1255-P: IA-2A Autoantibody Titers Predict Subsequent Divergence between Nonprogressors (NP) and Progressors (P) to Type 1 Diabetes with Similar Degree of Initial Metabolic Abnormality

Even after stratification based on established risk factors, the progression to T1D is variable. Thus, we aimed to examine differences in metabolic patterns of change between NP and P to T1D, and identify non-metabolic factors contributing to the differences. Specifically, we analyzed OGTT and autoantibody (Aab) data from children <18 yrs participating in Diabetes Prevention Trial-Type 1 (DPT-1) or TrialNet Pathway to Prevention (PTP) , with “baseline” DPT-1 Risk Scores (DPTRS) at initial testing in the abnormal range of 6.50 to <7.50. No difference in AUC ratio (AUC C-peptide/AUC glucose) was present between P (n=85) and NP (n=161) in DPT-1 or between P (n=171) and NP (n=332) in PTP at baseline. However, during follow-up we found that by the first 6-month OGTT the AUC ratio had diverged, with lower AUC ratio in P both in DPT-1 (p=0.05) and PTP (p<0.001) , adjusting for baseline age, BMI, DPTRS, and AUC ratio. Moreover, in yearly change from baseline to last OGTT (before diagnosis in P) , AUC ratio decreased in P (p<0.001) and increased in NP (p<0.01) in DPT-1 and PTP. In assessments of factors relating to this divergence we observed that despite their metabolic similarity, at baseline P had higher harmonized IA-2A Aab positivity (70.8 vs. 49.1%, p<0.001) and titers (median 194 vs. 3, p<0.001) in PTP (not harmonized in DPT-1) . Based on this, we compared P with NP for yearly changes in IA-2A from baseline to the last visit, with adjustment for baseline values. P had a greater increase in IA-2A titer over time (p=0.025) . Furthermore, T1D progression was associated with yearly increases in IA-2A titer (HR: 1.006, 95%CI: 1.003, 1.009; p<0.001) .

In conclusion, when NP and P have a similar degree of metabolic abnormality, IA-2A titers are greater in P. Moreover, as AUC ratio declines in P and improves in NP, IA-2A titers increase more in P than in NP. These findings suggest that IA-2A is a sensitive indicator of active β-cell pathology.