Doubly Reactive INS‐IGF2 Autoantibodies in Children with Newly Diagnosed Autoimmune (type 1) Diabetes

The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n=676), 0-18years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n=363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P<0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P<0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR=1.509; 95th CI 1.011, 2.252; P=0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.