Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies

Background: Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INSAb can improve T1D prediction in children with positive standard islet autoantibodies (AAB). Methods: We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AAB-positive (AAB(+)) children from the general population (median follow-up 8.8 years). Results: oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INSAb was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA(+) children. Risk for diabetes was higher (P = 0.03) among multiple AAB(+) who were also oxPTMINS- Ab(+) compared with those who were oxPTM-INS-Ab(-). Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTMINS- Ab(+) in combination with GADA(+) and IA-2A(+), compared with 84.37% in those with IAA(+), GADA(+), and IA-2A(+) (P = 0.04). Conclusions: Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB(+) children.