Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes

Bonifacio, Ezio; Shattock, Marion; Dean, B M; Bottazzo, Gian Franco; Bingley, P; Gale, E.A.M.; Dunger, David B.

doi:10.1016/0140-6736(90)90013-u

Cited by 350 publications

(249 citation statements)

References 8 publications

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“…All our ICA positive relatives who became diabetic had ICA above 20 JDF units. As previously documented by Bonifacio et al [16], quantification of ICA in follow-up samples is therefore clearly needed to accurately predict onset of Type 1 diabetes. However, the results presented here suggest a higher level of heterogeneity.…”

Section: Discussionmentioning

confidence: 92%

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

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Summary.Factors associated with diabetes onset were analysed for their predictive value in 708 first-degree relatives of Type 1 (insulin-dependent) diabetic patients including 374 parents and 308 siblings of Type i diabetic patients. Relatives were prospectively followed for 2 304 subject years with blood samples for specific autoantibody evaluation. Islet cell cytoplasmic autoantibody titres were quantified in Juvenile Diabetes Foundation units with a threshold of positivity of 5 units. Insulin autoantibodies were determined using Tyr-A14 iodinated human insulin. HLA typing was performed in 92% of the relatives. During the time of study, 17 of 646 (2.6%) relatives showed islet cell antibodies. During follow-up, eight relatives developed diabetes, including six with high islet cell antibody titre. Taking titres above 20 units increased the positive predictive value from 35% to 75% whereas the presence of insulin autoantibodies did not increase the positive predictive value for the disease. Analysis of metabolic profiles months before the onset of diabetes by either oral or intravenous glucose loads, indicated a considerable level of heterogeneity with relatives with a high islet cell antibody titre who rapidly developed insulin-dependent diabetes, whereas others remained insulin-independent during the same observation period despite comparable titres. This study clearly indicates that initial islet cell antibody titre is not sufficient to predict individual outcome. Follow-up samples are clearly needed to monitor progression of the disease. Few relatives with persistent immunologic positivity progress to clinical Type 1 diabetes, suggesting that non-progressive and sub-clinical Beta-cell dysfunction is common. Despite current knowledge and available genetic and immune markers, early identification of the relatives progressing to clinical diabetes is still difficult and does not allow at the present time aggressive immunointervention at the prediabetic stage.

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Section: Discussionmentioning

confidence: 92%

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

et al. 1991

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“…Islet cell antibodies (ICA) have been found in 3-21% of first-degree relatives of Type 1 diabetic patients [35,38], but also in as many as 2-4% of the general population [39,40]. ICA-positive individuals therefore outnumber those eventually developing clinical Type i diabetes, since the prevalence of Type I diabetes in the general population is 0.15-0.3% [41,42].…”

Section: Resultsmentioning

confidence: 99%

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

et al. 1991

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Summary. First-degree relatives of Type i (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a Mr 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type i diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type i diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n = 6) and low (n = 30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive While six (20%) were positive for 64K antibodies. In contrast, of the six subjects with progressively declining Beta-cell function who are therefore at high risk, two of whom have already developed Type i diabetes, two (33%) were positive for insulin autoantibodies, four (67%) were islet cell antibody positive, while all six (100%) were positive for 64K antibodies. We conclude that antibodies to the Mr 64,000 islet protein correlate with progressive Beta-cell dysfunction more closely than either islet cell antibodies or insulin autoantibodies, but can sometimes be present in individuals whose Beta-cell function remains stable over several years.

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“…ICA positivity was taken as 5 JDF units or more and GADA positivity as 20 reference units or more. The sensitivity and specificity of the assays for the diagnosis of diabetes at these thresholds were 88 and 97% for ICA [12] and 75 and 100% for GADA under the conditions of the JDF Combinatorial Autoantibody Workshop of 1995 [13].…”

Section: Subjects Materials and Methodsmentioning

confidence: 98%

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71)

et al. 2005

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Aims/hypothesis: Established autoimmune markers of type 1 diabetes, including islet cell autoantibodies (ICA) and autoantibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 (IA-2A) and IA-2β/phogrin (IA-2βA) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these autoantibodies in predicting requirement for insulin therapy. Methods: IA-2A and IA-2βA were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25-65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not randomised to insulin. Results: IA-2A and IA-2βA were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p<0.0001), and their presence increased the likelihood of insulin therapy requirement within 6 years from diagnosis [relative risk (95%CI) 12.2 (9.8-15.3)]. The presence of IA-2A together with GADA increased the relative risk of requiring insulin therapy from 5.4 (4.1-7.1) for GADA alone to 8.3 (3.7-18.8) and the corresponding positive predictive value from 33 to 50%. Conclusions/interpretation: In type 2 diabetes, the presence of IA-2A is infrequent, associated with the HLA-DR4 haplotype, and highly predictive of future need for insulin therapy. The measurement of IA-2βA does not provide additional information.

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Quantification of islet-cell antibodies and prediction of insulin-dependent diabetes

Cited by 350 publications

References 8 publications

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Autoantibodies and genetic factors associated with the development of Type 1 (insulin-dependent) diabetes mellitus in first degree relatives of diabetic patients

Risk for developing Type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71)

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