Regular ArticleAntibodies to Glutamic Acid Decarboxylase in At-risk and Clinical Insulin-dependent Diabetic Subjects: Relationship to Age, Sex and Islet Cell Antibody Status, and Temporal Profile
Abstract
Antibodies to glutamic decarboxylase (GADAb) are present in insulin-dependent diabetes (IDD) but their association with age and sex and their temporal profile in relation to disease onset have not been fully documented. We have examined the association between GADAb and islet cell antibodies (ICA), age and sex, and have cross-sectionally and longitudinally measured the levels of GADAb before and after diagnosis of IDD. GADAb were measured by allowing serum immunoglobulin prebound to protein A Sepharose to precipitate GAD enzymatic activity from a fetal pig brain extract. GADAb levels were above the normal range (mean+3SD of healthy controls, 460 nU/M1) in 19/44 (43%) at-risk subjects (ICA positive first degree relatives of persons with IDD), 35/108 (32%) recent-onset IDD subjects and 22/46 (47%) established IDD subjects. When analysed according to age and sex, GADAb levels were significantly higher (P<0.05) in post-pubertal females in at-risk, recent-onset and established IDD groups. There was a significant association between GADAb and ICA>20 in both first degree relatives (P<0.001) and recent-onset subjects (P<0.01) and GADAb were uncommon in the absence of ICA. Levels of GADAb were similar in at-risk, recent-onset and established IDD subjects and GADAb status remained stable in all but 2/41 at-risk subjects followed for 17 (mean, range 3-33) months. In conclusion, GADAb levels are strongly influenced by age, sex and ICA status, and generally remain stable in at-risk subjects and after the onset of clinical IDD.
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Clinical and biochemical characteristics of nonobese type 2 diabetic patients with glutamic acid decarboxylase antibody in Korea
2006, Metabolism: Clinical and ExperimentalWe evaluated the prevalence of glutamic acid decarboxylase autoantibody (GADA) in nonobese patients with type 2 diabetes mellitus in Korea and investigated the characteristics of GADA-positive and GADA-negative patients. Two years later, we assessed the progression of beta-cell function in these patients. Of the 647 nonobese patients with type 2 diabetes mellitus enrolled in the study, 10.1% was positive for GADA. Glutamic acid decarboxylase antibody–positive patients had lower fasting and stimulated C-peptide levels compared with GADA-negative patients (1.70 ± 0.72 vs 1.24 ± 0.59 μg/L, P < .001; 2.59 ± 1.51 vs 1.99 ± 0.82 μg/L, P < .001). Patients treated with insulin had lower fasting and stimulated C-peptide levels than those not treated (1.13 ± 0.52 vs 1.66 ± 0.73 μg/L, P = .002; 1.85 ± 0.69 vs 2.49 ± 0.91 μg/L, P = .004) and had higher titers of GADA (30.5 ± 7.3 vs 6.0 ± 4.8 U/mL, P < .001). In terms of progression of beta-cell function, fasting and stimulated C-peptide levels were significantly lower in GADA-positive patients after 2 years (from 1.24 ± 0.59 to 0.95 ± 0.54 μg/L, P = .004; from 1.99 ± 0.82 to 1.61 ± 0.77 μg/L, P = .007), whereas no such difference was observed in the GADA-negative patients. We demonstrate that a significant proportion of Korean patients may be positive for GADA; this is consistent with studies of white subjects, although disagrees with previous reports on Korean subjects. By assessing the presence of GADA in Korean type 2 diabetic patients, we are able to predict their course of beta-cell function and identify in advance those who are likely to require insulin treatment.
Evidence of autoantibodies to glutamic acid decarboxylase in oral fluid of type 1 diabetic patients
2002, Diabetes Research and Clinical PracticeCirculating antibodies to glutamic acid decarboxylase (GADab) are a major indicator for autoimmune destruction of pancreatic islet cells (type 1 diabetes). Previously reported detection of GADab in oral fluid, however, was assayed by enzyme-linked immunosorbent assay (ELISA) with low diagnostic sensitivity and high non-specific binding. We re-assessed oral fluid GADab detection using a different sampling technique and a more robust assay. Type 1 diabetic subjects (n=32; mean age±SD: 13.9±3.7 years) provided Orasure® oral fluid and venous blood samples. Orasure® collections were assayed for total immunoglobulin G (IgG), then concentrated to 1/10 of their volume using mini-centrifugal protein concentrators. All samples were assayed by a GAD65 antibody radio-immunoprecipitation method. Oral fluid antibodies were detected (>99th percentile of radio-binding (%counts per min (%cpm)) for seronegatives) in 10/16 seropositive subjects, with %cpm (median: 6.4%; range: 4.6–25.8) significantly greater (P<0.001) than for seronegatives (median: 4.7%; range: 3.4–5.7). A highly significant correlation (Spearman's rho: 0.85; P<0.001) was demonstrated between %cpm of concentrates and respective serum titres for seropositive diabetics. Median IgG concentration of Orasure® collections was 22.8 mg/l (range: 9.4–168.0). GADab recovery from Orasure® collectors was estimated at 90%. This is the first confirmatory detection of diabetes-specific autoimmune markers in oral fluid. Acceptable correlation between concentrated oral fluid radio-binding and serum titre was achieved. Improved antibody recovery and assay re-optimisation could provide a basis for more extensive studies that may lead to an alternative non-invasive screening method for pre-clinical autoimmune diabetes.
Antibodies to diabetes-associated autoantigens in Indian patients with Type 1 diabetes: Prevalence of anti-ICA512/IA2 and anti-SOX13
2001, Diabetes Research and Clinical PracticeWe ascertained frequencies of autoantibodies to a suite of islet cell antigens including ICA512/IA2 and SOX13 in Asian Indians with Type 1 diabetes and in other forms of diabetes. Autoantibodies to ICA512/IA2 and SOX13 were tested by radioimmunoprecipitation assay, and results were amalgamated with previous data on antibodies to glutamic acid decarboxylase (GAD) and to islet cell cytoplasmic antigens (ICA). The frequency of anti-SOX13 was higher in Asian Indians than in Europids. Overall, the combined frequency for all autoantibodies to diabetes-associated antigens in Type 1 diabetes in Indians approached the frequency reported for Europids. There was an unexpectedly high frequency of autoantibody reactions to any one of the autoantigens tested (24%) in fibrocalculous pancreatic diabetes, however, individual autoantibody frequencies were relatively low. Our data indicate that, whatever the population studied, testing for multiple autoantigenic reactivities is more informative than more limited testing, and that there may be regional (presumably ethnically based) differences in levels of particular autoantibodies in cases of Type 1 diabetes.
GAD autoantibodies in a selection-free population of insulin-treated diabetic patients: Indicator of a high prevalence of LADA?
2000, Diabetes Research and Clinical PracticeUp to the present only few data have been available concerning the prevalence of diabetes-specific autoantibodies (anti-GAD, ICA, IAA, IA-2) in unselected populations, in particular in type 2 diabetic patients. Hence, the aim of the present study was to determine the prevalence of anti-GAD in a selection-free population of insulin-treated diabetic patients. Accordingly, 90% of all the insulin-treated diabetic patients (type 1, n=127, type 2, n=117) aged 16–60 years and living in the city of Jena (100 242 inhabitants) were examined. In order to test sera for anti-GAD, serum samples were taken in 75% of type 1 (n=95) and in 80% of insulin-treated type 2 diabetic (n=94) patients. Results: In the group of type 1 diabetic patients 55% of the patients tested were positive for anti-GAD. But, interestingly, in the type 2 group, a total of 21% patients were positive. With respect to this high percentage of anti-GAD positive type 2 diabetic patients it must be suggested that the frequency of patients with latent autoimmune diabetes mellitus in adults (LADA) was underestimated in the past.
Autoantibodies and type 1 diabetes
1999, Immuno-Analyse et Biologie SpecialiseeLe diabète de type I résulte de la destruction auto-immune des cellules β des îlots de Langerhans du pancréas. La détection d'autoanticorps anti-cellules d'îlots (ICA) et plus récemment d'autoanticorps reconnaissant des antigènes insulaires identifiés, insuline (IAA), glutamate décarboxylase (GAD), tyrosines phosphatases (IA-2, IA2-β) est utilisée dans le diagnostic de formes atypiques de la maladie ou en médecine prédictive chez des apparentés normoglycémiques de diabétiques de type 1. La mise en évidence d'une auto-immunité anti-cellules β lors d'une longue phase asymptomatique appelée prédiabète conduit à développer des stratégies préventives spécifiques et précoces. La présence simultanée de plusieurs marqueurs de risque comme les ICA, les anti-GAD, anti-insuline (IAA) et anti- IA-2 attribue un risque d'insulino-dépendance proche de 100 %. La majorité des essais actuels tels que l'insuline sous-cutanée, la nicotinamide, la vaccination par voie muqueuse concerne les apparentés du premier degré de diabétiques de type 1. Quatre-vingt dix pour cent des nouveaux diabétiques survenant dans la population générale, les essais devront s'intéresser à cette population dans un deuxième temps afin d'obtenir un réel impact au niveau santé publique. Ce temps est proche puisque le dosage des ICA semble pouvoir être remplacé par le dosage combiné automatisable anti-GAD/IA-2.
Autoantibodies and type 1 diabetes. Type J diabetes is an auto-immune disease with progressive destruction of Langerhans islet β cells. Detection of islet cell autoantibodies (aAb) (ICA), and aAb directed against recently identified islet antigens, antiinsulin (IAA), anti-glutamic acid decarboxylase (GADA), and anti-tyrosine phosphatase (IA-2A) is helpful to diagnose atypical diabetes or to predict disease set-up in normoglycemic relatives of type 1 diabetic subjects. The prediabetic period offers an opportunity to start intervention aimed at preventing the clinical disease. Predictive value of the combined presence of ICA, IAA, GADA and IA2-A is 100 %. Most of present clinical trials are performed in individuals with a diabetic relative. Since 90 % of new cases of type 1 diabetes occur sporadically, the next challenge is to set-up prevention trials in the general population. Recent data suggest that single-step detection of GADA and 1A-2A can replace ICA test and provides the means for large-scale screening in relatives and general population.
Onset age-dependent variations of three islet specific autoantibodies in Japanese IDDM patients
1998, Diabetes Research and Clinical PracticeThe age related incidence rate of insulin-dependent diabetes mellitus shows a bimodal distribution, not only in Caucasians but also in Japanese. To evaluate the onset age-related autoimmune profile at presentation in insulin-dependent diabetes mellitus (IDDM), glutamic acid decarboxylase (GAD) autoantibody, islet cell antibody (ICA), and insulin autoantibody (IAA) were measured in 137 newly diagnosed Japanese IDDM patients with onset ages between 0–29 years. The prevalence of GAD autoantibody was significantly increased from the lowest (32%) in the 0–5 years onset age group to 75% in the 13–19 years onset age group (P<0.05), whereas the IAA prevalence significantly decreased from the peak (48%) in the 6–12 years onset age group to 10% in the 20–29 years onset age group (P<0.05). The ICA prevalence was increased from the lowest (32%) in the 0–5 years onset age group to the highest (53%) in the 20–29 years onset age group similar to that for the GAD autoantibody. Such results demonstrate that there was age-related autoimmune characteristics at presentation of IDDM in Japanese as well as in Caucasians.