Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Diabetes Prevention Trial-Type 1

Tihamer Orban, Jay M Sosenko, David Cuthbertson, Jeffrey P Krischer, Jay S Skyler, Richard Jackson, Liping Yu, Jerry P Palmer, Desmond Schatz, George Eisenbarth, Diabetes Prevention Trial-Type 1 Study Group, Tihamer Orban, Jay M Sosenko, David Cuthbertson, Jeffrey P Krischer, Jay S Skyler, Richard Jackson, Liping Yu, Jerry P Palmer, Desmond Schatz, George Eisenbarth, Diabetes Prevention Trial-Type 1 Study Group

Abstract

Objective: There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes.

Research design and methods: Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial-Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA(+)). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA(+)).

Results: In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes.

Conclusions: The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Figures

Figure 1
Figure 1
Curves indicate the occurrence of type 1 diabetes (T1D) over follow-up according to the number of autoantibodies present at the initial screening in the Questionnaire cohort (A), in the Trials cohort (B), and in the cohorts combined (C). In all three panels, there were significant trends among the groups of an increasing occurrence of type 1 diabetes with increasing autoantibody number. The numbers (1–4) indicate the number of autoantibodies. (The fraction in parentheses indicates the number who developed type 1 diabetes among the number in the group at baseline.)
Figure 2
Figure 2
Curves indicate the occurrence of type 1 diabetes (T1D) in the Questionnaire cohort over follow-up for the presence of one autoantibody and for the additional presence of a second autoantibody at the initial screening. Thus, in each panel the groups that included a specific second positive autoantibody were compared with the group that had one positive autoantibody from any of the others. The panels show that when ICA (A), GAD65 (B), or ICA512 (C) each was present as a second autoantibody, there were significant and similar increases in the occurrence of type 1 diabetes; however, there was no increase when mIAA was present as a second autoantibody (D). The number shown for each curve (1, 2) indicates the number of autoantibodies. Proportions of those who developed type 1 diabetes are shown for each curve. (The fraction in parentheses indicates the number who developed type 1 diabetes among the number in the group at baseline.)

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