Zinc Transporter 8 Autoantibodies Research Articles

Enzyme-linked immunosorbent assay of 3 Screen Islet Cell Autoantibody in patients with autoimmune thyroid disease.

In recent years, the emergence of multiplex technology that can simultaneously measure multiple anti-islet autoantibodies has become particularly valuable for the staging and early diagnosis of immune-mediated type 1 diabetes (T1D). While it has been established that 20%-30% of T1D patients suffer from autoimmune thyroid disease (AITD), there is limited available data regarding the presence of anti-islet autoantibodies in AITD patients. Among commercially available anti-islet autoantibodies, glutamic acid decarboxylase 65 autoantibodies (GADAs) are often the first marker measured in general clinical practice. To investigate the frequency of anti-islet autoantibodies in AITD patients. Our study involved four hundred ninety-five AITD patients, categorized into three distinct groups: AITD with T1D (n = 18), AITD with phenotypic type 2 diabetes (T2D) (n = 81), and AITD without diabetes (n = 396), and the enzyme-linked immunosorbent assay (ELISA) was employed to determine the frequencies of 3 Screen Islet Cell Autoantibody (3 Screen ICA), GADA, insulinoma-associated antigen-2 autoantibodies (IA-2As), and zinc transporter 8 autoantibodies (ZnT8As) within these groups. The frequency of 3 Screen ICA in AITD patients with T1D, T2D, and those without diabetes were 88.9%, 6.2%, and 5.1%, respectively, with no significant difference seen between the latter two groups. Notably, the frequency of 3 Screen ICA was 11.1% higher in AITD patients with T1D, 1.3% higher in AITD patients with T2D, and 1.1% higher in AITD patients without diabetes compared to GADA, respectively. Furthermore, 12.5%, 20.0%, and 20.0% of the 3 Screen ICA-positive patients were negative for GADA. Additionally, 1.3% of the AITD patients who tested negative for 3 Screen ICA in both the AITD with T2D and non-diabetic AITD groups were found to be positive for individual autoantibodies. Among the 3 Screen ICA-positive patients, there was a significantly higher proportion of individuals with multiple autoantibodies in AITD patients with T1D compared to those without diabetes (37.5% vs 5.0%, P < 0.05). However, this proportion was similar to that in AITD patients with T2D (20.0%). Nevertheless, there was no significant difference in 3 Screen ICA titers between AITD patients with T1D and those without diabetes (436.8 ± 66.4 vs 308.1 ± 66.4 index). Additionally, no significant difference in 3 Screen ICA titers was observed between Graves' disease and Hashimoto's thyroiditis in any of the groups. Our findings reveal that some AITD patients without diabetes exhibit 3 Screen ICA titers comparable to those in AITD patients with T1D. Thus, 3 Screen ICA outperforms GADA in identifying latent anti-islet autoantibody-positive individuals among AITD patients.

Prevalence, diagnostic utility, and clinical characteristics of ZnT8 antibody in children with type 1 diabetes in Northern Taiwan

BackgroundThe ZnT8 autoantibody is used to independently diagnose type 1 diabetes (T1D) and as a prediction factor in high-risk populations. This is the first report in Taiwan on the prevalence, diagnostic utility, and clinical characteristics of zinc transporter 8 autoantibody (ZnT8A) in children with T1D. MethodsWe performed a retrospective analysis of 268 children (130 boys, 138 girls) newly diagnosed with T1D at three hospitals in North Taiwan from February 1994 to August 2021. ResultsZnT8A was detected in 117 patients (43.7 %). The combined diagnostic rate of the four antibodies, including glutamic acid decarboxylase autoantibody (GADA), islet antigen 2 autoantibody (IA2A), insulin autoantibody (IAA), and ZnT8A, can reach 86.19 % while that of the original three antibodies is 84.3 %. IA2A (64.9 %) showed the highest positive rate, followed by GADA (64.2 %), ZnT8A (43.7 %), and IAA (22.0 %). Of the 268 patients, five (1.9 %) were only ZnT8A+. All antibodies were positive in 19 (7.1 %) people, whereas 37 others (13.8 %) had all antibodies negative. ZnT8A has the strongest relationship with IA2A. 5 patients had ZnT8A positive only. 5/(37 + 5) (about 12 %) T1D patients were diagnosed by ZnT8A testing. ConclusionsZnT8A testing can diagnose up to 12 % more patients with T1D along with three other antibodies. Furthermore, since the ZnT8A titer decreased over time, it should be tested within six months of onset in Taiwanese patients with T1D.

Potential Protective Effect of Anti-zinc Transporter 8 Autoantibodies on Gestational Diabetes Mellitus in Iraqi Population

Background: The human zinc transporter 8 (ZNT8), also known as the solute carrier family 30A, member 8 (SLC30A8), is a β-cell specific integral membrane protein, mainly restricted to the membrane of insulin secretory granules. ZnT8 plays a crucial role in both insulin synthesis and secretion as well as the viability of β-cells. The recently identified autoantibodies targeting the β-cell surface epitopes of ZnT8 have been proposed as a new risk factor for gestational diabetes mellitus (GDM). Due to the lack of prior research studies on the role of β-cell surface autoantibodies against ZnT8 in the immunologic etiology of GDM in Iraqi population, this study has been designed to explore the association between the rs13266634 C&gt;T polymorphism in the SLC30A8 gene and the serum levels of ZnT8 as well as Zinc Transporter-8 Autoantibody (ZnT8A) in women diagnosed with GDM. Methods: A total of 50 participants with GDM and 50 controls from the Baghdad Teaching Hospital/Pregnancy Care unit at the Medical City, Baghdad, Iraq, were recruited in this case–control study. Serum levels of ZnT8 and ZnT8A were assayed with enzyme-linked immunosorbent assay, and Taqman real time polymerase chain reaction (RT-PCR) was used for rs13266634 single nucleotide polymorphism (SNP) genotyping. Results: ZnT8A levels were significantly lower in women with GDM than non-GDM women (P ≤ 0.01). A ZnT8A level lower than 20.0 pg/mL was significantly associated with a threefold higher risk for GDM with P ≤ 0.001. ZnT8 levels were significantly higher in the GDM subjects (P ≤ 0.05). The T allele at the rs13266634 C&gt;T SNP significantly conferred a higher risk of GDM (P = 0.002). In view of that, the TT genotype, compared to the CC genotype, showed a significant association with increased GDM risk (P ≤ 0.01). Serum ZnT8A concentrations were significantly low among GDM women who had CT genotype (P = 0.003). Conclusion: The T variant at the SLC30A8 rs13266634 C&gt;T polymorphism appears to play a key role in determining the β-cell autoimmunity by inducing an autoantibody response due to its hyperactivity of zinc transportation.

A novel, high-performance, low-volume, rapid luciferase immunoprecipitation system (LIPS) assay to detect autoantibodies to zinc transporter 8.

Zinc transporter 8 autoantibodies (ZnT8A) are thought to appear close to type 1 diabetes (T1D) onset and can identify high-risk multiple (≥2) autoantibody positive individuals. Radiobinding assays (RBA) are widely used for ZnT8A measurement but have limited sustainability. We sought to develop a novel, high-performance, non-radioactive luciferase immunoprecipitation system (LIPS) assay to replace RBA. A custom dual C-terminal ZnT8 (aa268-369; R325/W325) heterodimeric antigen, tagged with a NanoluciferaseTM (Nluc-ZnT8) reporter, and LIPS assay was developed. Assay performance was evaluated by testing sera from new onset T1D (n = 573), healthy schoolchildren (n = 521), and selected first-degree relatives (FDRs) from the Bart's Oxford family study (n = 617; 164 progressed to diabetes). In new-onset T1D, ZnT8A levels by LIPS strongly correlated with RBA (Spearman's r = 0.89; P < 0.0001), and positivity was highly concordant (94.3%). At a high specificity (95%), LIPS and RBA had comparable assay performance [LIPS pROC-AUC(95) 0.032 (95% CI: 0.029-0.036); RBA pROC-AUC(95) 0.031 (95% CI: 0.028-0.034); P = 0.376]. Overall, FDRs found positive by LIPS or RBA had a comparable 20-year diabetes risk (52.6% and 59.7%, respectively), but LIPS positivity further stratified T1D risk in FDRs positive for at least one other islet autoantibody detected by RBA (P = 0.0346). This novel, high-performance, cheaper, quicker, higher throughput, low blood volume Nluc-ZnT8 LIPS assay is a safe, non-radioactive alternative to RBA with enhanced sensitivity and ability to discriminate T1D progressors. This method offers an advanced approach to current strategies to screen the general population for T1D risk for immunotherapy trials and to reduce rates of diabetic ketoacidosis at diagnosis.

The expression of GADA, ZnT8A and IA-2A in patients with type 1 diabetes mellitus with thyroid disease and their correlation with thyroid autoantibodies.

The aim of this research was to study the expression of anti-glutamate decarboxylase antibody (GADA), zinc transporter-8 autoantibody (ZnT8A), and insulinoma-associated protein-2 antibody (IA-2A) in patients with type 1 diabetes (T1DM) with thyroid disease (TD) and its correlation with thyroid autoantibodies. 380 patients with T1DM were included in the study, of which 313 patients with T1DM alone were included in the control group. In the TD group, 41 patients with T1DM and Hashimoto's thyroiditis (HT) were included, and 26 cases of T1DM patients with Graves' disease were included in the Graves group. The clinical features of the control group, the HT group, and the Graves group were compared. The positive rates of insulin autoantibodies in the control group and the TD group were analyzed. The clinical characteristics of patients with and without insulin autoantibody positivity were compared. The positive rates of thyroid autoantibodies in T1DM patients with positive GADA, ZnT8A, IA-2A, and different numbers of positive insulin autoantibodies were analyzed. The levels of total cholesterol (TC) and thyroid stimulating hormone (TSH) in the HT group were significantly higher than those in the control and Graves groups, and the levels of free thyroid hormone (FT4) and low-density lipoprotein cholesterol (LDL-C) were significantly lower than those in the control and Graves groups (p<0.001). The levels of TC and TSH in the Graves group were significantly lower than those in the control group, the levels of HbA1c, LDL-C, and FT4 were significantly higher than those in the control group, and the levels of FT3 were significantly higher than those in the control and HT groups (p<0.001). The levels of C peptide, triglyceride (TG), and LDL-C of insulin autoantibodies positive patients were significantly lower than those of negative patients (p<0.05). The positive rates of GADA, ZnT8A, and IA-2A in the TD group, as well as the positive rates of double antibodies and triple antibodies, were significantly higher than those of the control group (p<0.05). In T1DM patients, the positive rates of thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) in GADA and IA-2A-positive patients were significantly higher than those in GADA and IA-2A-negative patients (p<0.05). The positive rate of TPOAb in ZnT8A-positive patients was significantly higher than that in ZnT8A-negative patients (p<0.05). The positive rates of TRAb, TPOAb, and TGAb in T1DM patients positive for two of the three insulin autoantibodies and three insulin autoantibodies were significantly higher than those positive for one of the three insulin autoantibodies (p<0.001). TD can exacerbate the disorder of glucose and lipid metabolism in patients with T1DM, and multiple insulin autoantibodies positive T1DM patients it is more likely to have thyroid autoantibody positivity. It is suggested that patients with aggravated glucose and lipid metabolism and multiple insulin autoantibody positivity should be routinely screened for thyroid antibodies to help early diagnosis of TD.

Relationship between β-Cell Autoantibodies and Their Combination with Anthropometric and Metabolic Components and Microvascular Complications in Latent Autoimmune Diabetes in Adults.

Our study aimed to investigate the relationship between three autoantibodies and their combination with anthropometric and metabolic components and microvascular complications in patients with latent autoimmune diabetes in adults (LADA). Our study included 189 LADA patients divided into four subgroups according to the autoantibodies present: glutamic acid decarboxylase autoantibodies (GADA) only; zinc transporter-8 autoantibodies (ZnT8A)+GADA; insulinoma-associated-2 autoantibodies (IA-2)+GADA; and ZnT8+IA-2+GADA. Compared to GADA positivity only, patients with ZnT8+GADA positivity and ZnT8+IA-2+GADA positivity had a shorter diabetes duration and lower body mass index (BMI); patients with ZnT8+GADA positivity were younger and showed an increase in glomerular filtration rate, while those with ZnT8+IA-2+GADA positivity had lower C-peptide and lower insulin resistance measured with HOMA2-IR. In a multiple regression analysis, ZnT8 positivity was associated with lower BMI (p = 0.0024), female sex (p = 0.0005), and shorter duration of disease (p = 0.0034), while IA-2 positivity was associated with lower C-peptide levels (p = 0.0034) and shorter diabetes duration (p = 0.02). No association between antibody positivity and microvascular complications of diabetes, including retinopathy, neuropathy, and microalbuminuria, as well as with variables of glucose control and β-cell function were found. The results of our study suggest that ZnT8 and IA-2 autoantibodies are present in a significant number of LADA patients and associated with clinical and metabolic characteristics resembling classic type 1 diabetes. Due to increased LADA prevalence, earlier identification of patients requiring frequent monitoring with the earlier intensification of insulin therapy might be of special clinical interest.

Study of the diagnostic efficiency of anti-ZnT8 autoantibodies for type 1 diabetes in pediatric patients.

Zinc transporter 8 autoantibodies (ZNt8A) are 1 of the 4 main autoantibodies used for the diagnosis of type 1 diabetes (T1D), with glutamic acid decarboxylase autoantibodies (GADA), islet antigen-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA). The objective of this study is to evaluate the diagnostic efficiency of these autoantibodies for the diagnosis of T1D in pediatric patients. A retrospective analysis of patients under 16 years of age with suspected T1D was made between June 2020 and January 2021. A total of 80 patients were included in the study, with 1 sample per patient. Subjects were classified according to diagnosis. Of the subjects included in the study, 50 developed T1D. The diagnostic efficacy was IA-2A (cutoff ≥ 28 U/L) sensitivity 0.26 (95% CI: 0.14-0.38) and specificity 0.97 (95% CI: 0.79-1.0); GADA (cutoff ≥ 17 U/mL) sensitivity 0.40 (95% CI: 0.26-0.54) and specificity 0.87 (95% CI: 0.75-0.99); ZnT8A (cut off ≥ 15 U/L) sensitivity 0.62 (95% CI: 0.49-0.75) and specificity 0.97 (95% CI: 0.90-1.0). ZnT8A obtained the most significantly global diagnostic accuracy (0.75), and GADA with ZnT8A showed the highest correlation. The results obtained indicate a higher efficiency of anti-ZnT8 autoantibodies for the diagnosis of T1D in pediatric patients. Clinical efficiency of diabetic autoantibodies is method and assay dependent and influences combined diagnostic strategies.

1298-P: Independent Associations of GAD65, IA2, and ZnT8 Autoantibody (Ab) Positivity with C-Peptide (CPep) in a Diverse Cohort of Youth with Diabetes (DM)

The current DM classification does not fully enable precision medicine in DM due to heterogeneity between and within DM types, especially in racially diverse populations. Insulin deficiency (ID) is one of the most clinically actionable DM outcomes and, while its association with islet autoimmunity is known, the influence of Ab type and number after DM onset is uncertain. Thus, we assessed the effect of Ab characteristics on ID (measured as Cpep loss) in youth with established DM. We studied 151 youth with DM (median [IQR] age 15.0 [4.2] yrs, DM duration 5.4 [3.4] yrs), 61% female, 53% Hispanic and 17% non-Hispanic African American. We measured postprandial serum Cpep, glucose and Ab (GAD65, IA2 and ZnT8) and collected clinical/demographic data. Cpep loss was pre-specified as postprandial CPep &amp;lt;0.6 ng/ml. We found 0, 1, 2, or 3 +Ab in 34%, 22%, 31% and 13% of participants, respectively (Figure, left panel). A Breslow-Day statistic suggested homogeneity of the risk ratios across the 3 Ab types for CPep loss (p = 0.42), which were all larger than 1 (Figure, right panel). Cpep loss was significantly associated with ≥1 (vs 0) Ab+ (p &amp;lt; 0.0001) but not with single (vs multiple) Ab+ (p = 0.60). In sum, each of GAD65, IA2 and ZnT8 Ab are significantly associated with ID among diverse youth with DM. This suggests that models predicting ID post-onset should include each of GAD65, IA2 and ZnT8 Ab. Disclosure M.J.Redondo: None. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. D.Dabelea: None. W.Hagopian: Research Support; Janssen Research &amp; Development, LLC, Provention Bio, Inc., Randox R &amp; D. Discover study group: n/a. K.K.Harrall: None. D.H.Glueck: None. M.Tosur: Advisory Panel; Provention Bio, Inc. S.Uysal: None. A.Muir: None. K.Vehik: None. T.M.Brusko: Consultant; Repertoire Immune Medicines, Quell Therapeutics, Research Support; Immunocore, Ltd., Adaptive Biotechnologies. M.A.Atkinson: None. Funding National Institutes of Health (R01DK124395)

Islet Autoantibodies to Pancreatic Insulin-Producing Beta Cells in Adolescent and Adults with Type 1 Diabetes Mellitus: A Cross-Sectional Study.

(1) Background: Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease caused by the destruction of pancreatic insulin-producing beta cells. T1D is one of the most common endocrine and metabolic disorders occurring in children. Autoantibodies against pancreatic insulin-producing beta cells are important immunological and serological markers of T1D. Zinc transporter 8 autoantibody (ZnT8) is a recently identified autoantibody in T1D; however, no data on ZnT8 autoantibody in the Saudi Arabian population have been reported. Thus, we aimed to investigate the prevalence of islet autoantibodies (IA-2 and ZnT8) in adolescents and adults with T1D according to age and disease duration. (2) Methods: In total, 270 patients were enrolled in this cross-sectional study. After meeting the study's inclusion and exclusion criteria, 108 patients with T1D (50 men and 58 women) were assessed for T1D autoantibody levels. Serum ZnT8 and IA-2 autoantibodies were measured using commercial enzyme-linked immunosorbent assay kits. (3) Results: IA-2 and ZnT8 autoantibodies were present in 67.6% and 54.6% of patients with T1D, respectively. Autoantibody positivity was found in 79.6% of the patients with T1D. Both the IA-2 and ZnT8 autoantibodies were frequently observed in adolescents. The prevalence of IA-2 and ZnT8 autoantibodies in patients with a disease duration < 1 year was 100% and 62.5%, respectively, which declined with an increase in disease duration (p < 0.020). Logistic regression analysis revealed a significant relationship between age and autoantibodies (p < 0.004). (4) Conclusions: The prevalence of IA-2 and ZnT8 autoantibodies in the Saudi Arabian T1D population appears to be higher in adolescents. The current study also showed that the prevalence of autoantibodies decreased with disease duration and age. IA-2 and ZnT8 autoantibodies are important immunological and serological markers for T1D diagnosis in the Saudi Arabian population.

Comparison of positive rates between glutamic acid decarboxylase antibodies and ElisaRSR™ 3 Screen ICA™ in recently obtained sera from patients who had been previously diagnosed with slowly progressive type 1 diabetes.

This study aimed to compare the positivity rates of glutamic acid decarboxylase autoantibodies (GADA) and ElisaRSR™ 3 Screen ICA™ (3 Screen ICA), a newly developed assay for the simultaneous measurement of GADA, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter 8 autoantibodies (ZnT8A), in recently obtained sera from patients who had been previously diagnosed with slowly progressive type 1 diabetes (SPIDDM). We enrolled 53 patients with SPIDDM who were positive for GADA at the diagnosis and 98 non-diabetic individuals, and investigated the diagnostic accuracy of the 3 Screen ICA (cutoff index ≥30 units) compared with that of GADA. In addition, we compared the clinical characteristics of patients with SPIDDM who were negative or positive on 3 Screen ICA. The positivity rates of 3 Screen ICA, GADA, IA-2A, and ZnT8A were 88.7, 86.8, 24.5, and 13.2%, respectively. The respective sensitivity, specificity, and positive and negative predictive values for SPIDDM were 88.7, 100, 100, and 94.2% by 3 Screen ICA and 86.8, 100, 100.0, and 93.3% by GADA. There were no significant differences in age at onset, duration of diabetes, body mass index, glycated hemoglobin and C-peptide levels, and the prevalence of autoimmune thyroiditis between patients with SPIDDM who were positive or negative on 3 Screen ICA. However, the prevalence of insulin users was significantly higher in those who were positive than in those who were negative on 3 Screen ICA. Similar to GADA, 3 Screen ICA may be a useful diagnostic tool for detecting patients with SPIDDM.

The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes

Aims/hypothesisThe reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.MethodsWe analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.ResultsThe T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).Conclusions/interpretationThe inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.Graphical abstract

PSUN261 Diabetic Ketoacidosis Complicating Gestational Diabetes Mellitus: A Case Report

Abstract Diabetic ketoacidosis (DKA) in pregnancy is a rare but serious medical emergency. Its incidence ranges between 0.2%-9% and carries a fetal mortality rate up to 90%. DKA remains to be an extremely rare complication of gestational diabetes (GDM). Early diagnosis and management may be delayed due to its atypical presentation. We present a case of DKA in GDM with no pre-existing diagnosis of type 1 diabetes (T1DM) or type 2 diabetes (T2DM). A 33-year-old African American woman G2P0010 with GDM on insulin diagnosed in current pregnancy, presented at 30-weeks of gestation with a 3-day history of general malaise, altered mentation, and emesis. Severe DKA (blood glucose 920 mg/dL, pH 7.02, anion gap 38, bicarbonate 5.0 mEq/L, and positive serum ketones), systemic inflammatory response syndrome (tachycardia, WBC of 24,000/mcL), and intrauterine fetal demise via ultrasound were determined upon presentation. MICU admission for prompt and vigorous medical management with intravenous fluid resuscitation, insulin and bicarbonate infusions, and broad-spectrum antibiotic therapy was required. Clinical course was complicated by worsening hypokalemia. Spontaneous vaginal delivery of a non-viable fetus occurred at the MICU. After delivery, resolution of DKA was achieved. Once the patient's mentation was back to her baseline, she admitted complete cessation of insulin 1-week prior to admission. Workup revealed negative glutamic acid decarboxylase, islet cell, and zinc transporter-8 autoantibodies in addition to normal C-peptide levels. A new HbA1C of 9% compared to HbA1C of 5.5% at 6 weeks of gestation, made pre-existing T2DM unlikely. Eventually, the patient was downgraded to the medicine wards for continuity of care. DKA in pregnancy is a rare complication typically associated with T1DM. It may occur at near-normal blood glucose levels, known as euglycemic DKA, causing a delay in diagnosis. Physiologic changes during the last trimester of gestation explain the higher incidence of DKA at this stage. These include the relative state of insulin resistance, which in addition to insulin-antagonistic hormones such as human placental lactogen, prolactin, cortisol, and progesterone contribute to this state. Furthermore, a relative accelerated state of starvation with an increase in maternal ketone body formation, and a reduction in the buffering capacity when exposed to ketonemia places gravida women with impaired glucose tolerance at higher risk to develop DKA. Fetal loss may result from reduced uteroplacental perfusion and fetal hypokalemia leading to fatal arrhythmia. The most common precipitating factors of DKA in pregnancy are infection, including COVID-19, insulin therapy non-adherence, steroid use, dehydration, and unrecognized new-onset diabetes which accounts for up to 30% of cases. It has been described that a genetic polymorphism in SLC26A6 gene may increase the susceptibility to develop DKA in GDM. Prevention, early diagnosis, and vigorous medical management of DKA in pregnancy may possibly reduce maternal and fetal mortality. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

HERV-K Envelope Protein Induces Long-Lasting Production of Autoantibodies in T1DM Patients at Onset in Comparison to ZNT8 Autoantibodies.

Human endogenous retroviruses (HERVs) have been thought of as silent passengers within our genomes, but their reactivation has been linked with several autoimmune diseases, including type 1 diabetes (T1DM). In order to evaluate the potential role of HERVs, in addition to the recognized role of HERV-W, we focused on the debated role of the HERV-K family in T1DM. Therefore, we performed a serological evaluation of IgG antibodies against HERV-K Env epitope (HERV-K Env19–37) in comparison to an important β-cellular autoimmunity biomarker, ZnT8, from plasma samples of Sardinian children at the onset of T1DM, different T1DM groups (1–5 and 6–12 years since diagnosis), and healthy controls (HCs), by an indirect enzyme-linked immunosorbent assay (ELISA). A significant antibody response was observed against HERV-K Env19–37 (p < 0.0001) in T1DM patients compared to HCs, and significantly higher IgG responses were detected in the group at the onset compared to the other T1DM groups and HCs. Unlike the trend of the β-cellular autoimmunity autoantibodies, for HERV-K Env antibodies we observed positive values that persist over time up to 5 years since the onset of T1DM. Our results add new evidence about the presence of antibodies against HERV-K in T1DM, but further investigations are necessary to relate these results with the established role of HERVs, considering the contrasting results for HERV-K.

Characteristic of CTLA-A49G Gene Polymorphism and ZnT-8 autoantibody in Indonesian Children with T1DM

Characteristic of CTLA-A49G Gene Polymorphism and ZnT-8 autoantibody in Indonesian Children with T1DM

Characteristic of CTLA-A49G Gene Polymorphism and ZnT-8 autoantibody in Indonesian Children with T1DM

Characteristic of CTLA-A49G Gene Polymorphism and ZnT-8 autoantibody in Indonesian Children with T1DM

1251-P: Aß Classification Defines Four Distinct Forms of Diabetes in Children

A comprehensive classification accounting for the heterogeneity of pediatric diabetes is lacking. The Aβ classification system, based on islet autoantibody status (A+ or A-) and preserved beta-cell functional reserve (β+ or β-) , was used successfully to define variable phenotypes in adults with Ketosis-prone Diabetes. We set out to investigate the utility of the Aβ classification system in children with new-onset diabetes. “A+” was defined as the presence of ≥1 islet autoantibodies (GAD65, ICA512, insulin or ZnT8 autoantibodies) and "β+" as random C-peptide level ≥0.6 ng/mL at diagnosis. We calculated T1D genetic risk score 2 (T1D GRS2) for each participant, and compared clinical characteristics at diabetes onset and T1D GRS2 between the groups. The study cohort (n=76) was 50% female, 29% non-Hispanic white, 46% Hispanic, 22% non-Hispanic black, and 3% Other. The mean age was 11.7 years and the mean BMI was 58.3%ile. Aβ classification at diagnosis defined the following groups: A+β- (34%) , A+β+ (30%) , A-β+ (33%) and A-β+ (3%) . Results are summarized in Table 1. The Aβ classification system defines phenotypically and genetically distinct diabetes groups in children with new-onset diabetes. This classification system may be useful in clinical settings as well as the design of clinical trials. Disclosure M.Tosur: Advisory Panel; Provention Bio, Inc. S.Deen: None. S.Uysal: n/a. M.Astudillo: None. F.Jahoor: None. W.Hagopian: Research Support; Janssen Research &amp; Development, LLC. R.A.Oram: Consultant; Janssen Research &amp; Development, LLC, Research Support; Randox R &amp; D. M.J.Redondo: Advisory Panel; Provention Bio, Inc. A.Balasubramanyam: None. Funding Texas Children's Pilot Award

1235-P: A Prospective Characterization of Metabolic and Metabolomic Profiles of COVID-19–Associated New-Onset Diabetes Patients Presenting with DKA from India

Background: Recent evidence suggests a bidirectional relationship between COVID-infection and new-onset diabetes (NOD) presenting with DKA. Methodology: This one-year prospective study comprised of 29 COVID-negative DKA (controls) and 52 COVID-positive-DKA patients (18 NOD, 15 T1DM ,T2DM) . NOD were previously normoglycemic and negative for GAD/IA-2/ZnT8 autoantibodies. After 75g- OGTT with estimation of glucose, C-peptide, FFA and insulin at 0,15, 30,45, 60,90 ,120, 150 and 180minutes, Insulin secretion rate (ISR) [C-peptide-deconvolution] , Hepatic insulin sensitivity [AUC-glucose × AUC-insulin during first 30-minutes of OGTT ], Peripheral insulin sensitivity [ dG/dt ÷ mean plasma insulin concentration; dG/dt rate of decline in plasma glucose concentration]were calculated alongwith Metabolomics and Adipose tissue gene expression. All tests were performed at admission and 4, 8, and 12-months of followup. Results: At baseline, ISR in NOD was significantly reduced than controls (p=0.001) but similar to T1DM (p=0.15) . Nearly 83% (n=17) of NOD with DKA had near-complete recovery of ISR on follow-up compared to T1DM (all p&amp;lt;0.01) ,with non-remitters (n=3) having significantly worse admission Hba1c and IL-6 (all p&amp;lt;0.01) . NOD had significantly increased hepatic and peripheral insulin resistance compared to T1DM (all p&amp;lt;0.05) ,but similar to T2DM (all p&amp;gt;0.05) . Their Metabolomics revealed increased inflammatory phosphatidylcholines, that correlated with peripheral glucose uptake (p&amp;lt;0.01) ,while RNA sequencing showed significantly enhanced WNT5A , TLR4 (Toll-like Receptor-4) and RETN (resistin) than T1DM and T2DM (both p=0.001) . Conclusion: Our study provides novel insights into COVID-associated NOD with DKA. Majority have near-complete recovery of insulin secretion while simultaneous multi-tissue insulin resistance and inflammatory adipose tissue profiles persist as drivers of hyperglycemia . Disclosure R.Dasgupta: None. S.Mondal: None. R.Garai: None. B.Chowdhury: None. A.Hazra: None. M.Lodh: None. A.Ganguly: None.

ZnT8 autoantibody prevalence is low in youth with type 2 diabetes and associated with higher insulin sensitivity, lower insulin secretion, and lower disposition index

AimZnT8 autoantibody positivity (ZnT8+) is associated with risk for type 1 diabetes and with metabolic complications in adults. Our aim was to assess prevalence of ZnT8 + in the Treatment of T2D in Adolescents and Youth (TODAY) cohort and describe associated phenotypic outcomes. MethodsTODAY participants were 13.98 ± 2.03 years with a confirmed diagnosis of T2D, BMI percentile of 97.69 ± 3.32 (64% female), and GAD- and IA2- at baseline. ZnT8 autoantibodies were measured at baseline and end of study. Results3 of 687 participants (0.29%) were ZnT8 + and there was one conversion (0.15%) from ZnT8- to ZnT8 + during the study. ZnT8A + individuals had higher HbA1c, HDL and LDL cholesterol, and IL-1β concentrations, and lower BMI, IL-6, and triglyceride concentrations compared to the TODAY cohort and ZnT8A- individuals. They also had higher insulin sensitivity with lower insulin secretion and disposition index, metabolically resembling T1D. All ZnT8 + participants experienced loss of glycemic control on randomized treatment, but exhibited lower rates of diabetic complications than other groups. ConclusionGiven the low rate of complications in ZnT8 + individuals, ZnT8 likely does not impact the clinical course of the disease in this population.

Improved diagnosis of type-1 diabetes mellitus using multiplexed autoantibodies ELISA array

Autoantibodies are currently the most robust biomarkers of type 1 diabetes. However, single autoantibody targeted detection is still limited in diabetes diagnosis with poor performance. Here, we develop a multiplexed Array-ELISA assay that can detect five diabetes-related autoantibodies including glutamic acid decarboxylase antibody (GADA), insulinoma antigen 2 antibody (IA-2A), islet cell antibody (ICA), zinc transporter 8 autoantibody (ZnT8-A) and insulin antibody (IAA) simultaneously. This assay achieved 100% accuracy in identifying the positive and negative control samples with good repeatability (CV<15%). We applied the Array-ELISA assay to 140 clinical serum samples of healthy subjects and diabetes patients and the assay showed improved diagnosis accuracy (sensitivity of 62.5%, specificity of 94.3%) compared with the single target immunoblotting test. These data suggest that the Array-ELISA assay can provide diagnostic and predictive ability in the clinical practice of type 1 diabetes.

Epidemiology and phenotypes of diabetes in children and adolescents in non-European-origin populations in or from Western Pacific region.

BACKGROUNDType 1 diabetes (T1D) incidence varies substantially between countries/ territories, with most studies indicating increasing incidence. In Western Pacific region (WPR), reported rates are much lower than European-origin populations. In contrast, there are reports of substantial numbers of young people with type 2 diabetes (T2D). A deeper understanding of T1D and T2D in the WPR may illuminate factors important in pathogenesis of these conditions. Furthermore, with varying resources and funding for diabetes treatment in this region, there is a need to more clearly determine the current burden of disease and also any gaps in knowledge.AIMTo compile and summarise published epidemiologic and phenotypic data on childhood diabetes in non-European populations in and from WPR.METHODSResearch articles were systematically searched from PubMed (MEDLINE), Embase, Cochrane library, and gray literature. Primary outcome measures were incidence and prevalence, with secondary measures including phenotypic descriptions of diabetes, including diabetes type categorization, presence of diabetic ketoacidosis (DKA) at onset, autoantibody positivity, C-peptide levels, and human leucocyte antigen phenotype. Extracted data were collected using a customized template. Three hundred and thirty relevant records were identified from 16 countries/territories, with analysis conducted on 265 (80.3%) records published from the year 2000.RESULTST1D incidence ranged from < 1-7.3/100000 individuals/year, rates were highest in emigrant/ mixed populations and lowest in South-East Asia, with most countries/territories (71.4%) having no data since 1999. Incidence was increasing in all six countries/territories with data (annual increases 0.5%-14.2%, highest in China). Peak age-of-onset was 10-14 years, with a female case excess. Rate of DKA at onset varied from 19.3%-70%. Pancreatic autoantibodies at diagnosis were similar to European-origin populations, with glutamic acid decarboxylase-65 autoantibody frequency of 44.1%-64.5%, insulinoma-associated 2 autoantibody 43.5%-70.7%, and zinc transporter-8 autoantibody frequency 54.3% (one study). Fulminant T1D also occurs. T2D was not uncommon, with incidence in Japan and one Chinese study exceeding T1D rates. Monogenic forms also occurred in a number of countries.CONCLUSIONT1D is less common, but generally has a classic phenotype. Some countries/ territories have rapidly increasing incidence. T2D is relatively common. Registries and studies are needed to fill many information gaps.