Glutamic Acid Decarboxylase 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.

Type 1 Diabetes Mellitus And Its Complications In Children Aged ≤20 Years From Punjab, Pakistan

Background — Type 1 diabetes mellitus causes serious disease complication in children. Objectives- The main objective of this study was to assess the frequency and severity of diabetic complication in children ≤ 20 years of age from Punjab, Pakistan. Methods — The data of diabetic patients and their blood samples were collected from the diabetic registries at three districts of Punjab, Pakistan. Fasting plasma glucose, random plasma glucose, HbA1c, and GAD-65 autoantibodies were measured in sampled blood serum. The data on other clinical symptoms at the onset of disease were recorded as well. Results — Out of 310 patients, 54.2% were male, and their mean age at the onset of disease was 13.22 years. Among all patients, according to clinical indicators, high severity of the disease and serious complications were revealed. Conclusions — The diabetic complications were severe in all patients from three districts of Punjab, Pakistan, at and below the age of 20 years.

Elevated Serum IgA at Onset of Type 1 Diabetes in Children

Background. Elevated serum IgA levels have been observed in various autoimmune conditions, including type 1 diabetes (T1D). However, whether children with T1D and elevated serum IgA have unique features has not been studied. We aimed to evaluate the prevalence and characteristics associated with elevated serum IgA at the onset of pediatric T1D. Materials and Methods. We analyzed demographic, clinical, and laboratory data retrospectively collected from 631 racially diverse children (6 months–18 years of age) with T1D who had serum IgA levels measured within 90 days of T1D diagnosis. Univariable and multivariable logistic regression models were used to identify characteristics that were significantly associated with elevated versus normal IgA. Results. Elevated serum IgA was present in 20.3% (128/631) of the children with newly diagnosed T1D. After adjusting for other variables, A1c level (p=0.029), positive insulin autoantibodies (IAA) (p=0.041), negative glutamic acid decarboxylase autoantibodies (GADA) (p=0.005) and Hispanic ethnicity (p &lt;0.001) were significantly associated with elevated serum IgA. After adjustment for confounders, the odds of elevated serum IgA were significantly increased with positive IAA (OR 1.653, 95% CI 1.019–2.679), higher HbA1c (OR 1.132, 95% CI 1.014–1.268) and Hispanic ethnicity (OR 3.279, 95% CI 2.003–5.359) but decreased with GADA positivity (OR 0.474, 95% CI 0.281–0.805). Conclusions. Elevated serum IgA is present in 20.3% of the children at T1D onset and is associated with specific demographic and clinical characteristics, suggesting a unique pathogenesis in a subset of individuals. Further studies are warranted to investigate the IgA response, its role in T1D pathogenesis, and whether these associations persist over time.

Detection of Islet Autoantibodies in Whole Blood by Antibody Detection by Agglutination-PCR (ADAP) Technology Is Sensitive and Suitable for General Population Screening Programs

Background. Detection of type 1 diabetes (T1D) at the preclinical stage is possible by detecting islet autoantibodies (IAs) years before the appearance of symptomatic diabetes. The Antibody Detection Israeli Research is a general population screening program searching for children with multiple IAs who are at risk of developing T1D. IAs are measured in capillary or venous whole blood (WB) samples using the novel ultrasensitive antibody detection by agglutination-PCR (ADAP) technology. Objective. To assess the accuracy and reliability of the ADAP assay in venous and capillary WB. Materials and Methods. In total, 50 children with T1D and 50 healthy controls participated in the study. Venous and capillary blood samples were drawn from participants with T1D, while only venous blood was drawn from the controls. The ADAP assay in venous and capillary blood was compared to the currently used assays in their ability to detect glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), and insulin autoantibodies (IAAs). Results. The area under the curve using the receiver operating characteristic curves was comparable between the ADAP assay in WB and standard enzyme-linked immunosorbent assay (ELISA)/radioimmunoassay (RIA) for all three IAs GADA 0.946 (95% CI: 0.900–0.991) vs. 0.949 (0.906–0.992), P=0.873; IA-2A 0.747 (0.649–0.844) vs. 0.666 (0.587–0.744), P=0.106; IAA 1.000 (1.000–1.000) vs. 1.000 (1.000–1.000), P=1.000. The correlation between the levels of IA in venous and capillary WB using ADAP was R2 = 0.958 (P &lt;0.01), R2 = 0.943 (P &lt;0.01), and R2 = 0.711 (P &lt;0.01) for GADA, IA-2A, and IAA, respectively. IA levels in venous and capillary WB using ADAP were comparable without a proportional bias in Bland–Altman’s plots of agreement, suggesting the two methods may be used interchangeably. Conclusions. The ADAP assay is reliable in detecting IA in venous and capillary WB samples with comparable performance to standard RIA and ELISA. These findings open avenues for widespread use of the ADAP assay in future general population screening programs to detect children at risk of developing T1D.

Prediction of future insulin-deficiency in glutamic acid decarboxylase autoantibody enzyme-linked immunosorbent assay-positive patients with slowly-progressive type 1 diabetes.

This study aimed to identify risk factors that contribute to the progression of slowly-progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin-dependent state. We selected 60 slowly-progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) techniques. Compared with the non-progressor group (fasting C-peptide [F-CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F-CPR levels and a higher prevalence of insulinoma-associated antigen-2 autoantibodies (IA-2A). The PPV of RIA-GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2 , F-CPR <1.41 ng/mL and IA-2A positivity, respectively. In contrast, the PPV of ELISA-GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F-CPR level, respectively. Our findings show that, unlike RIA-GADA, ELISA-GADA shows no association between GADA titers and the risk of progression to an insulin-dependent state. The PPV improves when age at diagnosis, BMI and F-CPR levels are considered in combination.

Preserved C-peptide is common and associated with higher time in range in Chinese type 1 diabetes.

The aim of this study is to determine the residual C-peptide level and to explore the clinical significance of preserved C-peptide secretion in glycemic control in Chinese individuals with type 1 diabetes (T1D). A total of 534 participants with T1D were enrolled and divided into two groups, low-C-peptide group (fasting C-peptide ≤10 pmol/L) and preserved-C-peptide group (fasting C-peptide >10 pmol/L), and clinical factors were compared between the two groups. In 174 participants who were followed, factors associated with C-peptide loss were also identified by Cox regression. In addition, glucose metrics derived from intermittently scanned continuous glucose monitoring were compared between individuals with low C-peptide and those with preserved C-peptide in 178 participants. The lack of preserved C-peptide was associated with longer diabetes duration, glutamic acid decarboxylase autoantibody, and higher daily insulin doses, after adjustment {OR, 1.10 [interquartile range (IQR), 1.06-1.14]; OR, 0.46 (IQR, 0.27-0.77); OR, 1.04 (IQR, 1.02-1.06)}. In the longitudinal analysis, the percentages of individuals with preserved C-peptide were 71.4%, 56.8%, 71.7%, 62.5%, and 22.2% over 5 years of follow-up. Preserved C-peptide was also associated with higher time in range after adjustment of diabetes duration [62.4 (IQR, 47.3-76.6) vs. 50.3 (IQR, 36.2-63.0) %, adjusted P = 0.003]. Our results indicate that a high proportion of Chinese patients with T1D had preserved C-peptide secretion. Meanwhile, residual C-peptide was associated with favorable glycemic control, suggesting the importance of research on adjunctive therapy to maintain β-cell function in T1D.

Investigation of Monogenic Diabetes Genes in Thai Children with Autoantibody Negative Diabetes Requiring Insulin.

The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin. Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES). All participants were ten men and twenty women. The median age to onset of diabetes was 8 years and 3 months. A total of 20 people with monogenic diabetes carried genes related to monogenic diabetes. The PAX4 (rs2233580) in ten patients with monogenic diabetes was found. Seven variants of WFS1 (Val412Ala, Glu737Lys, Gly576Ser, Cys673Tyr, Arg456His, Lys424Glu, and Gly736fs) were investigated in patients in this study. Furthermore, the pathogenic variant, rs115099192 (Pro407Gln) in the GATA4 gene was found. Most patients who carried PAX4 (c.575G>A, rs2233580) did not have a history of DKA. The pathogenic variant GATA4 variant (c.1220C>A, rs115099192) was found in a patient with a history of DKA. This study demonstrated significant genetic overlap between autoantibody-negative diabetes and monogenic diabetes using WES. All candidate variants were considered disease risk with clinically significant variants. WES screening was the first implemented to diagnose monogenic diabetes in Thai children, and fourteen novel variants were identified in this study and need to be investigated in the future.

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.

Autoantibodies predict type 1 diabetes after gestational diabetes - a 23-year cohort study.

To study the predictive value of autoantibodies for type 1 (T1DM) and type 2 (T2DM) diabetes morbidity after gestational diabetes (GDM) in a 23-year follow-up study. Prospective population-based cohort study. We studied 391 women with GDM, and 391 age- and parity-matched controls, who delivered in 1984-1994. Four autoantibodies were analysed in first-trimester blood samples: islet cell autoantibodies (ICAs), glutamic acid decarboxylase autoantibodies (GADAs), insulin autoantibodies (IAAs) and insulinoma-associated antigen-2 autoantibodies (IA-2As). Two follow-up questionnaires (1995-1996, 2012-2013) were sent to assess development of T1DM and T2DM. Predictive value of autoantibodies and clinical factors were analysed by conditional linear regression and ROC analyses. Single autoantibody positivity was detected in 12% (41/342) of the GDM cohort and in 2.3% (8/353) of the control cohort. In the GDM cohort, 2.6% (9/342) tested positive for two autoantibodies and 2.3% (8/342) for three autoantibodies, whereas only one subject in the control cohort had two autoantibodies. ICA positivity was found in 12.5% of the cases, followed by GADA (6.0%), IA-2A (4.9%) and IAA (1.2%). In the control cohort, GADA positivity was found in 1.4%, IA-2A in 0.8%, IAA in 0.6%, and ICA in 0.3% of the subjects. Detection of ICA, GADA and/or IA-2A autoantibodies decreased T1DM-free survival time and time to diagnosis. All subjects with three positive autoantibodies developed T1DM within seven years from the GDM pregnancy. Development of T2DM after GDM occurred independent of autoantibody positivity. Development of T1DM can be reliably predicted with GADA and ICA autoantibodies during early pregnancy.

Impact of GAD65 and IA2 autoantibodies on islet allograft survival.

Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade's nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance. ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 - 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 - 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 - 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival.

Prolonged Honeymoon Period in Type I Diabetes (T1D) Patients on Low-Carbohydrate Diet (LCD)

The presented case is a 68-year-old female with Type 1 diabetes (T1D). She was admitted for an emergency case with acute distress in January 2018 and was diagnosed with T1D with a blood glucose (BG) level of 459 mg/dL, HbA1c of 13.7%, glutamic acid decarboxylase autoantibody (GADA) level &gt;2000 U/mL (&lt;5 U/mL), and C-reactive protein (CRP) level of 1.10 ng/mL. She received Multiple Daily Injections (MDI) of insulin for 3 months, and then her HbA1c decreased to 7.3%. After that, she has been on a super-low carbohydrate diet (LCD) and received only Lantus XR and ipragliflozin. Serum CRP showed 0.2 ng/mL, suggesting a prolonged honeymoon period for years through continuous LCD.

THU296 Effect Of Tirzepatide In GADA-positive Individuals With T2D: A Post Hoc Analysis Of The SURPASS 2-5 Trials

Abstract Disclosure: A.L. Peters: Advisory Board Member; Self; Abbott Diabetes Care, Eli Lilly &amp; Company, Medscape, Novo Nordisk, Zealand. Grant Recipient; Self; Dexcom, Insulet Corporation. Stock Owner; Self; Omada Health, Teladoc. Other; Self; Abbott Diabetes Care. R. Buzzetti: Consulting Fee; Self; Sanofi, Novo Nordisk, Eli Lilly &amp; Company. Speaker; Self; AstraZeneca, Abbott Laboratories. C.J. Lee: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. I. Pavo: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. M. Liu: Other; Self; Eli Lilly &amp; Company. J.S. Paik: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. Tirzepatide, a novel once weekly GIP and GLP-1 receptor agonist, is approved for treatment of type 2 diabetes (T2D). People with T2D and positive glutamic acid decarboxylase autoantibodies (GADA), which is also referred to as latent autoimmune diabetes in adults (LADA), may often remain undetected and may be associated with more rapid progression to insulin therapy. The diagnosis is primarily made by the presence of GADA in patients previously diagnosed with T2D. The aim of this post hoc analysis was to evaluate the effect of tirzepatide on hemoglobin A1c (HbA1c) levels in people with T2D who were GADA-positive versus GADA-negative from the Phase 3 SURPASS clinical trial program. Tirzepatide-treated patients from SURPASS 2-5 studies were included in this analysis. Patients who had GADA concentrations ≥5 IU/mL were categorized as GADA-positive (ELISA, RSR Ltd., Cardiff, UK). Change from baseline in HbA1c at 40/42 weeks was assessed in GADA-positive vs GADA-negative patients using mixed model repeated measures from the efficacy analysis set, adjusting for baseline covariates including study, sex, HbA1c, and body mass index (BMI). All randomized patients who took at least one dose of study drug, excluding patients who discontinued study drug due to inadvertent enrollment and excluding data after initiation of rescue medication or premature discontinuation of study drug, were included in this analysis. Of the 3827 tirzepatide-treated patients who were tested for GADA, 3671 (95.9%) were GADA-negative, 120 (3.2%) were GADA-positive, and 36 (0.9%) were “no GADA status”. Baseline parameters were similar between the groups, except for baseline BMI and serum triglyceride concentration which were slightly lower in GADA-positive patients compared to GADA-negative patients (mean baseline BMI [SD] 32.2 [6.1] vs 33.6 [6.3] kg/m2, mean triglycerides 169.2 [101.3] vs 188.1 [131.4] mg/dL). At 40/42 weeks, both groups achieved significant reductions in HbA1c (-2.11% vs -2.32%; p&amp;lt;0.001 for both groups) and body weight (-9.2 kg vs -9.6 kg; p&amp;lt;0.001 for both groups), for GADA-positive vs. GADA-negative patients, respectively. Reductions in HbA1c were slightly greater in GADA-negative patients (estimated treatment differences [95% confidence interval]: 0.21% [0.03, 0.39]; p=0.024), whereas reductions in body weight did not significantly differ between groups (0.38 kg [-0.99, 1.75]; p=0.588). These data demonstrate that tirzepatide was effective in reducing HbA1c and body weight, irrespective of GADA status in adults with T2D, thus suggesting that tirzepatide may be effective to improve glycemic control in GADA-positive individuals. Future studies could help elucidate the long-term impact of GADA positivity on the progression of diabetes. Presentation: Thursday, June 15, 2023

SAT078 A Case Of MODY Due To A Rare Activating Variant In The ABCC8 Gene

Abstract Disclosure: J. Milosavljevic: None. J.M. Greally: None. S. Milman: None. Background: ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the beta cell ATP-sensitive K+ channel (KATP). Activating mutations in the ABCC8 cause both neonatal and maturity-onset diabetes of the young (MODY). The majority of patients (85%) with diabetes due to ABCC8 gene mutations could be successfully treated with oral sulfonylureas. A substitution c.2473C&amp;gt;T in the ABCC8 gene results in R825W change in the nucleotide-binding domain 1 of SUR1 and in activation of the KATP channel. We report a case of MODY with an activating mutation of ABCC8 gene (R825W). Clinical Case: A 23-year old woman with a history of ventricular septal defect was diagnosed with diabetes mellitus after she presented with a 2-month history of polyuria and polydipsia. At the time of diagnosis, random serum glucose level was 242 mg/dL, Hemoglobin A1c 7.6%, and BMI was 18 kg/m2. There was absence of acanthosis nigricans on exam or a family history of diabetes, although paternal medical history was unknown. A history of low birth weight was reported, but no developmental delays, neonatal diabetes or history of hypoglycemia. A history of seizure during childhood was also noted but was not associated with hypoglycemia. Additional work-up revealed absence of glutamic acid decarboxylase, islet cell, and insulin autoantibodies. C-peptide level was 2.0 ng/mL with blood glucose 113 mg/dL. The patient did not experience microvascular complications of diabetes. Genetic testing was negative for known mutations in HNF1A, HNF1B, HNF4A, GCK, and PPX1 genes. The patient was initially treated with metformin, but never achieved adequate glycemic control and experienced side effects. She was subsequently treated with sitagliptin and ertugliflozin, however, glycemic control remained inadequate (HbA1C 8.1%). At the age of 33 she was referred for clinical exome sequencing. This detected heterozygous ABCC8 variant c.2473 C&amp;gt;T; p.(R825W). Glucose control improved once therapy was switched to glipizide, resulting in the most recent HbA1C of 6.0%. Conclusion: Activating mutations of ABCC8 gene are infrequent genetic causes of diabetes in adults. Sequencing of the ABCC8 gene should be considered in select adult patients, as diagnosis can guide management decisions. Presentation: Saturday, June 17, 2023

THU027 Challenges In The Management Of Extreme Hyperglycemia In An Acromegalic Patient

Abstract Disclosure: M. Sonbol: None. M. Novitskaya: None. J. Monye: None. S. Jafri: None. E. Japp: None. Introduction: Hyperglycemia in acromegalic patients presents a unique challenge given the disruption GH has on glucose homeostasis. Chronic hypersecretion of GH causes severe insulin resistance which can progress to uncontrolled DM. We describe a patient with acromegaly requiring &amp;gt;180 units/day of insulin in the perioperative period while awaiting transsphenoidal surgery. Clinical Case: A 49-year-old female with HTN and recent diagnosis of uncontrolled type 2 DM presented with several months of blurry vision and headaches. She had several prior admissions for hyperglycemia and DKA (with normal C-peptide, and negative GAD-65 and islet cell autoantibodies) despite compliance with insulin therapy. Her HbA1c was 12.2% on 2 units/kg TDD of insulin. Imaging was significant for a sellar/suprasellar solid mass with cystic components measuring 8.3 x 6.3 x 7.8 cm encasing bilateral internal carotid arteries, encroaching the left orbital apex, and applying mass effect on bilateral frontal lobes, and right temporal lobe and midbrain. Labwork was significant for IGF-1 1083 ng/mL (n&amp;lt;238), and GH of 96.4 ng/mL (n&amp;lt;8). FSH and LH were suppressed, with otherwise normal pituitary hormone levels. Interestingly, the patient did not exhibit classic clinical features of acromegaly such as macroglossia, enlarged digits or coarse facial features. Transsphenoidal biopsy demonstrated mature PIT-1 lineage NET with expression of GH and PRL. Given the significant tumor mass effect, she was placed on dexamethasone 4 mg q12h. Preoperatively, her blood glucose worsened and reached 500 mg/dL despite &amp;gt;180 units of insulin/day on a subcutaneous insulin regimen. Glycemic management was escalated with addition of regular insulin gtt up to 25 units/hr to achieve target blood glucose of 140-180 mg/dL. After successful surgical resection of the tumor, HbA1c decreased to 7.7% on 1.3 units/kg TDD of insulin, metformin and empagliflozin at eight weeks postoperatively. Clinical Lessons: Unusual presentations of rapidly increasing insulin requirements in newly diagnosed DM should raise clinical suspicion for secondary causes such as acromegaly. The degree of insulin resistance is often out of proportion to the patient’s body habitus given the GH-mediated lipodystrophy and adipose tissue dysfunction. In this case, the patient’s insulin requirement was 2 units/kg TDD of insulin, with her BMI being only 22.14 kg/m2. Given the need for semi-urgent surgery due to the tumor’s mass effect, SSA therapy or GH-receptor antagonist was not initiated, and insulin therapy was the mainstay for preoperative glucose management. In severe cases of acromegaly-related hyperglycemia, subcutaneous insulin alone may not be sufficient for adequate glucose control, especially in the setting of preoperative steroids, and large doses of IV insulin may be needed to reach inpatient glucose goals. Presentation: Thursday, June 15, 2023

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.

Anti-CASPR2, Anti-LGI1, and Anti-GAD65 Autoantibodies in Patients with Intractable Epilepsy

Abstract Background Autoimmunity is increasingly being recognized as a cause of intractable epilepsy. The autoimmune epilepsies (AE) are immunologically mediated disorders in which recurrent seizures are a primary and persistent clinical feature. When other etiologies have been excluded, an autoimmune etiology of epilepsy is suggested in the presence of resistance to anti-epileptic drugs (AED). In such patients, immunotherapy may be highly effective, depending on the particular autoimmune epilepsy syndrome present. Objective To investigate the presence of Contactin associated protein like 2 (CASPR2), leucine rich Glioma inactivated1 (LGI1) and Glutamic acid decarboxylase 65 (GAD65) autoantibodies in intractable epilepsy, and their association with clinical and imaging findings. Subjects and Methods Seventeen patients with intractable epilepsy were included. LGI1, CASPR2 and GAD65 autoantibodies testing by indirect immunofluorescence cellbased assay in both serum and cerebrospinal fluid (CSF) were assessed in all patients. Results Both serum and CSF samples of the 17 patients were tested negative for the 3 autoantibodies (Anti CASPR2, Anti LGI1 and Anti GAD 65). Regarding CSF examination, only 5 patients had normal CSF, the other 12 showed some changes; 7 had elevated levels of proteins, 3 showed positive oligoclonal bands and elevated IgG index and 2 patients showed both elevated proteins and cells. Conclusion Some cases of AE are associated with specific autoantibodies to neuronal proteins. Clinicians must make a diagnosis based on a combination of clinical phenotypes, CSF results, and neuroimaging. Meanwhile, patients should be followed-up systematically due to the constant discovery of new neuronal auto antibodies.

Subgroups of adult-onset diabetes: a data-driven cluster analysis in a Ghanaian population

Adult-onset diabetes mellitus (here: aDM) is not a uniform disease entity. In European populations, five diabetes subgroups have been identified by cluster analysis using simple clinical variables; these may elucidate diabetes aetiology and disease prognosis. We aimed at reproducing these subgroups among Ghanaians with aDM, and establishing their importance for diabetic complications in different health system contexts. We used data of 541 Ghanaians with aDM (age: 25–70 years; male sex: 44%) from the multi-center, cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) Study. Adult-onset DM was defined as fasting plasma glucose (FPG) ≥ 7.0 mmol/L, documented use of glucose-lowering medication or self-reported diabetes, and age of onset ≥ 18 years. We derived subgroups by cluster analysis using (i) a previously published set of variables: age at diabetes onset, HbA1c, body mass index, HOMA-beta, HOMA-IR, positivity of glutamic acid decarboxylase autoantibodies (GAD65Ab), and (ii) Ghana-specific variables: age at onset, waist circumference, FPG, and fasting insulin. For each subgroup, we calculated the clinical, treatment-related and morphometric characteristics, and the proportions of objectively measured and self-reported diabetic complications. We reproduced the five subgroups: cluster 1 (obesity-related, 73%) and cluster 5 (insulin-resistant, 5%) with no dominant diabetic complication patterns; cluster 2 (age-related, 10%) characterized by the highest proportions of coronary artery disease (CAD, 18%) and stroke (13%); cluster 3 (autoimmune-related, 5%) showing the highest proportions of kidney dysfunction (40%) and peripheral artery disease (PAD, 14%); and cluster 4 (insulin-deficient, 7%) characterized by the highest proportion of retinopathy (14%). The second approach yielded four subgroups: obesity- and age-related (68%) characterized by the highest proportion of CAD (9%); body fat-related and insulin-resistant (18%) showing the highest proportions of PAD (6%) and stroke (5%); malnutrition-related (8%) exhibiting the lowest mean waist circumference and the highest proportion of retinopathy (20%); and ketosis-prone (6%) with the highest proportion of kidney dysfunction (30%) and urinary ketones (6%). With the same set of clinical variables, the previously published aDM subgroups can largely be reproduced by cluster analysis in this Ghanaian population. This method may generate in-depth understanding of the aetiology and prognosis of aDM, particularly when choosing variables that are clinically relevant for the target population.

Neuronal autoantibodies in a sample of Egyptian patients with drug-resistant epilepsy

BackgroundEpilepsy is one of the most common and chronic neurological diseases. About one-third of epilepsy patients do not achieve seizure freedom despite adequate therapy with antiseizure medications (ASMs) and develop drug-resistant epilepsy (DRE). Autoimmunity is increasingly being recognized as a cause of epilepsy in those patients. Some cases are associated with antibodies against several target antigens, including neuronal extracellular proteins as well as intracellular structures. In such patients, immunotherapy may be highly effective. This study aimed to investigate the presence of NMDA-R, AMPA1-R, AMPA2-R, CASPR2, LGI1, GABAB-R, and GAD65 autoantibodies in a sample of Egyptian patients with new-onset DRE; also, to assess the clinical, cerebrospinal fluid (CSF), electroencephalogram (EEG), and radiological characteristics of those patients. Twenty-five patients with recent onset DRE were recruited from the department of Neurology at Ain Shams University (ASU) hospitals. All patients underwent serum and CSF antibody testing using cell-based assay (CBA) at the Immunology unit of the Clinical pathology laboratory at ASU hospitals. This is beside routine CSF analysis, EEG and MRI brain with contrast.ResultsOut of 25 patients with recent onset DRE, one (4%) patient tested positive to anti-NMDA-R antibodies and another one (4%) tested positive to anti-GAD 65 in both serum and CSF. Although the remaining 23 patients tested negative for the 7 autoantibodies, yet 92% of them achieved either seizure freedom or more than 50% reduction in the frequency of seizure and 84% had marked improvement in seizure-associated symptoms after receiving immunotherapy trial. Also, evidence of neuroinflammation was detected in the CSF and MRI brain of the majority of those patients.ConclusionsAutoimmunity should be considered as a possible etiology of new-onset DRE. It is essential to provide insight into the clinical phenotypes and other associated features of those patients, as there are probably numerous patients who are not positive for one of the available antibodies via clinical laboratory testing. In addition to early diagnosis, early treatment and empirical immunotherapy trial based on the clinical judgment is crucial and is likely to improve outcomes with near-complete seizure freedom.

1388-P: Clinical Features Associated with Glutamic Acid Decarboxylase Autoantibodies (GADA) in Adults with Type 2 Diabetes

Islet autoantibodies in adults classified as having type 2 diabetes (T2D) have been associated with lower adiposity and early insulin requirement. We examined the association between GADA, the most prevalent islet autoantibody, and baseline clinical features in Look AHEAD (Action for Health in Diabetes), a randomized trial of adults with clinically-diagnosed T2D and overweight/obesity from 16 geographically diverse U.S. study centers. GADA was measured by radioligand binding assay in 87% of the randomized cohort at study baseline and categorized as negative (GADA-), low-level (35-199 U/mL, GADA+) or high-level (≥200 U/mL, GADA++). We compared clinical features across GADA categories using Fisher’s exact or Kruskal-Wallis tests. There were 4,492 participants who had a median age 59 years and diabetes duration 5 years. Participants were 59% female, 67% white, 16% Black and 13% Hispanic. GADA was positive (≥35 U/mL) in 216 participants (4.8%); 131 were GADA+ (2.9%) and 85 GADA++ (1.9%). Insulin was used by 15% of GADA-, 25% of GADA+, and 40% of GADA++ (p&amp;lt;0.001). The median HbA1c was 7.0% in GADA-, 7.1% in GADA+, and 7.4% in GADA++ (p=0.004). There was a history of hypothyroidism in 12% of GADA-, 14% of GADA+, and 29% of GADA++ (p&amp;lt;0.001). There was a history of hyperthyroidism in 2% of GADA-, 2% of GADA+, and 7% of GADA++ (p=0.006). GADA level was not associated with age, sex, race/ethnicity, diabetes duration, BMI, waist circumference, or history of microvascular or macrovascular complications. In conclusion, a substantial minority of this population of adults with overweight/obesity who were clinically diagnosed as T2D have GADA positivity, and high levels were strongly associated with phenotypic differences including insulin use and thyroid disease. In contrast to prior studies, GADA was not associated with lower adiposity. These findings highlight the heterogeneity of this population and the need to further study the clinical implications of GADA positivity. Disclosure S.J.Pilla: None. A.Ramelius: None. R.Bennet: None. Å.Lernmark: Advisory Panel; Diamyd Medical. N.N.Mathioudakis: None. J.Clark: None. N.M.Maruthur: Other Relationship; Johns Hopkins HealthCare Solutions. W.C.Knowler: None. A.Balasubramanyam: None. C.S.Hampe: Employee; Immusoft corp. S.Pietropaolo: None. A.M.Anderson: None. M.Li: None. N.Zhao: None. S.L.Zeger: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK126825, K23DK128572)