Notice of Availability of Serum, RNA, and Peripheral Blood Mononuclear Cell Samples From Subjects Enrolled In The Type 1 Diabetes TrialNet Natural History Study: For Validation Of New Biomarkers Of Type 1 Diabetes

Notice Number: NOT-DK-08-018

Key Dates
Release Date:  May 5, 2008
Application Deadlines:  Applications accepted any time

Issued by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), (


Type 1 diabetes (T1D) is a disease that results from the autoimmune destruction of pancreatic β-cells. It can occur at any age, but its incidence is highest in children and adolescents. Relatives of individuals with T1D are at 10-20-fold greater risk for development of the disease compared to the general population, but most new cases of T1D occur in persons with no family history of the disease.

Prospective cohort studies in individuals at risk for T1D have established that diagnosis of the disease occurs at a late stage in the progressive decline in β-cell function, when the majority of β-cell function has been lost.  Current measures of autoantibodies, HLA typing, and oral glucose tolerance tests are able to identify persons with up to an 80% five-year risk of developing the disease.  However, new biomarkers are needed to improve early risk characterization and to monitor the autoimmune disease process before the complete destruction of beta cells. 

The Natural History Study is an observational study divided into three phases: Screening (Phase 1), Baseline Risk Assessment (Phase 2), and Follow-up Risk Assessments (Phase 3).  A prospective cohort design is used. First or second-degree relatives of persons with T1D between ages 1 and 45 years are eligible to participate in Phase 1.  Eligibility for Phase 2 and Phase 3 is based on the results of tests from the prior study phases.

Phase 1 involves screening for the presence in serum of the autoantibodies anti-GAD65, anti-ICA512 or anti-Insulin, followed by measurement of islet cell cytoplasmic autoantibodies (ICA test).  Subjects can enter Phase 2 if positive for one or more of the same autoantibodies on two blood samples (i.e., confirmed autoantibody positive). 

Phase 2 (Baseline Risk Assessment) includes an OGTT, measurement of HbA1c, and HLA typing.  Participants with protective HLA alleles are not excluded from this study.  Additional samples are stored from all consenting participants for future immunologic and metabolic assessments that bear upon mechanisms of β-cell destruction, and genetic studies related to the risk of developing T1D.

Phase 2 participants are classified into one of three T1D 5-year risk categories:  < 25%, >25, and >50%.  The risk categories are defined according to the OGTT results and number of confirmed positive autoantibodies.  Individuals who complete Phase 2 may enter Phase 3 (Follow-Up Risk Assessments). 

Exclusion Criteria are:
1.  Previous or current use of insulin or oral hypoglycemic agents,
2.  Currently use of immunosuppressive or immunomodulatory therapy, including systemic steroids.
3.  Already have diabetes (FPG > 126 mg/dL or 2 hour PG > 200 mg/dL)
4.  Have known severe active diseases, and/or diseases which are likely to limit life expectancy or lead
     to the use of immunosuppressive or immunomodulatory  therapy during the course of the study. 
5.  Be deemed unable or unlikely to comply with the protocol.

After 5 years of recruiting and follow-up, over 40,000 subjects have been screened, and over 700 risk of developing type 1 diabetes and are being followed.  TrialNet is currently recruiting 100 autoantibody negative controls.

Key Measurements:

Subjects are seen at six-month intervals for five years or until T1D is diagnosed as defined by the American Diabetes Association (ADA) criteria.  At each visit, procedures include an OGTT and collection of blood for autoantibody testing, measurement of HbA1c.  There are peripheral blood mononuclear cells (PBMC), plasma, serum, RNA, DNA collections for mechanistic studies


NIDDK invites investigators to apply for access to the samples for the purposes of validation of their assays relevant to the T1D disease process, especially risk prediction in the case of this Notice.   Access will be determined based on scientific merit as reviewed by the TrialNet Mechanistic Outcomes/Ancillary Studies Committee, with additional reviewers selected from outside of the TrialNet network based on relevant expertise.   TrialNet investigators will provide help with study design for approved assays.  Samples will be masked for subject personal identification, and sample characteristics (i.e., the investigator will not know whether individual samples are from pre-diabetic or control subjects, etc. until assays are completed).  Exceptions to sample characteristic blinding will be considered upon request, but must be well justified in the application.  Data from the Applicant’s assay will be transmitted to the DCC in a mutually agreed-upon format and frequency.  Once the Applicant’s study is completed, analysis of the data and unblinding will occur, and conclusions, interpretations, and publications will be collaborative involving the assay provider (Applicant), coordinating center biostatisticians, and the members of the TrialNet Mechanistic Outcomes Committee as appropriate. 

Full application instructions can be downloaded here:

For an updated table of currently available samples, please refer to the following public website:


To request additional detail on the sample collection, or any other questions, please contact:

Lisa Spain, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd. Rm. 695
Bethesda, MD 20892-5460
Telephone: (301) 451-9871
FAX: (301) 480-2688

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