologic and metabolic factors related to the pathogenesis of T1D by analyzing stored blood samples. The Immune Tolerance Network will function as a core laboratory for TrialNet for the development of specialized immunologic procedures.9. To accrue additional information about genetic markers associated with risk for the development of T1D by analyzing stored blood samples.10. For those who participated in the DPT-1 study, to examine associations of characteristics (e.g. demographics, immunologc, metabolic, etc.) assessed during the DPT-1 study with characteristics and outcomes assessed in TrialNet.RESEARCH PLAN AND METHODS: The study is divided into three phases: Screening, Baseline Risk Assessment and Follow-up Risk Assessment. Each of these phases will require separate informed consent for entry. A prospective cohort design will be usd for the study.Phase 1 involves overall screening and measurements of biochemical autoantibodies (GAD65, ICA512 and mIAA) along with ICA to determine eligibility for the Phase 2 risk assessment. It is possible that individuals who do not qualify for Phase 2 might still be eligible for other TrialNet studies. Therefore, they may be contacted in the future so that they can be informed of these studies. In addition, they will be contacted periodically to learn if they have developed T1D. Individuals under the age of 18 years, who do not qualify for Phase 2, will be invited back for rescreening on an annual basis until they reach their 18th birthday. The baseline risk assessment will include an OGTT, the measurement of HbA1c, testing for autoantibodies, and HLA typing in consent participants. Participants with protective HLA alleles will not be excluded from this study.Upon completion of Phase 2, participants will be classified into one of three risk categories for the occurrence of T1D within five years: = 25%, and =50%. These categories are based on the OGTT results and number of confirmed positive antibodies. Participants will be informed of their risk categories when all test results are available.Individuals who participate in Phase 2 will also be offered the opportunity (through written consent) to enter Phase 3 for follow-up risk assessments. They will be seen at six month intervals for five years or until the end of the study. At each visit, procedures will include an OGTT, collection of blood for autoantibody testing and measurement of HbA1c levels. Although there will not be a formal categorization of risk following each assessment, participants will be informed of their test results upon request.During each phase of the sudy, residual blood samples and DNA samples in Phase 2 from consenting participants will be stored indefinitely at a TrialNet core laboratory and/or an NIDDK repository site for future immunologic and metabolic assessments that bear upon mechanisms of B-cell destruction and to obtain additional information about genetic markers associated with the risk for development of T1D. Subjects may still participate in all phases of the study even if they choose not to give consent for storage.Mechanistic samples will aso be collected at Phase 2 and 3 at designated sites (we are one) participating in the Mechanistic Addendum for Clinical Centers and Major Affiliates for the collection of samples for storage for mechanistic studies.Individuals who qualify for prevention trials based on their risk assessments will be invited to participate in those trials as they become available. Individuals who enter a prevention trial will be followed according to the protocol of that trial. However, pertinent data accrued during the trial (conditional upon treatment status in the trial) such as the development of T1D, may be incorporated into the database for study.The primary study outcome is diabetes mellitus (T1D) as defined by the American Diabetes Association (ADA) criteria. For most subjects, this will be based upon the results of an OGTT in the absence of symptomatic hyperglycemia. Confirmation of a diagnosis of diabetes by a second OGTT test in asymptomatic individuals will be required. Individuals who are hospitalized at diagnosis will be assessed through medical records.
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