Islet Autoantibody Level Distribution in Type 1 Diabetes and Their Association With Genetic and Clinical Characteristics.

CONTEXT: The importance of the autoantibody level at diagnosis of type 1 diabetes (T1D) is not clear. OBJECTIVE: We aimed to assess the association of glutamate decarboxylase (GADA), islet antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A) autoantibody levels with clinical and genetic characteristics at diagnosis of T1D. METHODS: We conducted a prospective, cross-sectional study. GADA, IA-2A, and ZnT8A were measured in 1644 individuals with T1D at diagnosis using radiobinding assays. Associations between autoantibody levels and the clinical and genetic characteristics for individuals were assessed in those positive for these autoantibodies. We performed replication in an independent cohort of 449 people with T1D. RESULTS: GADA and IA-2A levels exhibited a bimodal distribution at diagnosis. High GADA level was associated with older age at diagnosis (median 27 years vs 19 years, P = 9 × 10-17), female sex (52% vs 37%, P = 1 × 10-8), other autoimmune diseases (13% vs 6%, P = 3 × 10-6), and HLA-DR3-DQ2 (58% vs 51%, P = .006). High IA-2A level was associated with younger age of diagnosis (median 17 years vs 23 years, P = 3 × 10-7), HLA-DR4-DQ8 (66% vs 50%, P = 1 × 10-6), and ZnT8A positivity (77% vs 52%, P = 1 × 10-15). We replicated our findings in an independent cohort of 449 people with T1D where autoantibodies were measured using enzyme-linked immunosorbent assays. CONCLUSION: Islet autoantibody levels provide additional information over positivity in T1D at diagnosis. Bimodality of GADA and IA-2A autoantibody levels highlights the novel aspect of heterogeneity of T1D. This may have implications for T1D prediction, treatment, and pathogenesis.

Clinical study of autoantibodies in type 1 diabetes mellitus children with ketoacidosis or microalbuminuria.

AIMS: The study aimed to investigate the value of autoantibodies in predicting the risk of ketoacidosis or microalbuminuria in children with type 1 diabetes mellitus. METHODS: Clinical data and laboratory indicators of 80 patients with type 1 diabetes admitted to the Department of Endocrinology in Tianjin Children's Hospital, from June 2017 to March 2019, were retrospectively analyzed. The patients were divided into two groups: diabetes without ketoacidosis group (n = 20) and diabetes with ketoacidosis group (n = 60). The differences in general data, laboratory test indexes, and autoantibodies between the two groups were analyzed. Finally, ROC curves and multivariate logistic regression analysis were used to explore the value of autoantibodies in patients with ketoacidosis or microalbuminuria. RESULTS: A total of 80 children with type 1 diabetes were assessed, including 35 boys and 45 girls, ranging in age from 10 months to 15 years. The concentration of GADA, IA2A, and ZnT8A was not statistically different between the two groups, but the positive rate of ZnT8A was statistically significant (p = 0.038) and had a diagnostic value for the occurrence of ketoacidosis (p = 0.025). ZnT8A-positive patients had a higher titer of IA2A and a more frequent prevalence of GADA and IA2A than ZnT8A-negative patients (p < 0.01). In multivariate logistic regression analyses, the presence of positive ZnT8A was associated with a higher risk of microalbuminuria independent of age, sex, and BMI (OR = 4.184 [95% CI 1.034~16.934], p = 0.045). CONCLUSIONS: The positive ZnT8A had diagnostic value for ketoacidosis in children with type 1 diabetes and had the highest specificity among the three kinds of autoantibodies. Moreover, ZnT8A positivity was related to a higher titer of IA2A and more frequent occurrence of multiple diabetes-related autoantibodies. Besides, the presence of positive ZnT8A was an independent risk factor of microalbuminuria in children with type 1 diabetes. Therefore, we can infer that positive ZnT8A may be related to ketoacidosis and microalbuminuria, accelerating the progression of T1DM.

Geographic location determines beta-cell autoimmunity among adult Ghanaians: Findings from the RODAM study.

INTRODUCTION: Beta-cell autoantibodies are established markers of autoimmunity, which we compared between Ghanaian adults with or without diabetes, living in rural and urban Ghana and in three European cities. METHODS: In the multicenter cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study (N = 5898), we quantified autoantibodies against glutamic acid decarboxylase (GAD65Ab) by radioligand binding assay (RBA) and established cut-offs for positivity by displacement analysis. In a subsample, we performed RBA for zinc transporter-8 autoantibodies (ZnT8Ab). Associations of environmental, sociodemographic, and clinical factors with GAD65Ab were calculated. RESULTS: In this study population (age: 46.1 ± 11.9 years; female: 62%; Ghana-rural: 1111; Ghana-urban: 1455; Europe: 3332), 9.2% had diabetes with adult-onset. GAD65Ab concentrations were the highest in Ghana-rural (32.4; 10.8-71.3 U/mL), followed by Ghana-urban (26.0; 12.3-49.1 U/mL) and Europe (11.9; 3.0-22.8 U/mL) with no differences between European cities. These distributions were similar for ZnT8Ab. Current fever, history of fever, and higher concentrations of liver enzymes marginally explained site-specific GAD65Ab concentrations. GAD65Ab positivity was as frequent in diabetes as in nondiabetes (5.4% vs 6.1%; P = .25). This was also true for ZnT8Ab positivity. CONCLUSION: Geographic location determines the occurrence of GAD65Ab and ZnT8Ab more than the diabetes status. Beta-cell autoimmunity may not be feasible to differentiate diabetes subgroups in this population.

Zinc transporter 8 autoantibodies complement glutamic acid decarboxylase and insulinoma-associated antigen-2 autoantibodies in the identification and characterization of Japanese type 1 diabetes.

AIMS/INTRODUCTION: This study aimed to investigate the significance of zinc transporter 8 autoantibody (ZnT8A) in identifying and characterizing autoimmune-mediated type 1 diabetes in Japanese individuals. METHODS: ZnT8A were determined in 324 patients with type 1 diabetes, 191 phenotypic type 2 diabetes and 288 healthy control individuals using bridging-type enzyme-linked immunosorbent assay in addition to autoantibodies to glutamic acid decarboxylase and insulinoma-associated antigen-2. RESULTS: We set a cut-off value of 10.0 U/mL, and 25% of the type 1 diabetic patients had ZnT8A levels exceeding this level. The prevalence of ZnT8A was significantly higher in patients with acute-onset type 1 diabetes than in those with slowly progressive and fulminant type 1 diabetes (P < 0.05). ZnT8A were more frequent in patients aged ≤10 years, but less frequent in patients with duration ≥5 years (P < 0.05). ZnT8A were detected in 5.2% of phenotypic type 2 diabetic patients, with 90% of these being ZnT8A-single-positive. Furthermore, the ZnT8A levels in the phenotypic type 2 diabetes cohort (143.8 ± 194.9 U/mL) were significantly higher than those in the type 1 diabetes cohort (22.9 ± 8.3 U/mL, P < 0.05). In the acute-onset and slowly progressive type 1 diabetic patients with duration ≤5 years, additional measurement of glutamic acid decarboxylase autoantibodies significantly increased the disease sensitivity in patients aged ≤10 years, but not in patients aged ≥11 years (11.7 vs 3.6%, P < 0.05). Multivariate analysis showed that ZnT8A positivity was independently associated with age at sampling and insulinoma-associated antigen-2 autoantibody positivity. CONCLUSIONS: These results suggest that the bridging-type ZnT8A enzyme-linked immunosorbent assay might provide a valuable additional marker for Japanese patients with type 1 diabetes, which could, in turn, allow for an increase in the number of identifiable cases and differentiate clinical phenotypes.

Analysis of diabetes-associated autoantibodies in children and adolescents with autoimmune thyroid diseases.

Background Zinc transporter 8 autoantibodies (ZnT8Abs) together with glutamic acid decarboxylase autoantibodies (GADAbs), insulinoma antigen 2 autoantibodies (IA-2Abs) and insulin autoantibodies (IAbs) are markers of type 1 diabetes mellitus (T1DM). We studied the prevalence of ZnT8Ab in children with autoimmune thyroid diseases (AITDs) to assess the association of AITDs and T1DM at the serological level. Methods The study groups consisted of 44 children with Graves' disease (GD), 65 children with Hashimoto's thyroiditis (HT), 199 children with T1DM with or without AITDs and 58 control children. ZnT8Ab, GADAb, IA-2Ab, IAb, 21-hydroxylase autoantibodies (21-OHAbs) and acetylcholine receptor autoantibodies (AChRAbs) were measured. Results ZnT8Abs were found in 4/44 (9.1%) patients with GD, and 4/44 (9.1%) patients with GD were positive for GADAb. Of the 65 HT patients, six (9.2%) were positive for ZnT8Ab, while four (6.2%) were positive for GADAb. In the T1DM group, 128/199 (64%) of the patients were positive for ZnT8Ab, 133/199 (67%) for GADAb and 109/199 (55%) for IA-2Ab. One GD patient and one HT patient were positive for all the four diabetes-associated autoantibodies. Two HT patients were positive for three diabetes autoantibodies. Two GD (4.5%) and five HT (7.7%) patients were positive for 21-OHAb only. None of the patients had AChRAb. In the control group, 2/58 (3.4%) were positive for GADAb and 2/58 (3.4%) were positive for ZnT8Ab. Conclusions Diabetes-associated autoantibodies including ZnT8Ab were found in children and adolescents with GD and HT.

Zinc transporter 8 autoantibodies (ZnT8-ab) are associated with higher prevalence of multiple diabetes-related autoantibodies in adults with type 1 diabetes.

AIM: The study aimed to assess the prevalence of zinc transporter 8 autoantibodies (ZnT8-ab), other diabetes-related autoantibodies and clinical manifestation of type 1 diabetes in adults, depending on age of the onset of disease. METHODS: 119 patients with type 1 diabetes, 66 at age <35 years (T1DM < 35) and 53 T1DM at age ≥35 years (T1DM ≥ 35). We assessed clinical features, GAD-ab, IA2-ab, ICA, ZnT8-ab and thyroid peroxidase antibodies (ATPO). RESULTS: In T1DM < 35 lower initial serum C-peptide concentration was observed and diabetes ketoacidosis (DKA) was more common. ATPO positivity was more prevalent in T1DM ≥ 35 (35.8 vs 21.2%, p = 0.04). The prevalence of GAD-ab, IA2-ab and ZnT8-ab was similar in both groups, the titres of IA2-ab and ICA were higher in T1DM < 35 but titre of ZnT8-ab was higher in T1DM ≥ 35. The majority of T1DM < 35 patients were positive for three autoantibodies (40.9%), while T1DM ≥ 35 subjects most often presented with only one (30.2%) antibody, most commonly GAD-ab (81.2%). 45% T1DM < 35 and 34% T1DM ≥ 35 subjects were positive for ZnT8-ab. ZnT8-ab positive patients had higher titre and more frequent occurrence of multiple diabetes-related autoantibodies than ZnT8-ab negative patients. CONCLUSIONS: Adults with T1DM < 35 and T1DM ≥ 35 differ in the severity of autoimmune response at diagnosis. ZnT8-ab positivity is related to higher titre and more frequent occurrence of multiple diabetes-related autoantibodies.

Could ZnT8 antibodies replace ICA, GAD, IA2 and insulin antibodies in the diagnosis of type 1 diabetes?

BACKGROUND: The zinc transporter 8 (ZnT8) is an islet ß-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. PATIENTS AND METHODS: 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. RESULTS: 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=122.25UI/mL versus males=51.38UI/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) CONCLUSION: 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.