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

Abstract

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), 0-18 years 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.

Mining for Candidate Genes Related to Pancreatic Cancer Using Protein-Protein Interactions and a Shortest Path Approach

“…The fusion of a tumor-associated gene and a pancreas-related gene, INS-IGF2, probably participates in PC progression and invasion specifically. Recently, such fusion gene INS-IGF2 is reported to be specifically expressed in pancreatic islets especially in patients with autoimmune diseases under pathological conditions [ 147 , 148 ]. Since immune response is quite significant for tumor surveillance, INS-IGF2 is definitely associated with the unique tumor-associated immune response and may further contribute to the prognosis of pancreatic cancer [ 148 ].…”

From Anti-EBV Immune Responses to the EBV Diseasome via Cross-reactivity

“…Table 4 illustrates that the EBV epitope-derived pentapeptides are widespread among the most disparate human proteins able to cause, when altered, a vast spectrum of diseases, from diabetes and sterility to myocarditis and death, 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 the latter two being possibly associated with the Titin imposing peptide sharing (250 shared pentapeptides).…”

Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas

“…4), although conclusions regarding protein expression can not be made, this indicates that the INS-IGF2 chimeric protein may be expressed. Although the precise function of the INS-IGF2 protein remains unidentified, kanatsuna et al (30,31) recently found INS-IGF2 to be recognized by autoantibodies associated with diabetes mellitus type 1 (DM1). In DM1, pancreatic β-cells are destroyed due to the recognition of pancreatic islets autoantigens, like insulin, by autoreactive T lymphocytes leading to a T-lymphocyte-mediated immune response (32,33).…”

“…The appearance of several autoantibodies towards these pancreatic islets autoantigens is a sign of autoimmunity (32). The authors therefore suggested that INS-IGF2 may enhance the ability of insulin to trigger the development of DM1 (30,31).…”

“…Normal INS-IGF2 expression is restricted to the limbs, eyes, and pancreas (22,30). In the limbs and eyes, INS-IGF2 expression is maternally imprinted.…”