Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease

doi:10.1016/S0140-6736(94)92521-6

The Lancet

Volume 343, Issue 8910, 4 June 1994, Pages 1383-1385

https://doi.org/10.1016/S0140-6736(94)92521-6 Get rights and content

Abstract

We have done a study designed to ascertain the effectiveness of measuring antibodies to glutamic acid decarboxylase (anti-GAD) in predicting insulin-dependent diabetes mellitus (IDDM). Anti-GAD was measured in prediabetic sera from 151 women aged 20-39 years with newly diagnosed diabetes mellitus who had been identified through a nationwide diabetes register. Multiple serum samples had been collected from these women up to 10 years before the clinical onset of diabetes during their earlier pregnancies. Anti-GAD was measured with a radioimmunoprecipitation assay. Anti-GAD was detected in 82% of 28 women with IDDM, in 36% of 11 women with non-insulin-dependent diabetes mellitus, and in 5% of 112 women with gestational diabetes mellitus. In a random sample of 100 non-diabetic young Finnish women, none had anti-GAD. The sensitivity of the anti-GAD assay for predicting IDDM was 82 1% and the specificity was 100%. The longest time of anti-GAD positivity before clinical onset of IDDM was 10 years. Once positive, anti-GAD levels remained stable and no patients became negative after a positive test during the prediabetic period. Anti-GAD is a valuable early predictive marker and is associated with a very high risk for development of IDDM.

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Cited by (187)

Serum brain-derived neurotrophic factor and neurocognitive function in children with type 1 diabetes
2021, Journal of the Formosan Medical Association
This study aimed to clarify whether brain-derived neurotrophic factor (BDNF) is a biomarker for cognitive dysfunction in children with type 1 diabetes.
We conducted a cross-sectional case–control study of children aged between 6 and 18 years with type 1 diabetes and healthy volunteers. Serum BDNF level was measured in all of the studied children, and they all underwent intelligence tests with the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV). We further compared the cognitive function and BDNF levels in the diabetic children with positive glutamic acid decarboxylase 65 antibody (GAD65-Ab) and those with negative GAD65-Ab.
Forty-five children with type 1 diabetes (mean age 14.0 ± 2.6 years, 42% male) and 50 normal controls (mean age 13.2 ± 2.3 years, 54% male) were recruited. The serum BDNF level was significantly lower in the diabetes group than in the controls (15.92 ± 7.2 vs. 18.5 ± 5.1 ng/mL, respectively, t = −2.03, p = 0.045) and much lower in the subgroup with GAD65-Ab positive type 1 diabetes. The average Full-Scale IQ, verbal comprehension, perceptual reasoning and working memory scores in the diabetes group were significantly lower than in the controls (all p < 0.05). Among the children with type 1 diabetes, poor glycemic control was related to lower general cognitive abilities (r = −0.34, p < 0.02), lower verbal comprehension (r = −0.305, p < 0.05), and lower perceptual reasoning scores (r = −0.346, p = 0.02).
The children with type 1 diabetes had a lower serum BDNF level and poorer neurocognitive function than normal healthy children, especially those with GAD65-Ab positive diabetes. Poor glycemic control was correlated with worse cognitive performance.
The prognostic significance of glutamic acid decarboxylase antibodies in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation
2019, Diabetes and Metabolism
Citation Excerpt :
Glutamic acid decarboxylase is an enzyme mainly expressed in pancreatic β cells and neuron cells that catalyses the conversion of glutamic acid to γ-aminobutyric acid (GABA). Elevated GADA is a specific immunologic marker for the diagnosis of T1D [4,5], and may be elevated before the clinical diagnosis. However, GADA positivity has been observed in some non-diabetic populations and is of unclear significance in this setting [8,12,13].
Islet autotransplantation (IAT) is considered a ‘non-immune’ model of islet transplant, with no risk for autoimmune-mediated beta cell loss, but we have previously observed de novo type 1 diabetes in one total pancreatectomy with islet autotransplantation (TPIAT) recipient. We aimed to investigate the clinical significance of glutamic acid decarboxylase antibodies (GADA), as a sensitive marker for autoimmune diabetes mellitus (DM), in patients with chronic pancreatitis undergoing TPIAT.
We identified 9 patients undergoing TPIAT with elevated GADA pre-TPIAT (8 non-diabetic and 1 with C-peptide positive DM), otherwise demographically similar to GADA negative TPIAT recipients (n = 341). Metabolic and clinical measures related to islet cell function were recorded both before and after TPIAT.
None of the 9 TPIAT patients achieved insulin independence after surgery, vs. 33% of GADA negative patients (n = 318 with 1-yr follow-up). The two patients with the highest titters of GADA (> 250 IU/mL) both experienced islet graft failure, despite normoglycaemia pre-TPIAT and high islet mass transplanted (5276 and 9378 IEQ per kg), with elevated HbA1c levels post-TPIAT (8.3%, 9.6%). The remaining 7 seven were insulin dependent with partial graft function and HbA1c levels < 7%.
Insulin dependence was more frequent in 9 patients with elevated GADA prior to TPIAT than in GADA negative TPIAT recipients, with graft failure in 2 cases. We speculate that beta-cell autoimmunity may occur in a small subset of TPIAT recipients and that beta cell antibody testing prior to TPIAT may be warranted to identify individuals at higher risk for insulin dependence.
Prevalence of double diabetes in youth onset diabetes patients from east Delhi and neighboring NCR region
2018, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
However Reinehr et al. who reported a higher prevalence of double diabetes (32%) have not mentioned the duration of diabetes in their study. It is unclear whether shorter duration of diabetes in these subjects resulted in a higher rate of antibody positivity [15,16], which might be an important factor underlying the difference in prevalence of double diabetes from our study. When the subjects in our study were analyzed considering the duration of diabetes we found highest antibody positive with shorter duration of diabetes mellitus.
It is being increasingly reported that some of the youth onset diabetes patients cannot be classified clearly as type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) based on usual criteria and the term double diabetes (DD) coined for these cases.
The objective of the study was to find out the prevalence of DD in youth onset diabetes patients from east Delhi and neighboring NCR region.
A total of 200 patients with youth onset diabetes below 25 years of age were recruited from a tertiary care hospital in East Delhi. Clinical history, family history of diabetes and anthropometry of patients were recorded. Fasting serum C-peptide, Anti-IA2-antibody and Anti-GAD-antibody were measured in all patients. Patients positive for Anti-GAD-antibody (>1.05 U/ml) and C-peptide level >0.3 nmol/l were characterized as DD patients. Patients negative for Anti-GAD-antibody and C-peptide >0.3 nmol/l were kept under the category of T2DM. Patients with low C-peptide level along with one of the following, positive Anti-GAD-antibody, positive Anti-IA2-antibody and diabetic ketoacidosis (DKA) were considered as T1DM. Remaining patients were kept under the unknown category.
Mean age of study subjects was 18.2 ± 7.1 years. Seven percent (7%) of the subjects were classified as DD, 51% as T1DM, 13% as T2DM and 29% were kept under the unknown category. Mean age of subjects with 22.2 ± 9.7, 16.9 ± 6.7, 20.6 ± 7.7 and 19.4 ± 7.4 years in DD, T1DM, T2DM and unknown category respectively. Mean BMI of subjects with DD, T1DM, T2DM and unknown category was 19.8 ± 5.7, 16.6 ± 3.7, 19.3 ± 4.1 and 18.0 ± 4.6 kg/m² respectively.
Double diabetes is an important occurrence among youth onset diabetes subjects. Only half of the subjects with youth onset of diabetes had T1DM.
Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: A comparison of anti-GAD antibody titers and time-dependent changes between neurologic disease and type I diabetes mellitus
2018, Journal of Neuroimmunology
To determine clinical features of neurologic disorders associated with anti-glutamic acid decarboxylase antibodies (anti-GAD-Ab), we examined titers and time-dependent changes of anti-GAD-Ab. Six patients, stiff person syndrome (2), cerebellar ataxia (1), limbic encephalitis (1), epilepsy (1), brainstem encephalitis (1), were compared with 87 type I diabetes mellitus (T1DM) patients without neurologic disorders. Anti-GAD-Ab titers and index were higher in neurologic disorders than in T1DM, suggesting intrathecal antibody synthesis. Anti-GAD-Ab titers in T1DM decreased over time, whereas they remained high in neurologic disorders. Immunotherapy improved neurological disorders and anti-GAD-Ab titers and index provide clinically meaningful information about their diagnostic accuracy.
Could ZnT8 antibodies replace ICA, GAD, IA2 and insulin antibodies in the diagnosis of type 1 diabetes?
2018, Current Research in Translational Medicine
Citation Excerpt :
Interestingly, in our population, ZnT8ab was significantly more found in females and it was different from the results obtained in the study of Salonen and Knip, which did not show any significant difference between the ZnT8ab prevalence in both boys and girls [26]. We observed that GADab was significantly more present in the beginning of T1D and these results were in accordance with Tuomilehto et al., Tobon et al. and Chan et al. who showed a higher prevalence of GADab in young diagnosed patients [31–33], but controverted those of Serrano-Ríos et al. who did not find any correlation between the GADab and the diabetes duration [34]. The IAab was significantly more present in young diagnosed patients, our results were in accordance with the studies of Tung et al. and Delgado-Charro [35,36].
The zinc transporter 8 (ZnT8) is an islet β-cell secretory granule membrane protein coded by the SLC30A8 gene, identified as a novel autoantigen in human type 1 diabetes (T1D). As no data of ZnT8ab in Algerian patients have been reported, we aim to evaluate the prevalence of ZnT8ab in young Algerians with T1D and determine whether ZnT8ab could be a better diagnostic tool to replace the other conventional autoantibodies detected in patients with type 1 diabetes. For this purpose, we evaluated the prevalence of islets cells antibodies (ICA), glutamic acid decarboxylase (GAD), islet antigen type 2 (IA2), insulin (IA) autoantibodies (ab) and for the first time in Algeria, the zinc transporter 8 (ZnT8) in young Algerian patients with type 1 diabetes.
In our cross-sectional study, 160 patients between 1 and 35 years old, diagnosed with type 1 diabetes were enrolled. ICAab was analyzed by indirect immunofluorescence (IIF), GADab, IA2ab, IAab and ZnT8ab were analyzed by ELISA, fasting blood glucose was performed by enzymatic method (glucose-oxidase) and HbA1c by turbid metric method.
Our cohort was composed with 74 males and 86 females (OR = 1.16); the mean of age was 14.09 [1–35] years old and the median diabetes duration was 4.10 [1–18] years. Our cohort had a mean of HbA1c of 9.22 [5.40–15]%, the mean of birth weight was 3360.52 [2200–4800] g; the mean of BMI was 19.30 [16.04–22.46] kg/m². Out of 160 patients, 44 (27.5%) were under mother breastfeeding and 116/160 (72.5%) were under artificial feeding. One antibody, at least, was found in 94.38% and the ZnT8ab was significantly more positive in females (70.3%) than in males (10.7%) (***P = 8.033 × 10⁻¹⁵). The concentration of ZnT8ab was higher in females than in males (females = 122.25 UI/mL versus males = 51.38 UI/mL; *P = 0.03); ICAab, GADab and ZnT8ab were more present in patients with consanguineous parents (***P = 0.0002, *P = 0.019 and *P = 0.03; respectively)
Our study on ZnT8ab in T1D is the first in the Maghreb region and we observed a prevalence of 46.25%. The positivity of ZnT8ab enabled us to classify in T1DA 50% of diabetics with obvious T1D phenotype and negative routine autoantibodies, thus ZnT8ab is a good tool for differential diagnosis of type 1 diabetes. According to our results, a simultaneous analysis for ZnT8 and IA2 autoantibodies can be a better and efficient diagnosis of type 1A diabetes from the beginning of the disease.
ESC clinical practice guidelines on diabetes, prediabetes and cardiovascular disease, in collaboration with the European Association for the Study of Diabetes
2014, Revista Espanola de Cardiologia

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ArticlesAntibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease

Abstract

Lancet

Lancet

Hum Immunol

Islet cell surface antibodies in juvenile diabetes mellitus

N Engl J Med

Insulin antibodies in insulin-dependent diabetes before insulin treatment

Science

Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins

Nature

Antibodies to a Mr 64,000 islet cell protein in Swedish children with newly diagnosed type 1 (insulin-dependent) diabetes

Diabetologia

Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 65K autoantibody positivity at onset predicts diabetes type

J Clin Invest

Can islet cell antibodies predict IDDM in the general population

Diabetes Care

Identification of the 64K autoantigens in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase

Nature

GABA and pancreatic beta-cells: co-localization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion

EMBO J

Autoimmunity to two forms of glutamic decarboxylase in insulin-dependent diabetes mellitus

J Clin Invest

Glutamic acid decarboxylase (GAD) autoantibodies are additional predictive markers of type 1 (insulin-dependent) diabetes mellitus in high risk individuals

Diabetologia

Antibodies to glutamic acid decarboxylase discriminate major type of diabetes mellitus

Diabetes

Articles
Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease

Antibodies to a M_r 64,000 islet cell protein in Swedish children with newly diagnosed type 1 (insulin-dependent) diabetes