Developments in the prediction of type 1 diabetes mellitus, with special reference to insulin autoantibodies

Abstract

The prodromal phase of type 1 diabetes is characterised by the appearance of multiple islet-cell related autoantibodies (Aab). The major target antigens are islet-cell antigen, glutamic acid decarboxylase (GAD), protein-tyrosine phosphatase-2 (IA-2) and insulin. Insulin autoantibodies (IAA), in contrast to the other autoimmune markers, are the only beta-cell specific antibodies. There is general consensus that the presence of multiple Aab (> or = 3) is associated with a high risk of developing diabetes, where the presence of a single islet-cell-related Aab has usually a low predictive value. The most commonly used assay format for the detection of Aab to GAD, IA-2 and insulin is the fluid-phase radiobinding assay. The RBA does not identify or measure Aab, but merely detects its presence. However, on the basis of molecular studies, disease-specific constructs of GAD and IA-2 have been employed leading to somewhat improved sensitivity and specificity of the RBA. Serological studies have shown epitope restriction of IAA that can differentiate diabetes-related from unrelated IAA, but current assays do not distinguish between disease-predictive and non-predictive IAA or between IAA and insulin antibodies (IA). More recently, phage display technology has been successful in identifying disease-specific anti-idiotopes of insulin. In addition, phage display has facilitated the in vitro production of antibodies with high affinity. Identification of disease-specific anti-idiotopes of insulin should enable the production of a high affinity reagent against the same anti-idiotope. Such a development would form the basis of a disease-specific radioimmunoassay able to identify and measure particular idiotypes, rather than merely detect and titrate IAA.

Islet autoantibody development during follow-up of high-risk children from the general Norwegian population from three months of age: Design and early results from the MIDIA study

“…Half of these (7/14) seroconverted before they were 9 months old, including two before 6 months of age. IAA and anti-GAD were the first islet autoantibodies to appear, with anti-IA2 appearing closer to the onset of type 1 diabetes, consistent with previous studies [13,33]. In the same group of children, presence of type 1 diabetes in a first-degree relative was associated with significantly higher risk of islet autoimmunity, confirming other studies [34,35].…”

Celiac Disease—Sandwiched between Innate and Adaptive Immunity

“…Moreover, the anti-tTG antibodies do not seem to contribute to the formation of the intestinal lesions in CD because disease symptoms disappear rapidly after the introduction of a gluten-free diet and antibody titers drop much slower. Similarly, in type I diabetes autoantibodies against islet cells, glutamic acid decarboxylase, protein-tyrosine phosphatase-2, and insulin can be found, which might reflect the ongoing autoimmune process, but most likely do not participate in the tissue damage [52].…”

Identification of a Molecular Signature in Human Type 1 Diabetes Mellitus Using Serum and Functional Genomics

“…Clinical onset is often preceded by the presence of islet cell autoantibodies that are useful for predicting T1DM (1)(2)(3). Risk estimates vary, however; a titer for a single autoantibody among first-degree relatives imparts little risk, whereas high titers for two or three Abs are predictive (Ͼ80%) of disease within 5 years (4,5). T1DM patients have an estimated 80 -90% loss in ␤ cell mass at diagnosis, although functioning mass still remains (6).…”