Two-Step Islet Autoantibody Screening for Risk Assessment of Type 1 Diabetes in Relatives

Pastore, M. R.; Bazzigaluppi, Elena; Bonfanti, Riccardo; Dozio, Nicoletta; Sergi, Alessandro; Balini, Annalisa; Belloni, Cristina; Meschi, Franco; Bonifacio, Ezio; Bosi, Emanuele

doi:10.2337/diacare.21.9.1445

Cited by 35 publications

(17 citation statements)

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“…[27,29,42,89,[92][93][94][95][96][97]102,104,105,107,[112][113][114] children [89,146]. The broadening of the autoimmune response to epitopes of different islet-cell antigens, commonly referred to as intermolecular epitope spreading, is associated with an increased probability of developing diabetes, which is also reflected by an enhanced T-cell reactivity to different islet-cell antigens [40,41,[146][147][148][149].…”

Section: Insulinmentioning

confidence: 99%

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

Franke

Galloway

Wilkin

2005

Diabetes Metab. Res. Rev.

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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.

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Section: Insulinmentioning

confidence: 99%

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

Franke

Galloway

Wilkin

2005

Diabetes Metab. Res. Rev.

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“…GADAs and IA-2As were measured by radiobinding assay, using in vitro transcribed and translated recombinant human protein, as previously described (21). The thresholds for positivity were 3 U (GADA) and 1 U (IA-2A).…”

Section: Autoantibody Measurementsmentioning

confidence: 99%

Risk of Type 1 Diabetes Development in Children With Incidental Hyperglycemia

Lorini

Alibrandi²,

Vitali³

et al. 2001

Diabetes Care

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OBJECTIVE -The aim of our study was to determine whether children with incidental hyperglycemia are at an increased risk of developing type 1 diabetes. RESEARCH DESIGN AND METHODS-A total of 748 subjects, 1-18 years of age (9.04 Ϯ 3.62, mean Ϯ SD), without family history of type 1 diabetes, without obesity, and not receiving drugs were studied and found to have incidental elevated glycemia defined as fasting plasma glucose Ͼ5.6 mmol/l confirmed on two occasions. Subjects were tested for immunological, metabolic, and immunogenetic markers.RESULTS -Islet cell antibodies Ͼ5 Juvenile Diabetes Foundation units were found in 10% of subjects, elevated insulin autoantibody levels in 4.6%, GAD antibody in 4.9%, and antityrosine phosphatase-like protein autoantibodies in 3.9%. First-phase insulin response (FPIR) was Ͻ1st centile in 25.6% of subjects. The HLA-DR3/DR3 and HLA-DR4/other alleles were more frequent in hyperglycemic children than in normal control subjects (P ϭ 0.012 and P ϭ 0.005, respectively), and the HLA-DR other/other allele was less frequent than in normal control subjects (P ϭ 0.000027). After a median follow-up of 42 months (range 1 month to 7 years), 16 (2.1%) subjects (11 males and 5 females), 4.1-13.9 years of age, became insulin dependent. All had one or more islet autoantibodies, and the majority had impaired insulin response and genetic susceptibility to type 1 diabetes. Diabetes symptoms were recorded in 11 patients and ketonuria only in 4 patients. The cumulative risk of type 1 diabetes was similar in males and females, and it was also similar in subjects under or over 10 years, whereas the cumulative risk of type 1 diabetes was increased in subjects with one or more autoantibodies and in those with FPIR Ͻ1st centile.CONCLUSIONS -Children with incidental hyperglycemia have a higher-than-normal frequency of immunological, metabolic, or genetic markers for type 1 diabetes and have an increased risk of developing type 1 diabetes. Diabetes Care 24:1210 -1216, 2001T ype 1 diabetes results from cellmediated autoimmune destruction of ␤-cells in the pancreas (1). Multiple genes contribute to the predisposition of the disease, and major histocompatibility complex (MHC) is the most important one (1). Moreover, evidence suggests that environmental factors, which are still poorly defined, may play a role in either precipitating the disease and/or dominantly shaping its course (1). Various autoantibodies against ␤-cell components are present in the serum of newly diagnosed patients with type 1 diabetes (1). More importantly, these circulating autoantibodies may be present for months to years preceding the onset of clinical diabetes (2). The rate of ␤-cell destruction is quite variable, as it is rapid in some individuals and slow in others (3). Some patients, particularly children and adolescents, may present with ketoacidosis at the first manifestation of the disease (4). Others have modest fasting hyperglycemia that can rapidly change to severe hyperglycemia and/or ketoacidosis in the presence of infection ...

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“…There are several reports that describe the predictive characteristics of various autoantibodies (1)(2)(3)(4)(5)(6). We have previously shown that islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), antibodies to GAD (GADA), and insulin autoantibodies (IAA) are all useful predictive markers of type 1 diabetes in siblings initially tested at or close to the time of diagnosis of the first affected child in the family (7).…”

mentioning

confidence: 99%

Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.

et al. 2000

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and the Childhood Diabetes in Finland Study GroupThe relationships between genetic markers and disease-associated autoantibodies were studied in an unselected population of 701 siblings of children with t y p e 1 diabetes, and the predictive characteristics of these markers over a period of 9 years were determined. Increased prevalences of all the antibodies were closely associated with HLA identity to the index case, the DR4 and DQB1*0302 alleles, and the DR3/4 phenotype and the DQB1*02/0302 genotype. Antibodies to GAD (GADA) were also associated with the DR3 and DQB1*02 alleles. Siblings carrying the protective DR2 and DQB1*0602-3 alleles were characterized by lower frequencies of islet cell antibodies (ICA), antibodies to IA-2 (IA-2A), and GADA. Higher levels of ICA were related to HLA identity, the DR4 and DQB1*0302 alleles, and the susceptible DQB1 genotypes, while no significant differences were observed in the levels of I A-2A, GADA, or insulin autoantibodies among siblings with different HLA risk markers. The DR2 or DQB1*0602-3 alleles were not related to the levels of any antibody specificity. A combination of the genetic markers and autoantibodies increased the positive predictive values of all autoantibodies substantially, which may have clinical implications when evaluating the risk of developing type 1 diabetes at the individual level or when recruiting high-risk individuals for intervention trials. However, because such combinations also resulted in reduced sensitivity, autoantibodies alone rather than in combination with genetic markers are recommended as the first-line screening in siblings.

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Two-Step Islet Autoantibody Screening for Risk Assessment of Type 1 Diabetes in Relatives

Abstract: A two-step antibody screening, based first on GADA and IA-2A and then on ICA and IAA measurements in identified individuals, is likely to be a practical, sensitive, and effective strategy for predicting type 1 diabetes in first-degree relatives.

Cited by 35 publications

References 0 publications

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

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

Risk of Type 1 Diabetes Development in Children With Incidental Hyperglycemia

Genetic markers, humoral autoimmunity, and prediction of type 1 diabetes in siblings of affected children. Childhood Diabetes in Finland Study Group.

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