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

Abstract

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.

GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77

“…The difference in the proportion of GADA-positive patients requiring insulin by 6 years in this study (73%) compared with those previously reported for UKPDS LADA (33 and 38%) [7,22] could be due to differences in ascertainment by antibody assays of variable sensitivities [23].…”

“…Although GADA levels at diagnosis can help to predict the need for insulin therapy within the next 6 years [7,22] subsequent GADA measurements and fluctuations in levels are not indicators of disease progression or therapy requirement. Genetic and autoimmune markers in LADA indicate a similar aetiology to juvenile-onset diabetes [5,23,34,35] but these markers do not provide important aids to clinical management of LADA patients.…”

HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden

“…Indeed, IA-2A concentration was highest among patients with the HLA-DQB1 *0302/X genotype. IA-2A are known to be associated with a rapid onset of type 1 diabetes as well as with young age at onset [34][35][36].…”

“…GADA were measured by a radioligand binding assay, based on human 35 S-labeled recombinant GAD 65 [15]. The results are presented as an index: GADA index=100 * (un)/(p-n), where u is CPM (mean activity of all four measurements for a sample) of the unknown sample, n is CPM of the negative control, and p is CPM of the positive control.…”

Clinical phenotype and β-cell autoimmunity in Italian patients with adult-onset diabetes

“…Most of these studies assessed patients attending a single diabetes clinic and few of them evaluated the correlation between the presence of GADA and the clinical features of affected patients. While GADA is recognized as the marker with the highest sensitivity for LADA, fewer data are available on IA-2A in adult-onset diabetes (25), while IAAs are unlikely to be useful since they are a feature of childhood diabetes (26).…”