CLINICAL TRIAL: TRIALNET SCREENING TO ASSESS RISK OF TYPE 1 DIABETES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes mellitus (T1D) is a disease that results from the destruction of pancreatic beta-cells. It can occur at any age, but its incidence is highest in children and adolescents. Although all people are susceptible, relatives of individuals are at a much greater risk for T1D. It is clear that genetic factors contribute to most cases of T1D. HLA-associated antigens have been found to be strongly predictive of T1D. However, environmental factors also appear to contribute to the disorder. Although identical twins of T1D patients are at very high risk, many never develop the condition. Also, some epidemiologic studies have suggested that other factors such as viral infections may be involved in the pathogenesis of T1D. It is thought that the pathogenesis for most cases of T1D involves the immunologic destruction of pancreatic beta-cells. There is good evidence that cell-mediated immunity contributes to this. In addition, most patients who develop T1D have at least one autoantibody to islet cell antigens. These autoantibodies include ICAs, GAD65, IAA, and IA2 autoantibodies. Relatives of T1D patients who develop these autoantibodies are at greater risk for T1D than relatives negative for autoantibodies and the risk becomes greater when subtle metabolic abnormalities are evident even within the nondiabetic state. There has been recent interest in the possibility that T1D is preventable. The elucidation of the mechanisms of its pathogenesis suggests that manipulations of the immunologic milieu could disrupt the disease process. In addition, prevention trials have become more feasible because it is now possible to identify individuals who are at high risk for T1D. The Diabetes Prevention Trial-Type 1 (DPT-1) study was one of the first large-scale prevention trials of T1D. The aim of this trial was to study whether either low dose parenteral insulin or oral insulin administration would prevent the development of T1D. Relatives of patients with T1D were screened for the presence of autoantibodies associated with T1D. Those with autoantibodies were then staged through HLA and metabolic testing to determine whether subtle abnormalities were present that would increase the risk for T1D. Individuals who met criteria were offered entry in the clinical trial. Those at greater risk were eligible for enrollment in the parenteral insulin study, while those at lower risk were offered enrollment in the oral insulin study. The parenteral insulin trial was recently completed and its findings published in the New England Journal of Medicine. (Diabetes Prevention Trial - Type 1 Diabetes Study Group. Effects of Insulin in Relatives of Patients with Type 1 Diabetes Mellitus. New England Journal of Medicine 2002; 346:1685-91. The oral insulin study continues. Although it was disappointing that there was no evidence of an insulin effect in the parenteral insulin trial, a great deal was learned from this study. Much information was ascertained about the natural history of the development of T1D. Importantly, the findings from DPT-1 confirmed that the incidence of T1D could be accurately predicted on the basis of autoantibody and HLA testing and metabolic staging. Because of the continuing interest in the prevention of T1D, the NIDDK has provided funding to 14 centers to build a consortium (TrialNet) of investigators to develop and perform prevention trials. The rationale was that this group of experts in the field would facilitate the implementation of such studies. In addition to performing studies of individuals at high risk for T1D, TrialNet will also perform studies of individuals with new-onset diabetes. These studies will examine strategies for the prevention of further metabolic deterioration in those patients. The TrialNet screening process for studies of high risk individuals will be modeled after that for DPT-1. The accrual of participants for DPT-1 required a massive program to screen for autoantibody positive relatives of patients with T1D. This necessitated the development of a network of Clinical Centers, Affiliate Sites and Satellite Sites throughout the United States and Canada. Over 100,000 relatives had screening samples collected. Most of these sites will participate in TrialNet screening. The specific prevention studies are currently being developed. However, the screening program will be needed in the interim to identify potential participants for future prevention studies. Individuals who screen positive for autoantibodies will be offered participation in a Natural History Study if a prevention trial is not yet available to them. The screening program described herein represents the first step in the process of implementing the TrialNet prevention studies for T1D.