Characterization of Insulin Autoantibodies in Relatives of Patients With Type I Diabetes

Abstract

We studied in detail the anti-insulin autoantibodies in 29 nondiabetic relatives of patients with type I diabetes. The affinity of the autoantibodies for [125I]human insulin was high (1.34 x 10(9)-20.71 x 10(9) L/mol), and the capacity was low (0.84 x 10(-12)-37.80 x 10(-12) M). The product of affinity x capacity of each relative's antibodies directly correlated (r = 0.99) with the level of antibodies determined in our standard radioassay. The autoantibodies from each of the subjects studied had the same rank order of affinities for insulin from different species. Guinea pig, fish insulin, and insulin containing Trp rather than Leu in position 13 of the A-chain inhibited minimally the human insulin binding. Human proinsulin, insulin containing Gln rather than Glu in position 17 of the A-chain, and desoctapeptide insulin (des B23-30) all inhibited binding effectively. Insulin autoantibodies in relatives of patients with type I diabetes share common epitope(s), which suggests a common pathogenic mechanism for production of such antibodies. The epitopes from this initial analysis appear to include amino acids B1-B3 and A8-A13. The region recognized can be distinguished from the insulin receptor binding domain.

Murine High Specificity/Sensitivity Competitive Europium Insulin Autoantibody Assay

“…Thus it is particularly interesting that the current insulin autoantibody assay (utilizing human insulin) does not detect anti-insulin autoantibodies of humans. We believe this relates to extreme specificity of the human insulin autoantibodies recognizing an epitope 17,20 that is likely to be hidden when insulin is plate bound.…”

Peptide and Major Histocompatibility Complex–Specific Breaking of Humoral Tolerance to Native Insulin With the B9-23 Peptide in Diabetes-Prone and Normal Mice

“…Insulin is an important target of the autoimmunity of type 1 diabetes in humans and NOD mice (17)(18)(19)(20)(21). IAAs are detected before the clinical onset of diabetes (18,22).…”

“…IAAs are detected before the clinical onset of diabetes (18,22). Early expression of anti-insulin autoantibodies is associated with early development of diabetes (8).…”

Early and Quantal (by Litter) Expression of Insulin Autoantibodies in the Nonobese Diabetic Mice Predict Early Diabetes Onset

“…In particular, IAA are an important predictor in the diagnosis of T1D (3). IAA are frequently found and are among the first detectable autoantibodies in young children developing the disease (12)(13)(14)(15)(16). They precede T1D with reported appearance between 8 and 20 wk of age in the NOD mouse and they correlate with diabetes incidence (3).…”