Prediction of Type I Diabetes in First-Degree Relatives Using a Combination of Insulin, GAD, and ICA512bdc/IA-2 Autoantibodies

Abstract

Islet cell antibodies (ICAs) are predictive of type I diabetes in first-degree relatives, but this immunohistochemical assay has proven difficult to standardize. As an alternative, we assessed the use of radioassays for antibodies against three molecularly characterized islet autoantigens, including ICA512bdc (amino acid residues 256-979 of the IA-2 molecule, incorporating the intracellular domain). We measured insulin autoantibodies (IAAs), GAD autoantibodies (GAAs), and ICA512bdc autoantibodies (ICA512bdcAAs) by radioassay, in addition to ICAs, in 882 first-degree relatives of patients with type I diabetes, 50 of whom later developed diabetes with a median follow-up of 2.0 years (maximum 11.3 years). The cutoff for each radioassay was determined by testing >200 control subjects. When autoantibody frequencies among the relatives were analyzed according to relationship to the proband, the offspring of diabetic fathers had a higher frequency of ICA5I2bdcAAs (P = 0.008), IAAs (P = 0.0001) and GAAs (P = 0.0001) than the offspring of diabetic mothers. ICA512bdcAAs and IAAs both showed a significant association with HLA-DR4-DQ8 (P = 0.0005). Among relatives developing diabetes, 98% had one or more of IAAs, GAAs, or ICA512bdcAAs, and 80% had two or more of these autoantibodies, compared with none of the control subjects. Using survival analysis to allow for different lengths of follow-up, there was a significant increase in the risk of diabetes with the number of these autoantibodies present, comparing zero, one, two, and three autoantibodies (P < 0.0001, log-rank test), and by Cox regression analysis, this was independent of ICAs and age. For relatives with two or more of these autoantibodies, the risk of diabetes within 3 years was 39% (95% CI, 27-52) and the risk within 5 years was 68% (95% CI, 52-84). Relatives with all three autoantibodies had a risk within 5 years estimated to be 100%. The presence of low first-phase insulin release further increased the risk for relatives with one or two autoantibodies. We conclude that the presence of two or more autoantibodies (out of IAAs, GAAs, and ICA512bdcAAs) is highly predictive of the development of type I diabetes among relatives.

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…Later studies contributed evidence that recurrence of islet autoimmunity may occur regardless of HLA matching 18, 24 and despite immunosuppression 11, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 35. We initially reported 11 three patients in whom T1D recurrence was characterized by 1 hyperglycemia requiring insulin with impaired insulin secretion; 2 seroconversion of autoantibodies years prior to recurrence; 3 circulating autoreactive T cells around the time of diagnosis, often with simultaneous detection in pancreas transplant and associated lymph nodes; 4 insulitis and/or beta cell loss in the pancreas transplant biopsy, with no or minimal rejection; and 5 lack of laboratory evidence of rejection (unchanged urine amylase and serum creatinine levels).…”

“…Standardized assays measure autoantibodies to insulin, the 65‐kDa glutamic acid decarboxylase isoform (GAD65), the insulinoma‐associated tyrosine phosphatase‐like protein (IA‐2), and zinc transporter 8 (ZnT8). Autoantibodies are robust diagnostic and predictive T1D markers, with multiple autoantibodies conferring much higher risk than single autoantibody positivity 2, 3, 4, 5, 6, 7.…”

Apportioning Blame: Autoreactive CD4+ and CD8+ T Cells in Type 1 Diabetes

“…The presence of these autoantibodies is used in the clinic to confirm diagnosis, and they can be also used to predict the development of the disease in prediabetic individuals (Verge et al 1996;Wenzlau and Hutton 2013).…”

Anti-CD38 autoantibodies: Characterisation in new-onset Type I diabetes and latent autoimmune diabetes of the adult (LADA) and comparison with other islet autoantibodies

“…Anti-IA-2 aAbs are responsible for another major subfraction of the ICA reactivity [8,11] and, together with anti-GAD aAbs, they account for about 90% of ICA immunofluorescence [8]. Anti-IA-2 aAbs are an early marker of islet autoimmunity, being mainly found at disease onset [8,11]; they are also found with higher frequency in younger patients [12] independently of disease duration [13], probably reflecting a severe beta-cell destruction leading to the clinical onset of the disease early in life [14,15,16,17]. Although these markers are mainly found in Type I diabetic patients, a subgroup of patients routinely classified as Type II was also found to show high prevalences of ICA and anti-GAD, but not of anti-IA-2 aAbs.…”