Screening for insulinoma antigen 2 and zinc transporter 8 autoantibodies: a cost-effective and age-independent strategy to identify rapid progressors to clinical onset among relatives of type 1 diabetic patients

Abstract

SummaryIn first-degree relatives of type 1 diabetic patients, we investigated whether diabetes risk assessment solely based on insulinoma antigen 2 (IA-2) and zinc transporter 8 (ZnT8) antibody status (IA-2A, respectively, ZnT8A) is as effective as screening for three or four autoantibodies [antibodies against insulin (IAA), glutamate decarboxylase 65 kDa (GAD) glutamate decarboxylase autoantibodies (GADA) and IA-2A with or without ZnT8A] in identifying children, adolescents and adults who progress rapidly to diabetes (within 5 years). Antibodies were determined by radiobinding assays during follow-up of 6444 siblings and offspring aged 0-39 years at inclusion and recruited consecutively by the Belgian Diabetes Registry. We identified 394 persistently IAA + , GADA + , IA-2A + and/or ZnT8A + relatives (6·1%). After a median follow-up time of 52 months, 132 relatives developed type 1 diabetes. In each age category tested (0-9, 10-19 and 20-39 years) progression to diabetes was significantly quicker in the presence of IA-2A and/or ZnT8A than in their joint absence (P < 0·001). Progression rate was age-independent in IA-2A + and/or ZnT8A + relatives but decreased with age if only GADA and/or IAA were present (P = 0·008). In the age group mainly considered for immune interventions until now (10-39 years), screening for IA-2A and ZnT8A alone identified 78% of the rapid progressors (versus 75% if positive for Ն 2 antibodies among IAA, GADA, IA-2A and ZnT8A or versus 62% without testing for ZnT8A). Screening for IA-2A and ZnT8A alone allows identification of the majority of rapidly progressing prediabetic siblings and offspring regardless of age and is more cost-effective to select participants for intervention trials than conventional screening.

Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes

“…All of the participants were positive for autoantibodies against insulinoma-associated protein 2 [IA-2A] or zinc transporter 8 [ZnT8A] and at least one other diabetes autoantibody, a profile that has previously been shown to confer about a 50% risk of developing diabetes within 5 years [18]. Seven FDRs carried the high-risk HLA-DQ2/DQ8 genotype ( Table 1).…”

“…None of these participants had a family history of type 1 diabetes or an FDR with type 2 diabetes. All tested negative for diabetes-associated autoantibodies (islet-cell cytoplasm autoantibodies, glutamate decarboxylase autoantibodies, IA-2A, insulin autoantibodies and ZnT8A) [18] and all had a normal OGTT (Table 1).…”

“…Because of the 100% cross-reactivity of proinsulin in the C-peptide assay, free C-peptide levels were obtained by subtracting the proinsulin concentration from the total C-peptide result [8]. Diabetes autoantibodies (insulin autoantibodies, glutamate decarboxylase autoantibodies, IA-2A and ZnT8A) were determined by liquid-phase radiobinding assays and HLA-DQ polymorphisms by allelespecific oligonucleotide genotyping, as previously described [18].…”

“…Here, we investigated this correlation in earlier disease phases (i.e. before and at clinical onset) [18].…”

Type 1 Diabetes: Disease Stratification

“…Faster rates of progression are observed with 3 or 4 versus 2 islet autoantibodies [25,70,71] . The presence of antibodies to IA-2 and ZnT8 as well as higher titers of antibody to Insulin and IA-2 are associated with a faster rate of progression [10,70,[72][73][74] . Islet autoantibody seroconversion at a young age is associated with a faster rate of progression [25] , and disease progression is also accelerated in children at stage 1 T1D with an increased BMI [75] and markedly accelerated in Hispanic children younger than 12 years of age who are overweight or obese [76] .…”