Inverse relationship between GAD65 antibody levels and severe retinopathy in younger type 1 diabetic patients

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Abstract

Several risk factors for severe non-proliferative and proliferative retinopathy in type 1 diabetes mellitus have been proposed without explaining the rapid progression of retinopathy in some patients. Since GAD65 autoantibodies (GAD65Abs) are detected against glutamic acid decarboxylase (GAD), which is mainly expressed in islets and nervous tissue in type 1 diabetic patients, the aim of the present investigation was to test the hypothesis whether GAD65Abs are associated with rapidly progressing severe retinopathy. Patients with severe non-proliferative or proliferative retinopathy (n=27) were compared with another group, which in spite of long diabetes duration had no or only mild signs of retinopathy (n=28). GAD65Abs were analysed in a radioimmunoassay using in vitro translated human GAD65, and the levels were expressed as an index in relation to positive and negative reference samples. Using a cut-off level representing the 99th percentile of normals, 6/27 (22%) with and 9/28 (32%) without severe retinopathy were considered GAD65Ab positive. Although there was no difference in the number of GAD65Ab positive patients, the GAD65Ab levels were lower in patients with (0.30; 0.11–0.64) than without (0.68; 0.34–1.12) severe retinopathy (P=0.03). The patients were also subjected to HLA-DR and DQ typing by PCR and hybridization with oligospecific probes. DQ2/8 was more common in patients with (56%) than without (29%) severe retinopathy (P=0.05), but DQ2/8 could not account for the lower GAD65Ab levels in patients with severe retinopathy. It is concluded that GAD65Ab levels are inversely correlated with severe retinopathy in young type 1 diabetic patients.

Introduction

A small group of patients with type 1 diabetes in their twenties developed severe florid retinopathy 1, 2, a rare form characterized by rapid progression from mild to severe non-proliferative or proliferative retinopathy which required prompt laser treatment to prevent blindness [3]. Suggested risk factors such as hypertension, poor metabolic control, nephropathy and growth hormone levels did not fully explain the rapid progress of retinopathy in these patients 4, 5, 6, 7, 8. Genetic risks are mainly unknown 9, 10, 11, 12, but in a previous study, we found that type 1 diabetic patients positive for HLA-DQ2/8 confer a higher risk of developing severe retinopathy [13]. Another factor associated with type 1 diabetes is GAD65Abs, which are detected in ∼80% of newly onset type 1 diabetic patients compared to 1.5% of the general population [14]. The number of GAD65Ab positive patients and the GAD65Ab levels slowly decrease with increasing diabetes duration, but antibodies may still be detected in 54% of patients with >10 years type 1 diabetes duration 15, 16. Since type 1 diabetic patients with severe retinopathy tend to be young and may retain GAD65Abs, the aim of the present study was to test if GAD65Abs are risk indicators for this severe form of retinopathy independent of HLA. The same group of patients with rapidly progressing severe non-proliferative or proliferative retinopathy previously described [13], was therefore compared to one, which in spite of long diabetes duration, had no or mild signs of retinopathy.

Section snippets

Subjects

Two groups of type 1 diabetic patients were selected, one with severe retinopathy (n=27) and one without, despite a long diabetes duration (n=28). When analysing possible effects of GAD65Abs, these two groups will be kept separate. Patient characteristics are given in Table 1. The data represent values at the time when blood samples were obtained for HLA and GAD65Ab analyses. In the severe retinopathy group, HbA1c levels 1 year before the diagnosis of severe retinopathy (10.3±2.3%) did not

GAD65Ab levels and severe retinopathy

GAD65Ab levels were first compared between the patients with and without severe retinopathy (Fig. 1). There was no difference in the number of GAD65Ab positive patients with (22%) and without (32%) severe retinopathy. However, GAD65Ab levels were lower in patients with (0.30; 0.11–0.64) than without (0.68; 0.34–1.12) severe retinopathy (P=0.03). In patients with severe retinopathy, but not in patients without, GAD65Ab positivity was associated with an older age at onset (P=0.02), shorter

Discussion

Autoantibodies against glutamate acid decarboxylase (GADAbs) is the strongest marker for predicting development of type 1 diabetes mellitus [14]. There are two isoforms of the GAD molecule, GAD65 and GAD67. Both have been localized to the human brain and GAD65 has also been isolated from the islets of Langerhans [21]. GAD65 autoantibodies (GAD65Abs) are detected in 80% of newly onset type 1 diabetic patients in comparison to 1.5% in the general population [14]. The number of GAD65Ab positive

Acknowledgements

This study was supported by funds from the Swedish Diabetes Federation, the Crafoord Foundation, the Crown Princess Margareta’s Committee for the Blind, the Stig and Astrid Almérs Foundation, the Malmö Diabetes Association, the Faculty of Medicine, University of Lund, the Novo Nordisk Research Foundation, the National Institutes of Health (DK 26190, DK 42654, DK 17047), and the Swedish Medical Research Council (Grant K98-19X-12662-OIA)..

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