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Grace SL, Gillespie KM, Williams CL, Lampasona V, Achenbach P, Pearson ER, Williams AJK, Long AE, McDonald TJ, Jones AG. Autoantibodies to Truncated GAD(96-585) Antigen Stratify Risk of Early Insulin Requirement in Adult-Onset Diabetes. Diabetes 2024; 73:1583-1591. [PMID: 38976498 DOI: 10.2337/db23-0980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 06/25/2024] [Indexed: 07/10/2024]
Abstract
We investigated whether characterization of full-length GAD (f-GADA) antibody (GADA) responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA-positive participants diagnosed with type 2 diabetes, we assessed associations of truncated GADA (t-GADA) positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA-positive without early insulin in comparison with f-GADA-positive type 2 diabetes requiring insulin within 5 years, and T1D (75% vs. 91% and 95% respectively, P < 0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher T1D genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, P = 0.003), lower C-peptide (1,156 pmol/L vs. 4,289 pmol/L, P = 1 × 10-7), and increased IA-2 antigen positivity (23% vs. 6%, P = 0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titer, and duration of diabetes (adjusted hazard ratio 5.7 [95% CI 1.4, 23.5], P = 0.017). The testing of t-GADA in f-GADA-positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to T1D and stratifies those at higher risk of early insulin requirement. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Sian L Grace
- Department of Clinical and Biological Science, University of Exeter Medical School, Exeter, U.K
- School of Translational Sciences, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Kathleen M Gillespie
- School of Translational Sciences, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Claire L Williams
- School of Translational Sciences, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Vito Lampasona
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Munich, German Center for Environmental Health, Munich, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Ewan R Pearson
- Biomedical Research Institute, University of Dundee, Dundee, U.K
| | - Alistair J K Williams
- School of Translational Sciences, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Anna E Long
- School of Translational Sciences, Bristol Medical School, University of Bristol, Bristol, U.K
| | - Timothy J McDonald
- Department of Clinical and Biological Science, University of Exeter Medical School, Exeter, U.K
- Academic Department of Clinical Biochemistry, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K
| | - Angus G Jones
- Department of Clinical and Biological Science, University of Exeter Medical School, Exeter, U.K
- Macleod Diabetes and Endocrine Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, U.K
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Ma S, He R, Jiang T, Hu Z, Ye Z, Mi W. Development of an isotope dilution mass spectrometry assay for the quantification of insulin based on signature peptide analysis. Anal Bioanal Chem 2024; 416:3085-3096. [PMID: 38556594 DOI: 10.1007/s00216-024-05258-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 04/02/2024]
Abstract
An isotope dilution mass spectrometry (IDMS) method that involves peptide-based protein analysis was developed to accurately quantify insulin. In this study, a signature peptide (GFFYTPK) obtained from tryptic digestion of insulin was selected as a surrogate for insulin. Then, the optimal conditions for signature peptide analysis through mass spectrometry detection and enzymatic digestion were determined. The analytical performance of this method was assessed and validated using porcine insulin-certified reference material. The linear range of the insulin calibration curve ranged from 0.05 ~ 2 mass ratios, with recoveries ranging from 96.15 to approximately 101.15%. The limit of detection was 0.19 ng/mL, and the limit of quantification was 0.63 ng/mL. The quantitative results corresponded well with a certified value that was obtained from measuring a porcine insulin reference material with amino acid-based IDMS. In addition, the target peptide GFFYTPK can be found in other species of insulin. This method was also applied for the quantification of human insulin-certified reference material. Finally, we applied the method to quantify the concentrations of simulated serum insulin. These findings suggested that this signature peptide-based IDMS approach can accurately quantify insulin levels, can assign a certified value to insulin reference materials, and has the potential to quantify serum insulin with traceable measurements.
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Affiliation(s)
- Shangying Ma
- College of Life Sciences, China Jiliang University, Xueyuan Street 258, Hangzhou, 310018, China
| | - Rimei He
- Guangxi Zhuang Autonomous Region Institute of Metrology and Test, Nanning, 530200, China
| | - Tingting Jiang
- College of Life Sciences, China Jiliang University, Xueyuan Street 258, Hangzhou, 310018, China
| | - Zhishang Hu
- National Institute of Metrology, No.18 Beisanhuan Donglu, Beijing, 100029, China.
| | - Zihong Ye
- College of Life Sciences, China Jiliang University, Xueyuan Street 258, Hangzhou, 310018, China.
| | - Wei Mi
- National Institute of Metrology, No.18 Beisanhuan Donglu, Beijing, 100029, China.
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Wenzlau JM, Gu Y, Michels A, Rewers M, Haskins K, Yu L. Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes. Diagnostics (Basel) 2023; 13:2859. [PMID: 37685398 PMCID: PMC10487141 DOI: 10.3390/diagnostics13172859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease that attacks the insulin-producing b cells of the pancreatic islets. Autoantibodies to b cell proteins typically appear in the circulation years before disease onset, and serve as the most accurate biomarkers of T1D risk. Our laboratory has recently discovered novel b cell proteins comprising hybrid proinsulin:islet amyloid polypeptide peptides (IAPP). T cells from a diabetic mouse model and T1D patients are activated by these hybrid peptides. In this study, we asked whether these hybrid molecules could serve as antigens for autoantibodies in T1D and prediabetic patients. We analyzed sera from T1D patients, prediabetics and healthy age-matched donors. Using a highly sensitive electrochemiluminescence assay, sera were screened for binding to recombinant proinsulin:IAPP probes or truncated derivatives. Our results show that sera from T1D patients contain antibodies that bind larger hybrid proinsulin:IAPP probes, but not proinsulin or insulin, at significantly increased frequencies compared to normal donors. Examination of sera from prediabetic patients confirms titers of antibodies to these hybrid probes in more than 80% of individuals, often before seroconversion. These results suggest that hybrid insulin peptides are common autoantigens in T1D and prediabetic patients, and that antibodies to these peptides may serve as valuable early biomarkers of the disease.
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Affiliation(s)
- Janet M. Wenzlau
- Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Mail Stop 8333, Aurora, CO 80045, USA; (J.M.W.); (K.H.)
| | - Yong Gu
- Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, Mail Stop B140, Aurora, CO 80045, USA; (Y.G.); (A.M.); (M.R.)
| | - Aaron Michels
- Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, Mail Stop B140, Aurora, CO 80045, USA; (Y.G.); (A.M.); (M.R.)
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, Mail Stop B140, Aurora, CO 80045, USA; (Y.G.); (A.M.); (M.R.)
| | - Kathryn Haskins
- Department of Immunology and Microbiology, University of Colorado School of Medicine, 12800 East 19th Avenue, Mail Stop 8333, Aurora, CO 80045, USA; (J.M.W.); (K.H.)
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, 1775 Aurora Court, Mail Stop B140, Aurora, CO 80045, USA; (Y.G.); (A.M.); (M.R.)
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Jia X, Yu L. Effective assay technologies fit for large-scale population screening of type 1 diabetes. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2023; 3:1034698. [PMID: 36992730 PMCID: PMC10012058 DOI: 10.3389/fcdhc.2022.1034698] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/24/2023]
Abstract
While worldwide prevention efforts for type 1 diabetes (T1D) are underway to abrogate or slow progression to diabetes, mass screening of islet autoantibodies (IAbs) in the general population is urgently needed. IAbs, the most reliable biomarkers, play an essential role in prediction and clinical diagnosis of T1D. Through laboratory proficiency programs and harmonization efforts, a radio-binding assay (RBA) has been well established as the current 'gold' standard assay for all four IAbs. However, in view of the need for large-scale screening in the non-diabetic population, RBA consistently faces two fundamental challenges, cost-efficiency and disease specificity. While all four IAbs are important for disease prediction, the RBA platform, with a separate IAb test format is laborious, inefficient and expensive. Furthermore, the majority of IAb positivity in screening, especially from individuals with single IAb were found to be low risk with low affinity. It is well documented from multiple clinical studies that IAbs with low affinity are low risk with less or no disease relevance. At present, two non-radioactive multiplex assays, a 3-assay ELISA combining three IAbs and a multiplex ECL assay combining all four IAbs, have been successfully used as the primary methods for general population screenings in Germany and the US, respectively. Recently, the TrialNet Pathway to Prevention study has been organizing an IAb workshop which aims to analyze the 5-year T1D predictive values of IAbs. A T1D-specific assay with high efficiency, low cost and requiring low volume of sample will definitely be necessary to benefit general population screening.
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Affiliation(s)
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
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Feng X, Tong W, Li J, Xu Y, Zhu S, Xu W. Diagnostic value of anti-Kaiso autoantibody in axial spondyloarthritis. Front Immunol 2023; 14:1156350. [PMID: 37063878 PMCID: PMC10098150 DOI: 10.3389/fimmu.2023.1156350] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/20/2023] [Indexed: 04/18/2023] Open
Abstract
Objective Axial spondyloarthritis (axSpA) is a chronic rheumatic disease predominantly characterized by inflammation and progressive structural damage. Patients are often diagnosed very late, which delays the optimal treatment period. Early diagnosis of axSpA, especially non-radiographic axSpA (nr-axSpA), remains a major challenge. This study aimed to investigate the diagnostic value of anti-Kaiso autoantibodies in axSpA and their correlation with clinical disease indicators. Methods Two pooled serum samples (seven patients with nr-axSpA and seven healthy controls) were profiled using HuProt arrays to investigate the diagnostic value of autoantibodies in nr-axSpA. Levels of anti-Kaiso autoantibodies in patients with axSpA and controls were determined using the Meso Scale Discovery assay system. Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of anti-Kaiso autoantibodies in axSpA. Pearson's correlation was used to assess the correlation between anti-Kaiso autoantibodies and clinical parameters. Results Seven candidate autoantibodies were present in the serum of patients with nr-axSpA. The levels of anti-Kaiso autoantibodies were significantly higher in the nr-axSpA group than in the other groups. It can differentiate nr-axSpA from ankylosing spondylitis (AS), healthy controls, and rheumatoid arthritis. The level of early-stage AS among patients with nr-axSpA decreased when they progressed to the late stage. Of all patients with axSpA, serum anti-Kaiso autoantibody levels were positively correlated with the C-reactive protein level and the Bath Ankylosing Spondylitis Disease Activity Index score and negatively correlated with disease duration. Conclusion Anti-Kaiso autoantibody may be a valuable diagnostic biomarker for early-stage AS in the nr-axSpA period and may be a potential therapeutic target.
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Qi Y, Chen S, Chen H, Chen Y, Shi Y, Qin Y, Zhang M, Yang T, Gu Y. Combined detection of islet autoantibodies for clinical diagnosis of type 1 diabetes in the low-prevalence population. J Clin Endocrinol Metab 2022; 108:e326-e333. [PMID: 36480302 DOI: 10.1210/clinem/dgac720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 11/29/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
CONTEXT Single positive islet autoantibodies (IAbs), sometimes detected in healthy individuals and low risk type 1 diabetes (T1D) patients, are considered to be irrelevant to the development of diabetes, making it difficult to diagnose and classify adult-onset diabetics. OBJECTIVE To determine the significance and clinical value of IAbs in T1D diagnosis in the low-prevalence population; and to explore whether electrochemiluminescence (ECL)-IAb detection assay can improve the clinical utility of IAbs in the immunodiagnosis of T1D in the low-prevalence population. PARTICIPANTS AND METHODS A total of 633 newly-diagnosed adult-onset diabetic patients (≥18 years old) were divided into two groups according to their clinical phenotypes: 575 patients with age at diagnosis ≥35 years and body mass index (BMI) ≥ 24 kg/m2 were considered a low-prevalence population (population with a low prevalence of T1D) and the other 58 patients were considered a high-prevalence population. All the samples from 633 participants were tested with IAbs using standard radiobinding assays (RBA) and electrochemiluminescence (ECL) assay, in parallel. RESULTS Compared with the high-prevalence population, fewer positive IAbs (94/575, 16.3% vs. 28/58, 48.3%) were detected in the low-prevalence population, and more of which (69/94, 73.4% vs. 9/28, 32.2%) were positive for a single IAb, with GADA being the most prevalent single-IAb. Single-IAb detection in the low-prevalence population did not always suggest T1D phenotype. Combined detection of IAbs by RBA and ECL assays had a significant clinical utility to distinguish autoimmune diabetes in the low-prevalence population with low BMI, poor β-cell function at the diagnosis, and an accelerated decline in β-cell function during the follow-up. CONCLUSIONS Combined autoantibody detection by RBA and ECL assays improved differentiating autoimmune from non-autoimmune diabetes in the low-prevalence population.
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Affiliation(s)
- Yanyan Qi
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Shuang Chen
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Heng Chen
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Chen
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Shi
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yao Qin
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mei Zhang
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tao Yang
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Gu
- The Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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He L, Jia X, Rasmussen CG, Waugh K, Miao D, Dong F, Frohnert B, Steck AK, Simmons KM, Rewers M, Yu L. High-Throughput Multiplex Electrochemiluminescence Assay Applicable to General Population Screening for Type 1 Diabetes and Celiac Disease. Diabetes Technol Ther 2022; 24:502-509. [PMID: 35238620 PMCID: PMC9464081 DOI: 10.1089/dia.2021.0517] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Objective: Large-scale screening of the general population for islet autoantibodies (IAbs) to detect type 1 diabetes (T1D) has started worldwide. The standard screening method of separate radio-binding assay (RBA) for each IAb is an inefficient bottleneck. Furthermore, most positive results by RBA in screening of general population individuals without a clinical diagnosis of T1D are low-affinity and not predictive of future diabetes. Research Design and Methods: We have developed and validated a novel 6-Plex assay based on electrochemiluminescence (ECL) technology that combines in a single well high-affinity IAbs (to insulin, GAD, IA-2, and ZnT8), transglutaminase autoantibodies for celiac disease, and severe acute respiratory syndrome coronavirus 2 antibodies. The Autoimmunity Screening for Kids (ASK) provided 880 serum samples, from 828 children aged 1-17 years without diabetes who were previously tested for IAbs using single ECL assays and RBA assays. Results: Levels of all six antibodies in the 6-Plex ECL assay correlated well with respective single ECL assay levels. Similar to single ECL assays, the 6-Plex ECL assay positivity was congruent with the RBA in 95% (35/37) of children who later developed T1D and in 88% (105/119) high-risk children with multiple IAbs. In contrast, only 56% (86/154, P < 0.0001) of children with persistent single IAb by RBA were found to be positive by 6-Plex ECL assay. Of 555 samples negative for all IAbs by RBA, few (0.2%-0.5%) were positive at low levels in the 6-Plex ECL assay. Conclusions: The study demonstrated that the 6-Plex ECL assay compares favorably to the standard RBAs in terms of disease specificity for general population screening in children. The 6-Plex ECL assay was therefore adopted as the primary screening tool in the general population screening ASK program with advantages of high efficiency, low cost, and low serum volume.
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Affiliation(s)
- Ling He
- Department of Endocrinology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong, China
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Xiaofan Jia
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Cristy Geno Rasmussen
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Kathleen Waugh
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Dongmei Miao
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Fran Dong
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Brigitte Frohnert
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Andrea K. Steck
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Kimber M. Simmons
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
- Address correspondence to: Marian Rewers, MD, PhD, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045, USA
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
- Address correspondence to: Liping Yu, MD, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045, USA
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Triolo TM, Pyle L, Broncucia H, Armstrong T, Yu L, Gottlieb PA, Steck AK. Association of High-Affinity Autoantibodies With Type 1 Diabetes High-Risk HLA Haplotypes. J Clin Endocrinol Metab 2022; 107:e1510-e1517. [PMID: 34850014 PMCID: PMC8947772 DOI: 10.1210/clinem/dgab853] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Electrochemiluminescence (ECL) assays are high-affinity autoantibody (Ab) tests that are more specific than Abs detected by traditional radiobinding assays (RBA) for risk screening and prediction of progression to type 1 diabetes. We sought to characterize the association of high-risk human leukocyte antigen (HLA) haplotypes and genotypes with ECL positivity and levels in relatives of individuals with type 1 diabetes. METHODS We analyzed 602 participants from the TrialNet Pathway to Prevention Study who were positive for at least 1 RBA diabetes-related Ab [glutamic acid decarboxylase autoantibodies (GADA) or insulin autoantibodies (IAA)] and for whom ECL and HLA data were available. ECL and RBA Ab levels were converted to SD units away from mean (z-scores) for analyses. RESULTS Mean age at initial visit was 19.4 ± 13.7 years; 344 (57.1%) were female and 104 (17.3%) carried the high-risk HLA-DR3/4*0302 genotype. At initial visit 424/602 (70.4%) participants were positive for either ECL-GADA or ECL-IAA, and 178/602 (29.6%) were ECL negative. ECL and RBA-GADA positivity were associated with both HLA-DR3 and DR4 haplotypes (all Ps < 0.05), while ECL and RBA-GADA z-score titers were higher in participants with HLA-DR3 haplotypes only (both Ps < 0.001). ECL-IAA (but not RBA-IAA) positivity was associated with the HLA-DR4 haplotype (P < 0.05). CONCLUSIONS ECL-GADA positivity is associated with the HLA-DR3 and HLA-DR4 haplotypes and levels are associated with the HLA-DR3 haplotype. ECL-IAA positivity is associated with HLA-DR4 haplotype. These studies further contribute to the understanding of genetic risk and islet autoimmunity endotypes in type 1 diabetes.
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Affiliation(s)
- Taylor M Triolo
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
- Correspondence: Taylor M. Triolo, MD, University of Colorado Denver School of Medicine, Barbara Davis Center for Diabetes, 1775 Aurora Ct, MS #A140, Aurora, CO, USA 80045-2581.
| | - Laura Pyle
- Department of Pediatrics, University of Colorado, Aurora, CO, USA
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, USA
| | - Hali Broncucia
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Taylor Armstrong
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
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Automation of a multiplex agglutination-PCR (ADAP) type 1 diabetes (T1D) assay for the rapid analysis of islet autoantibodies. SLAS Technol 2022; 27:26-31. [DOI: 10.1016/j.slast.2021.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Steck AK, Dong F, Geno Rasmussen C, Bautista K, Sepulveda F, Baxter J, Yu L, Frohnert BI, Rewers MJ. CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study. Diabetes Care 2022; 45:365-371. [PMID: 34880069 DOI: 10.2337/dc21-0602] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 11/15/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish continuous glucose monitoring (CGM) metrics that could predict imminent progression to diabetes. RESEARCH DESIGN AND METHODS In the Autoimmunity Screening for Kids study, 91 children who were persistently islet autoantibody positive (median age 11.5 years; 48% non-Hispanic White; 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range 0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range 0.4-29) months. RESULTS Compared with children who did not progress to clinical diabetes (nonprogressors), those who did (progressors) had significantly higher average sensor glucose levels (119 vs. 105 mg/dL, P < 0.001) and increased glycemic variability (SD 27 vs. 16, coefficient of variation, 21 vs. 15, mean of daily differences 24 vs. 16, and mean amplitude of glycemic excursions 43 vs. 26, all P < 0.001). For progressors, 21% of the time was spent with glucose levels >140 mg/dL (TA140) and 8% of time >160 mg/dL, compared with 3% and 1%, respectively, for nonprogressors. In survival analyses, the risk of progression to diabetes in 1 year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. Performance of prediction by receiver operating curve analyses showed area under the curve of ≥0.89 for both individual and combined CGM metric models. CONCLUSIONS TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year in autoantibody-positive children. CGM should be included in the ongoing monitoring of high-risk children and could be used as potential entry criterion for prevention trials.
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Gillespie KM, Fareed R, Mortimer GL. Four decades of the Bart's Oxford study: Improved tests to predict type 1 diabetes. Diabet Med 2021; 38:e14717. [PMID: 34655243 DOI: 10.1111/dme.14717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/13/2021] [Indexed: 11/29/2022]
Abstract
Recent success in clinical trials to delay the onset of type 1 diabetes has heralded a new era of type 1 diabetes research focused on the most accurate methods to predict risk and progression rate in the general population. Risk prediction for type 1 diabetes has been ongoing since the 1970s and 1980s when human leucocyte antigen (HLA) variants and islet autoantibodies associated with type 1 diabetes were first described. Development of prediction methodologies has relied on well-characterised cohorts and samples. The Bart's Oxford (BOX) study of type 1 diabetes has been recruiting children with type 1 diabetes and their first (and second)-degree relatives since 1985. In this review, we use the timeline of the study to review the accompanying basic science developments which have facilitated improved prediction by genetic (HLA analysis through to genetic risk scores) and biochemical strategies (islet cell autoantibodies through to improved individual tests for antibodies to insulin, glutamate decarboxylase, the tyrosine phosphatase IA-2, zinc transporter 8 and tetraspanin 7). The type 1 diabetes community are poised to move forward using the best predictive markers to predict and delay the onset of type 1 diabetes.
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Affiliation(s)
- Kathleen M Gillespie
- Diabetes and Metabolism, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, UK
| | - Rana Fareed
- Diabetes and Metabolism, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, UK
| | - Georgina L Mortimer
- Diabetes and Metabolism, Bristol Medical School, Southmead Hospital, University of Bristol, Bristol, UK
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Jia X, He L, Miao D, Waugh K, Rasmussen CG, Dong F, Steck AK, Rewers M, Yu L. High-affinity ZnT8 Autoantibodies by Electrochemiluminescence Assay Improve Risk Prediction for Type 1 Diabetes. J Clin Endocrinol Metab 2021; 106:3455-3463. [PMID: 34343303 PMCID: PMC8864749 DOI: 10.1210/clinem/dgab575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Indexed: 01/13/2023]
Abstract
CONTEXT Single ZnT8 autoantibody (ZnT8A) positivity by standard radiobinding assay (RBA) is commonly seen in nondiabetes population-based screening and the risk of progression to type 1 diabetes (T1D) in subjects with single ZnT8A is unknown. OBJECTIVE Identify the risk of progression to T1D in individuals positive only for ZnT8A. METHODS We developed an electrochemiluminescence (ECL) assay to detect high-affinity ZnT8A and validated it in 3 populations: 302 patients newly diagnosed with T1D, 135 nondiabetic children positive for ZnT8A by RBA among 23 400 children screened by the Autoimmunity Screening for Kids (ASK) study, and 123 nondiabetic children multiple autoantibody positive or single ZnT8A positive by RBA participating in the Diabetes Autoimmunity Study in the Young (DAISY). RESULTS In 302 patients with T1D at diagnosis, the positivity for ZnT8A was 62% both in RBA and ECL. Among ASK 135 participants positive for RBA-ZnT8A, 64 were detected ZnT8A as the only islet autoantibody. Of these 64, only 9 were confirmed by ECL-ZnT8A, found to be of high affinity with increased T1D risk. The overall positive predictive value of ECL-ZnT8A for T1D risk was 87.1%, significantly higher than that of RBA-ZnT8A (53.5%, P < .001). In DAISY, 11 of 2547 children who had no positivity previously detected for other islet autoantibodies were identified as single ZnT8A by RBA; of these, 3 were confirmed positive by ECL-ZnT8A and all 3 progressed to clinical T1D. CONCLUSION A large proportion of ZnT8A by RBA are single ZnT8A with low T1D risk, whereas ZnT8A by ECL was of high affinity and high prediction for T1D development.
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Affiliation(s)
- Xiaofan Jia
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, P. R. China
| | - Ling He
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
- Department of Endocrinology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, P. R. China
| | - Dongmei Miao
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Kathleen Waugh
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Cristy Geno Rasmussen
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Fran Dong
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Andrea K Steck
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Marian Rewers
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Liping Yu
- Barbara Davis Center for Diabetes University of Colorado School of Medicine, Aurora, Colorado 80045, USA
- Correspondence: Liping Yu, MD, Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B-140, Aurora, CO 80045, USA.
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So M, Speake C, Steck AK, Lundgren M, Colman PG, Palmer JP, Herold KC, Greenbaum CJ. Advances in Type 1 Diabetes Prediction Using Islet Autoantibodies: Beyond a Simple Count. Endocr Rev 2021; 42:584-604. [PMID: 33881515 DOI: 10.1210/endrev/bnab013] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Indexed: 02/06/2023]
Abstract
Islet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk individuals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number; it has been robustly shown that nearly all multiple-autoantibody-positive individuals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression among multiple-autoantibody-positive individuals is highly heterogenous. Accurate prediction of the most rapidly progressing individuals is crucial for efficient and informative clinical trials and for identification of candidates most likely to benefit from disease modification. This is increasingly relevant with the recent success in delaying clinical disease in presymptomatic subjects using immunotherapy, and as the field moves toward population-based screening. There have been many studies investigating islet autoantibody characteristics for their predictive potential, beyond a simple categorical count. Predictive features that have emerged include molecular specifics, such as epitope targets and affinity; longitudinal patterns, such as changes in titer and autoantibody reversion; and sequence-dependent risk profiles specific to the autoantibody and the subject's age. These insights are the outworking of decades of prospective cohort studies and international assay standardization efforts and will contribute to the granularity needed for more sensitive and specific preclinical staging. The aim of this review is to identify the dynamic and nuanced manifestations of autoantibodies in type 1 diabetes, and to highlight how these autoantibody features have the potential to improve study design of trials aiming to predict and prevent disease.
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Affiliation(s)
- Michelle So
- Diabetes Clinical Research Program, and Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Cate Speake
- Diabetes Clinical Research Program, and Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
| | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Markus Lundgren
- Department of Clinical Sciences Malmö, Lund University, Malmö 22200, Sweden
| | - Peter G Colman
- Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia
| | - Jerry P Palmer
- VA Puget Sound Health Care System, Department of Medicine, University of Washington, Seattle, WA 98108, USA
| | - Kevan C Herold
- Department of Immunobiology, and Department of Internal Medicine, Yale University, New Haven, CT 06520, USA
| | - Carla J Greenbaum
- Diabetes Clinical Research Program, and Center for Interventional Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA 98101, USA
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Jia X, Gesualdo P, Geno Rasmussen C, Alkanani AA, He L, Dong F, Rewers MJ, Michels AW, Yu L. Prevalence of SARS-CoV-2 Antibodies in Children and Adults with Type 1 Diabetes. Diabetes Technol Ther 2021; 23:517-521. [PMID: 33544017 PMCID: PMC8252893 DOI: 10.1089/dia.2020.0609] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Objective: As diabetes is a risk factor for severe symptoms, hospitalization, and death with COVID-19 disease, we aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in children and adults with and without type 1 diabetes in Colorado during 2020. Research Design and Methods: We developed a highly sensitive and specific test for antibodies against SARS-CoV-2 and measured the antibodies in children and adults with new-onset (n = 129) and established type 1 diabetes (n = 94) seen for routine diabetes care at our center between January and October 2020. The antibodies were also measured in 562 children and 102 adults from the general population of Colorado. Results: The prevalence of SARS-CoV-2 antibodies in persons with new-onset type 1 diabetes (0.8%; 95% confidence interval 0.1%-4.2%) or those with established disease (4.3%; 1.7%-10.4%) did not differ from that in the general population children (2.8%; 1.8%-4.6%) or adults (3.9%; 1.5%-9.7%). In a subset of individuals with positive antibodies (n = 31), antibodies remained positive for up to 9 months, although the levels decreased starting 3 months after the infection (P = 0.007). Conclusions: From January to October 2020, the prevalence of SARS-CoV-2 antibodies were not different in children and adults with and without type 1 diabetes in Colorado. We found no evidence for increased prevalence of COVID-19 infections among youth with newly diagnosed type 1 diabetes. (COMIRB Protocol 20-1007).
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Affiliation(s)
- Xiaofan Jia
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Patricia Gesualdo
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Cristy Geno Rasmussen
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Aimon A. Alkanani
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ling He
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Fran Dong
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Marian J. Rewers
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Aaron W. Michels
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Address correspondence to: Liping Yu, MD, Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Court, Building M20, B140, Aurora, CO 80045, USA
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Sabljic AV, Bombicino SS, Marfía JI, Guerra LL, Steinhardt AP, Faccinetti NI, Iacono RF, Poskus E, Trabucchi A, Valdez SN. Novel Flow Cytometric Immunoassay for Detection of Proinsulin Autoantibodies in Diabetes Mellitus Employing a Recombinant Autoantigen Expressed in E. coli. Front Immunol 2021; 12:648021. [PMID: 33889155 PMCID: PMC8056981 DOI: 10.3389/fimmu.2021.648021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/17/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction Insulin and proinsulin autoantibodies (IAA/PAA) are usually the first markers to appear in patients with type 1 Diabetes Mellitus (T1DM) and their prevalence ranges from 10 to 60% in the child-adolescent population. The reference method for IAA/PAA detection is the Radioligand Binding Assay (RBA), a highly specific and sensitive technique, but expensive and polluting. The aim of this work was to develop a novel flow cytometric microsphere-based immunoassay (FloCMIA) for PAA detection, employing recombinant human proinsulin (PI), as an alternative method to RBA, less expensive and harmful to the environment. Materials and Methods Human PI was expressed as Thioredoxin fusion protein (TrxPI) in E. coli and a fraction was biotinylated. A double paratope model was used in which samples were incubated with TrxPI-biotin and microspheres adsorbed with TrxPI. The immune complexes were revealed using Streptavidin-Phycoerythrin. The geometric mean of the signals was analyzed, and the results were expressed as Standard Deviation scores (SDs). Sera from 100 normal human control and from 111 type 1 diabetic patients were evaluated by FloCMIA. To correlate the novel assay with RBA, 51 diabetic patients were selected, spanning a wide range of PAA reactivity by RBA. Results The study of ROC curves allowed choosing a cut-off value of 3.0 SDs and the AUC was 0.705, indicating that FloCMIA has fair ability to distinguish between samples from each group. A prevalence of 50% for PAA was obtained in the population of diabetic patients studied. The specificity was 96% and the analytical sensitivity (percentage of patients RBA positive, also positive by FloCMIA) was 69%. There was a substantial agreement between methods (kappa statistic=0.700). Conclusions A novel immunoassay based on flow cytometry that uses easy-to produce recombinant PI was developed. This assay constitutes an innovative and cost-effective alternative to RBA for the determination of PAA in patients' sera. The method developed here, presents good performance and a wide dynamic range together with a small required sample volume. Furthermore, these results make it possible to develop multiplex immunoassays that allow the combined detection of autoantibodies present in T1DM and other related autoimmune diseases.
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Affiliation(s)
- Adriana Victoria Sabljic
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Silvina Sonia Bombicino
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Juan Ignacio Marfía
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Luciano Lucas Guerra
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
| | - Alberto Penas Steinhardt
- Universidad Nacional de Lujan, Departamento de Ciencias Básicas, Laboratorio de Genómica Computacional, Buenos Aires, Argentina
| | - Natalia Inés Faccinetti
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
| | - Rubén Francisco Iacono
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Edgardo Poskus
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Aldana Trabucchi
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
| | - Silvina Noemí Valdez
- Universidad de Buenos Aires (UBA), Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Inmunología, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Universidad de Buenos Aires, Instituto de Estudios de la Inmunidad Humoral “Prof. Ricardo A. Margni” (IDEHU), Buenos Aires, Argentina
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Triolo TM, Pyle L, Seligova S, Yu L, Simmons K, Gottlieb P, Evans-Molina C, Steck AK. Proinsulin:C-peptide ratio trajectories over time in relatives at increased risk of progression to type 1 diabetes. J Transl Autoimmun 2021; 4:100089. [PMID: 33748733 PMCID: PMC7972972 DOI: 10.1016/j.jtauto.2021.100089] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/04/2021] [Accepted: 02/12/2021] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Biomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes. METHODS We measured PI:C ratios and autoantibodies with both electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA and ECL-IA2A) and radiobinding (RBA) assays (mIAA, GADA, IA2A and ZnT8A) in 98 relatives of individuals with type 1 diabetes followed in the TrialNet Pathway to Prevention Study at the Barbara Davis Center for a mean of 7.4 ± 4.1 years. Of these subjects, eight progressed to T1D, 31 were multiple autoantibody (Ab) positive, 37 were single Ab positive and 22 were Ab negative (by RBA). RESULTS In cross-sectional analyses, there were no significant differences in PI:C ratios between type 1 diabetes and/or multiple Ab positive subjects (4.16 ± 4.06) compared to single Ab positive subjects (4.08 ± 4.34) and negative Ab subjects (3.72 ± 3.78) (p = 0.92) overall or after adjusting for age, sex and BMI. Higher PI:C ratios were associated with mIAA titers (p = 0.03) and showed an association with ECL-IA2A titers (p = 0.09), but not with ECL-IAA, GADA, ECL-GADA, IA2A nor ZnT8A titers. In mixed-effects longitudinal models, the trajectories of PI:C ratio over time were significantly different between the Ab negative and multiple Ab positive/type 1 diabetes groups, after adjusting for sex, age, and BMI (p = 0.04). CONCLUSIONS PI:C ratio trajectories increase over time in subjects who have multiple Ab or develop type 1 diabetes and may be a helpful biomarker to further characterize and stratify risk of progression to type 1 diabetes over time.
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Affiliation(s)
- Taylor M Triolo
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Laura Pyle
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA.,University of Colorado Anschutz Medical Campus, Pediatrics, Aurora, CO, USA
| | - Sona Seligova
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Liping Yu
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Kimber Simmons
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Peter Gottlieb
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
| | - Carmella Evans-Molina
- Indiana University School of Medicine, Indianapolis, IN, USA.,Indiana University Center for Diabetes and Metabolic Diseases. Indianapolis, IN, USA
| | - Andrea K Steck
- University of Colorado Denver School of Medicine - the Barbara Davis Center for Diabetes, Aurora, CO, USA
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Broome DT, Pantalone KM, Kashyap SR, Philipson LH. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab 2021; 106:237-250. [PMID: 33034350 PMCID: PMC7765647 DOI: 10.1210/clinem/dgaa710] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/02/2020] [Indexed: 12/14/2022]
Abstract
UNLABELLED Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES Upon completion of this educational activity, participants should be able to. TARGET AUDIENCE This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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Affiliation(s)
- David T Broome
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
- Correspondence and Reprint Requests: David T. Broome, MD, Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail code: F-20, Cleveland, OH 44195, USA. E-mail:
| | - Kevin M Pantalone
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Sangeeta R Kashyap
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Louis H Philipson
- Kovler Diabetes Center, Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois
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Cortez FDJ, Gebhart D, Robinson PV, Seftel D, Pourmandi N, Owyoung J, Bertozzi CR, Wilson DM, Maahs DM, Buckingham BA, Mills JR, Roforth MM, Pittock SJ, McKeon A, Page K, Wolf WA, Sanda S, Speake C, Greenbaum CJ, Tsai CT. Sensitive detection of multiple islet autoantibodies in type 1 diabetes using small sample volumes by agglutination-PCR. PLoS One 2020; 15:e0242049. [PMID: 33186361 PMCID: PMC7665791 DOI: 10.1371/journal.pone.0242049] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Islet autoantibodies are predominantly measured by radioassay to facilitate risk assessment and diagnosis of type 1 diabetes. However, the reliance on radioactive components, large sample volumes and limited throughput renders radioassay testing costly and challenging. We developed a multiplex analysis platform based on antibody detection by agglutination-PCR (ADAP) for the sample-sparing measurement of GAD, IA-2 and insulin autoantibodies/antibodies in 1 μL serum. The assay was developed and validated in 7 distinct cohorts (n = 858) with the majority of the cohorts blinded prior to analysis. Measurements from the ADAP assay were compared to radioassay to determine correlation, concordance, agreement, clinical sensitivity and specificity. The average overall agreement between ADAP and radioassay was above 91%. The average clinical sensitivity and specificity were 96% and 97%. In the IASP 2018 workshop, ADAP achieved the highest sensitivity of all assays tested at 95% specificity (AS95) rating for GAD and IA-2 autoantibodies and top-tier performance for insulin autoantibodies. Furthermore, ADAP correctly identified 95% high-risk individuals with two or more autoantibodies by radioassay amongst 39 relatives of T1D patients tested. In conclusion, the new ADAP assay can reliably detect the three cardinal islet autoantibodies/antibodies in 1μL serum with high sensitivity. This novel assay may improve pediatric testing compliance and facilitate easier community-wide screening for islet autoantibodies.
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Affiliation(s)
| | - David Gebhart
- Enable Biosciences Inc., South San Francisco, CA, United States of America
| | - Peter V. Robinson
- Enable Biosciences Inc., South San Francisco, CA, United States of America
| | - David Seftel
- Enable Biosciences Inc., South San Francisco, CA, United States of America
| | - Narges Pourmandi
- Enable Biosciences Inc., South San Francisco, CA, United States of America
| | - Jordan Owyoung
- Enable Biosciences Inc., South San Francisco, CA, United States of America
| | - Carolyn R. Bertozzi
- Department of Chemistry, Stanford University, Stanford, CA, United States of America
- Stanford Diabetes Research Center, Stanford, CA, United States of America
| | - Darrell M. Wilson
- Stanford Diabetes Research Center, Stanford, CA, United States of America
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - David M. Maahs
- Stanford Diabetes Research Center, Stanford, CA, United States of America
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Bruce A. Buckingham
- Stanford Diabetes Research Center, Stanford, CA, United States of America
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America
| | - John R. Mills
- Department of Laboratory Medicine/Pathology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
| | - Matthew M. Roforth
- Department of Laboratory Medicine/Pathology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
| | - Sean J. Pittock
- Department of Laboratory Medicine/Pathology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
| | - Andrew McKeon
- Department of Laboratory Medicine/Pathology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
- Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN, United States of America
| | - Kara Page
- T1D Exchange, Boston, MA, United States of America
| | | | - Srinath Sanda
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States of America
| | - Cate Speake
- Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, United States of America
| | - Carla J. Greenbaum
- Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, United States of America
| | - Cheng-ting Tsai
- Enable Biosciences Inc., South San Francisco, CA, United States of America
- * E-mail:
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Onengut-Gumuscu S, Paila U, Chen WM, Ratan A, Zhu Z, Steck AK, Frohnert BI, Waugh KC, Webb-Robertson BJM, Norris JM, Lange LA, Rewers MJ, Rich SS. Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes. Sci Rep 2020; 10:19193. [PMID: 33154504 PMCID: PMC7645414 DOI: 10.1038/s41598-020-75690-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 10/14/2020] [Indexed: 11/08/2022] Open
Abstract
Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10-8) and three regions, 1q21.3 (MRPS21-PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10-8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.
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Affiliation(s)
- Suna Onengut-Gumuscu
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA.
| | - Umadevi Paila
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
| | - Wei-Min Chen
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
| | - Aakrosh Ratan
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
| | - Zhennan Zhu
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Brigitte I Frohnert
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kathleen C Waugh
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Bobbie-Jo M Webb-Robertson
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jill M Norris
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Leslie A Lange
- Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, PO Box 800717, Charlottesville, VA, 22908, USA
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Kawasaki E, Oikawa Y, Okada A, Kanatsuna N, Kawamura T, Kikuchi T, Terasaki J, Miura J, Ito Y, Hanafusa T. Zinc transporter 8 autoantibodies complement glutamic acid decarboxylase and insulinoma-associated antigen-2 autoantibodies in the identification and characterization of Japanese type 1 diabetes. J Diabetes Investig 2020; 11:1181-1187. [PMID: 32175683 PMCID: PMC7477512 DOI: 10.1111/jdi.13251] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 03/06/2020] [Accepted: 03/11/2020] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
| | - Yoichi Oikawa
- Department of Internal MedicineTokyo Saiseikai Central HospitalTokyoJapan
- Department of Endocrinology and DiabetesSchool of MedicineSaitama Medical UniversitySaitamaJapan
| | | | - Norio Kanatsuna
- Department of Internal Medicine (I)Osaka Medical CollegeTakatsukiJapan
| | - Tomoyuki Kawamura
- Department of PediatricsOsaka City University Graduate School of MedicineOsakaJapan
| | | | - Jungo Terasaki
- Department of Internal Medicine (I)Osaka Medical CollegeTakatsukiJapan
| | - Junnosuke Miura
- Diabetes CenterTokyo Women’s Medical University School of MedicineTokyoJapan
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Jia X, Gu Y, High H, Yu L. Islet autoantibodies in disease prediction and pathogenesis. Diabetol Int 2020; 11:6-10. [PMID: 31949998 PMCID: PMC6942067 DOI: 10.1007/s13340-019-00414-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 10/03/2019] [Indexed: 01/01/2023]
Abstract
Type 1 diabetes (T1D) is now predictable by measuring specific islet autoantibodies (IAbs). Almost all children who developed multiple IAbs will progress to T1D with time, while individuals with single IAb have a very low risk although it is an important earlier biomarker. The poor prediction of single IAb has been found to be associated with IAb affinity. Majority of single IAb generated in current standard IAb radio-binding assay (RBA) are of low affinity, which have been demonstrated low risk in T1D development. New generation of nonradioactive IAb assay with electrochemiluminescence (ECL) technology has been shown to discriminate high-affinity from low-affinity IAbs and greatly improve sensitivity and disease specificity. With a high-affinity IAb assay, like ECL assay, single IAb will be expected to be a reliable biomarker for T1D early prediction. Although appearance of IAbs is most reliable biomarkers for T1D, there are no direct evidences that IAbs contribute to β-cell damage. With recent studies on ZnT8, a merging protein on β-cell surface membrane associated with insulin secretion, a subclass of ZnT8 autoantibodies directed to extra-cellular epitopes of ZnT8 on β-cell surface has recently been identified in T1D patients and these cell surface autoantibodies have been found to appear very early, before other IAbs. These findings lead us to a hypothesis that the immunogenic epitopes on β-cell surface might be early targets for autoimmune disease and IAbs to cell surface epitopes might be involved in β-cell destruction, which will change the paradigm of IAbs in T1D pathogenesis.
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Affiliation(s)
- Xiaofan Jia
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045 USA
- Department of Endocrinology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Yong Gu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045 USA
| | - Hilary High
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045 USA
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045 USA
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Shao F, Zheng P, Yu D, Zhou Z, Jia L. Follicular helper T cells in type 1 diabetes. FASEB J 2019; 34:30-40. [PMID: 31914661 DOI: 10.1096/fj.201901637r] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 11/09/2019] [Accepted: 11/25/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Feng Shao
- Department of Metabolism & Endocrinology The Second Xiangya HospitalCentral South University Changsha China
- Key Laboratory of Diabetes Immunology Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases Changsha China
| | - Peilin Zheng
- Department of Endocrinology, Shenzhen People’s Hospital The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology Shenzhen China
| | - Di Yu
- The University of Queensland Diamantina Institute, Translational Research Institute Brisbane Queensland Australia
- Shandong Analysis and Test Center Shandong Academy of Sciences Jinan China
- China‐Australia Centre for Personalised Immunology Shanghai Renji Hospital Shanghai Jiaotong University School of Medicine Shanghai China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology The Second Xiangya HospitalCentral South University Changsha China
- Key Laboratory of Diabetes Immunology Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases Changsha China
| | - Lijing Jia
- Department of Endocrinology, Shenzhen People’s Hospital The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology Shenzhen China
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Gu Y, Zhao Z, Waugh K, Miao D, Jia X, Cheng J, Michels A, Rewers M, Yang T, Yu L. High-throughput multiplexed autoantibody detection to screen type 1 diabetes and multiple autoimmune diseases simultaneously. EBioMedicine 2019; 47:365-372. [PMID: 31447394 PMCID: PMC6796526 DOI: 10.1016/j.ebiom.2019.08.036] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/16/2019] [Accepted: 08/18/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Islet autoantibodies (IAbs) are the most reliable biomarkers to assess risk of progression to clinical type 1 diabetes (T1D). There are four major biochemically defined IAbs currently used in clinical trials that are equally important for disease prediction. The current screening methods use a radio-binding assay (RBA) for single IAb measurement, which are laborious and inefficient for large-scale screening. More importantly, up to 40% of patients with T1D have other autoimmune conditions that can be identified through relevant autoantibody testing. Thus, there is a need to screen for T1D and other autoimmune diseases simultaneously. METHODS Based on our well-established electrochemiluminescence (ECL) assay platform, we developed a multiplexed ECL assay that combines 7 individual autoantibody assays together in one single well to simultaneously screen T1D, and three other autoimmune diseases including celiac disease, autoimmune thyroid disease and autoimmune poly-glandular syndrome-1 (APS-1). The 7-Plex ECL assay was extensively validated against single antibody measurements including a standard RBA and single ECL assay. FINDINGS The 7-Plex ECL assay was well correlated to each single ECL autoantibody assay and each RBA. INTERPRETATION The multiplexed ECL assay provides high sensitivity and disease specificity, along with high throughput and a low cost for large-scale screenings of T1D and other relevant autoimmune diseases in the general population. FUND: JDRF grants 2-SRA-2015-51-Q-R, 2-SRA-2018-533-S-B, NIH grants DK32083 and DK32493. NSFC grants 81770777.
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Affiliation(s)
- Yong Gu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America,Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, China
| | - Zhiyuan Zhao
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Kathleen Waugh
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Dongmei Miao
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Xiaofan Jia
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Jeremy Cheng
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Aaron Michels
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America
| | - Tao Yang
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, China
| | - Liping Yu
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, United States of America,Corresponding author at: Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, B140, Aurora, CO 80045, United States of America.
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Simmons KM, Fouts A, Pyle L, Clark P, Dong F, Yu L, Usmani-Brown S, Gottlieb P, Herold KC, Steck AK. Unmethylated Insulin as an Adjunctive Marker of Beta Cell Death and Progression to Type 1 Diabetes in Participants at Risk for Diabetes. Int J Mol Sci 2019; 20:ijms20163857. [PMID: 31398795 PMCID: PMC6719233 DOI: 10.3390/ijms20163857] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 08/01/2019] [Accepted: 08/02/2019] [Indexed: 12/12/2022] Open
Abstract
Islet autoantibody (iAb)-positive individuals have a high risk of progression to type 1 diabetes (T1D), although the rate of progression is highly variable and factors involved in the rate of progression are largely unknown. The ratio of unmethylated/methylated insulin DNA levels (unmethylated INS ratio) has been shown to be higher in participants at high risk of T1D compared to healthy controls. We aimed to evaluate whether an unmethylated INS ratio may be a useful biomarker of beta cell death and rate of progression to T1D. In TrialNet participants who were followed in the Pathway to Prevention Study and progressed to diabetes (n = 57, median age of onset 15.3 years), we measured unmethylated INS ratio and autoantibodies by electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA, and ECL-IA2) and radioimmunoassays (RIA) (mIAA, GADA, IA2A, and ZnT8A) longitudinally for 24 months prior to diagnosis. Linear models were used to test the association between unmethylated INS ratio and the age at T1D diagnosis and unmethylated INS ratio and iAb over time. Close to diabetes onset, the unmethylated INS ratio was associated with mIAA (p = 0.003), ECL-IAA (p = 0.002), and IA2A (p = 0.01) levels, but not with GADA, ECL-GADA, ECL-IA2, or ZnT8A levels. No significant associations were found at baseline (24 months prior to T1D diagnosis). Only mIAA levels were significantly associated with an unmethylated INS ratio over time, with a 0.24 change in the ratio for each 0.1 change in mIAA z-score (p = 0.02). Adjusting for a baseline unmethylated INS ratio, an increased rate of change in unmethylated INS ratio from baseline to diabetes onset was associated with a five-year decrease in age at T1D diagnosis (p = 0.04).
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Grants
- 5RA-2017 Juvenile Diabetes Research Foundation United States of America
- U01 DK061010 NIDDK NIH HHS
- U01 DK103153 NIDDK NIH HHS
- P30 DK045735 NIDDK NIH HHS
- K12 DK094712 NIDDK NIH HHS
- UL1 TR001863 NCATS NIH HHS
- 1-14-CD-17 American Diabetes Association
- U01 DK061010, U01 DK061034, U01 DK061042, U01 DK061058, U01 DK085465, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085466, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK103180, U01-DK103153, U01-DK085476, U01-DK103266 NIH HHS
- DK094712-08 NIDDK NIH HHS
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Affiliation(s)
- Kimber M Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA.
| | - Alexandra Fouts
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA
| | - Laura Pyle
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | | | - Fran Dong
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA
| | | | - Peter Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA
| | | | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, 1775 Aurora Ct, MSA140, Bldg 20, Aurora, CO 80045, USA
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Shi X, Huang G, Wang Y, Liu Z, Deng C, Li X, Zheng P, Zhou Z. Tetraspanin 7 autoantibodies predict progressive decline of beta cell function in individuals with LADA. Diabetologia 2019; 62:399-407. [PMID: 30594957 DOI: 10.1007/s00125-018-4799-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 11/27/2018] [Indexed: 12/26/2022]
Abstract
AIMS/HYPOTHESIS The aim of this work was to investigate whether tetraspanin 7 autoantibodies (TSPAN7A) are valuable in predicting poor beta cell function in individuals with latent autoimmune diabetes in adults (LADA). METHODS The cross-sectional study involved participants with LADA (n = 173), type 1 diabetes (n = 158), type 2 diabetes (n = 204) and healthy control participants (n = 170). The longitudinal study involved 53 participants with LADA, with a 3-year follow-up. In both cohorts, TSPAN7A in the sera were measured by a luciferase immunoprecipitation system assay, and physical and clinical characteristics were recorded. RESULTS The prevalence of TSPAN7A in LADA, type 1 diabetes, type 2 diabetes and healthy control participants was 21.4% (37/173), 26% (41/158), 0.5% (1/204) and 1.2% (2/170), respectively. Importantly, measurement of TSPAN7A significantly increased the number of individuals with LADA found to be positive for multiple antibodies (32.4% vs 22%; p < 0.001). Further logistic regression analysis demonstrated that positivity for TSPAN7A (OR 2.87, p = 0.034), disease duration (OR 1.83, p = 0.019) and GAD antibody titre (OR 2.67, p = 0.009) were risk factors for beta cell function in LADA, while BMI (OR 0.34, p = 0.001) was a protective factor. In the prospective study in individuals with LADA, the median annual decrease in rates of fasting C-peptide and 2 h postprandial C-peptide in individuals who were positive for TSPAN7A was significantly higher when compared with the decrease in those who were negative for TSPAN7A (34.6% vs 7.9%, p = 0.043 and 33.2% vs 11%, p = 0.041, respectively). CONCLUSIONS/INTERPRETATION TSPAN7A are valid islet autoantibodies for use in East Asian populations with autoimmune diabetes and can discriminate individuals with LADA who have lower beta cell function after disease progression.
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Affiliation(s)
- Xiajie Shi
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yanfei Wang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA, USA
| | - Chao Deng
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Peilin Zheng
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
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Zhao Z, Gu Y, Miao D, Hoffmeyer E, Liu Y, Yu L. Determination of Autoantibodies to Transglutaminase by Electrochemiluminescence (ECL) Assay. Methods Mol Biol 2019; 1901:197-203. [PMID: 30539579 DOI: 10.1007/978-1-4939-8949-2_16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Appearance of autoantibodies to tissue transglutaminase (TGA) is the most reliable biomarker to identify celiac disease autoimmunity. A nonradioactive assay of determination of TGA was newly developed using electrochemiluminescence (ECL) technology. This ECL assay has been demonstrated to be more sensitive than current standard radio-binding assay (RBA) in detecting TGA and can detect TGA earlier among high-risk young children followed from birth.
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Affiliation(s)
- Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
- Department of Endocrinology, The Second Hospital of Jilin University, Jilin, China
| | - Yong Gu
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Eric Hoffmeyer
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA
| | - Yu Liu
- Department of Endocrinology, The Second Hospital of Jilin University, Jilin, China
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA.
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Ling Y, Jiang P, Li N, Yan Q, Wang X. A luciferase immunoprecipitation assay for the detection of proinsulin/insulin autoantibodies. Clin Biochem 2018; 54:51-55. [DOI: 10.1016/j.clinbiochem.2018.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 02/13/2018] [Accepted: 02/15/2018] [Indexed: 12/29/2022]
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Gu Y, Zhao Z, Miao D, High H, Yang T, Yu L. Electrochemiluminescence Assays for Human Islet Autoantibodies. J Vis Exp 2018. [PMID: 29630056 PMCID: PMC5933252 DOI: 10.3791/57227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Pinpointing islet autoantibodies associated with type 1 diabetes (T1D) leads the way to project and deter this disease in the general population. A novel ECL assay is a nonradioactive fluid phase assay for islet autoantibodies with higher sensitivity and specificity than the current 'gold' standard radio-binding assay (RBA). ECL assays can more precisely define the onset of presymptomatic T1D by distinguishing the high-risk, high-affinity autoantibodies from the low-risk, low-affinity autoantibodies generated in RBAs, and conventional enzyme-linked immunosorbent assays (ELISA). The antigen protein used in this ECL assay is labeled with Sulfo-tag and Biotin, respectively. Each ECL autoantibody assay that uses a particular antigen protein needs an optimization step before it can be used for laboratory application. This step is especially vital in determining the requirements for serum acid treatments, concentrations, and ratios of the two different antigens labeled with Sulfo-tag and Biotin. To perform the assay, serum samples are mixed with Sulfo-tag-conjugated and biotinylated capture antigen protein in phosphate buffered solution (PBS), containing 5% Bovine Serum Albumin (BSA). Afterwards, the samples are incubated overnight at 4 °C. The same day, a streptavidin-coated plate is prepared with blocker buffer and incubated overnight at 4 °C. On the second day, wash the streptavidin plate and transfer the serum-antigen mixture onto the plate. Place the plate on the plate shaker, set it at low speed, and incubate at room temperature for 1 h. Subsequently, the plate is washed again, and reader buffer is added. The plate is then counted on the plate reader machine. The results are conveyed through an index, which is generated from internal standard positive and negative control serum samples.
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Affiliation(s)
- Yong Gu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver; Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver
| | - Hilary High
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver
| | - Tao Yang
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver;
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Liberati D, Wyatt RC, Brigatti C, Marzinotto I, Ferrari M, Bazzigaluppi E, Bosi E, Gillard BT, Gillespie KM, Gorus F, Weets I, Balti E, Piemonti L, Achenbach P, Williams AJK, Lampasona V. A novel LIPS assay for insulin autoantibodies. Acta Diabetol 2018; 55:263-270. [PMID: 29305766 DOI: 10.1007/s00592-017-1082-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2017] [Accepted: 11/20/2017] [Indexed: 12/26/2022]
Abstract
AIMS Insulin autoantibodies (IAA) are often the first marker of autoimmunity detected in children in the preclinical phase of type 1 diabetes (T1D). Currently, the vast majority of laboratories adopt the radiobinding micro-assay (RBA) for measuring IAA. Our aim was to replace RBA with a novel non-radioactive IAA Luciferase Immuno Precipitation System (LIPS) assay with improved performance. METHODS We developed (pro)insulin antigens with alternative placements of a NanoLuc™ luciferase reporter (NLuc). Performance in LIPS was evaluated by testing sera from new onset T1D (n = 80), blood donors (n = 123), schoolchildren (n = 186), first-degree relatives (FDRs) from the Bart's Oxford family study (n = 53) and from the Belgian Diabetes Registry (n = 136), coded sera from the Islet Autoantibody Standardization Program (IASP) (T1D n = 50, blood donors n = 90). RESULTS IAA LIPS based on B chain-NLuc proinsulin or B chain-NLuc insulin, in which NLuc was fused at the C-terminus of the insulin B chain, required only 2 μL of serum and a short incubation time, showed high concordance with RBA (Spearman r = 0.866 and 0.833, respectively), high assay performance (B chain-NLuc proinsulin ROC-AUC = 0.894 and B chain-NLuc insulin ROC-AUC = 0.916), and an adjusted sensitivity at 95% specificity ranking on par with the best assays submitted to the two most recent IASP workshops. In FDRs, the IAA LIPS showed improved discrimination of progressors to T1D compared to RBA. CONCLUSIONS We established a novel high-performance non-radioactive IAA LIPS that might replace the current gold standard RBA and find wide application in the study of the IAA response in T1D.
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Affiliation(s)
- Daniela Liberati
- Human Pathology Genomic Diagnostics Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rebecca C Wyatt
- Diabetes and Metabolism Unit, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Cristina Brigatti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ilaria Marzinotto
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maurizio Ferrari
- Human Pathology Genomic Diagnostics Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Elena Bazzigaluppi
- Department of Laboratory Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Ben T Gillard
- Diabetes and Metabolism Unit, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Kathleen M Gillespie
- Diabetes and Metabolism Unit, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Frans Gorus
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Department of Clinical Chemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Ilse Weets
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Department of Clinical Chemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Eric Balti
- Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- Department of Clinical Chemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany
| | - Alistair J K Williams
- Diabetes and Metabolism Unit, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Vito Lampasona
- Human Pathology Genomic Diagnostics Unit, Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
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Gu Y, Zhao Z, High H, Yang T, Yu L. Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay. ACTA ACUST UNITED AC 2017; 8. [PMID: 29487479 PMCID: PMC5796772 DOI: 10.4172/2155-9899.1000531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Yong Gu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA.,Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Hilary High
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Tao Yang
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
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Duan K, Ghosh G, Lo JF. Optimizing Multiplexed Detections of Diabetes Antibodies via Quantitative Microfluidic Droplet Array. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2017; 13:10.1002/smll.201702323. [PMID: 28990274 PMCID: PMC5755373 DOI: 10.1002/smll.201702323] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Revised: 08/11/2017] [Indexed: 05/02/2023]
Abstract
Sensitive, single volume detections of multiple diabetes antibodies can provide immunoprofiling and early screening of at-risk patients. To advance the state-of-the-art suspension assays for diabetes antibodies, porous hydrogel droplets are leveraged in microfluidic serpentine arrays to enhance reagent transport. This spatially multiplexed assay is applied to the detection of antibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2. Optimization of assay protocol results in a shortened assay time of 2 h, with better than 20 pg mL Supporting Information detection limits across all three antibodies. Specificity and cross-reactivity tests show negligible background, nonspecific antibody-antigen, and nonspecific antibody-antibody bindings. Multiplexed detections are able to measure within 15% of target concentrations from low to high ranges. The technique enables quantifications of as little as 8000 molecules in each 500 µm droplet in a single volume, multiplexed assay format, a breakthrough necessary for the adoption of diabetes panels for clinical screening and monitoring in the future.
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Affiliation(s)
- Kai Duan
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan at Dearborn, Dearborn, MI, 48128, USA
| | - Gargi Ghosh
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan at Dearborn, Dearborn, MI, 48128, USA
| | - Joe Fujiou Lo
- Bioengineering Program, Department of Mechanical Engineering, University of Michigan at Dearborn, Dearborn, MI, 48128, USA
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Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin and other pancreatic β cells proteins including GAD65 (GADA), islet antigen 2 (IA-2A), and zinc transporter 8 (ZnT8A). The assay technology for IAbs has made great progress; however, several important aspects still need to be addressed and improved. RECENT FINDINGS Currently a radio-binding assay has been well established as the 'gold' standard assay for all four IAbs. New generation of nonradioactive IAb assay with electrochemiluminescence technology has been shown to further improve sensitivity and disease specificity. Recently, multiplexed assays have opened the possibility of more efficient screening in large populations. Identification of potential new autoantibodies to neo-antigens or neo-epitopes posttranslational modification is a new important field to be explored. SUMMARY Individuals having a single positive autoantibody are at low risk for progression to T1D, whereas individuals expressing two or more positive autoantibodies, especially on multiple tests over time, have nearly 100% risk of developing clinical T1D when followed for over two decades. More efficient and cost effective IAb assays will hopefully lead to point-of-care screening in the general population.
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Affiliation(s)
- Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
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Sosenko JM, Yu L, Skyler JS, Krischer JP, Gottlieb PA, Boulware D, Miao D, Palmer JP, Steck AK. The Use of Electrochemiluminescence Assays to Predict Autoantibody and Glycemic Progression Toward Type 1 Diabetes in Individuals with Single Autoantibodies. Diabetes Technol Ther 2017; 19:183-187. [PMID: 28177779 PMCID: PMC5359659 DOI: 10.1089/dia.2016.0243] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Electrochemiluminescence (ECL) assays have shown promise for enhancing the prediction of type 1 diabetes (T1D) with autoantibodies. We thus studied relatives of T1D patients to determine whether ECL assays can be used to refine risk assessments for T1D among individuals either positive for single GADA or single mIAA autoantibodies. SUBJECTS AND METHODS TrialNet Pathway to Prevention (PTP) study participants with either GADA or mIAA single autoantibodies were tested for ECL positivity during their participation in the TrialNet PTP study. Those ECL positive (ECL+) were compared with those ECL negative (ECL-) for conversion to multiple autoantibodies, 6-month glycemic progression (PS6M), and the progression to T1D. RESULTS The progression to multiple autoantibodies was significantly higher for those GADA/ECL+ (n = 107) than those GADA/ECL- (n = 78) (P = 0.001) and for those mIAA/ECL+ (n = 24) than those mIAA/ECL- (n = 63) (P < 0.001). The hazard ratios with 95% confidence intervals were 3.42 (1.58-7.39; P < 0.01) for GADA and 8.15 (3.02-22.00; P < 0.001) for mIAA. GADA/ECL+ and mIAA/ECL+ participants had significantly higher PS6M values than their ECL- counterparts (P = 0.001 for GADA and P = 0.009 for mIAA). Of those GADA/ECL+, 14% progressed to T1D; of those mIAA/ECL+, 17% progressed to T1D. Only 1 individual (positive for GADA) of the 141 who was ECL- progressed to T1D (median follow-up: 5 years). CONCLUSION ECL measurements appear to have utility for natural history studies and prevention trials of individuals with single autoantibodies. Those ECL+ are at appreciable risk for developing multiple autoantibodies and for glycemic progression toward T1D, whereas those ECL- are at very low risk.
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Affiliation(s)
- Jay M. Sosenko
- Division of Endocrinology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Jay S. Skyler
- Division of Endocrinology, University of Miami, Miller School of Medicine, Miami, Florida
| | - Jeffrey P. Krischer
- Division of Informatics and Biostatistics, University of South Florida, Tampa, Florida
| | - Peter A. Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - David Boulware
- Division of Informatics and Biostatistics, University of South Florida, Tampa, Florida
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Jerry P. Palmer
- VA Puget Sound Health Care System, Division of Endocrinology, Metabolism, and Nutrition, University of Washington, Seattle, Washington
| | - Andrea K. Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
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Higher Sensitivity and Earlier Identification of Celiac Disease Autoimmunity by a Nonradioactive Assay for Transglutaminase Autoantibodies. J Immunol Res 2017; 2016:2904563. [PMID: 28127566 PMCID: PMC5239972 DOI: 10.1155/2016/2904563] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/06/2016] [Indexed: 12/03/2022] Open
Abstract
Higher sensitive transglutaminase autoantibody (TGA) assay will detect the onset of celiac disease (CD) autoimmunity earlier. In developing a nonradioactive assay for TGA, we utilized electrochemiluminescence (ECL) technology and compared it to a high-performance radioimmunoassay (RIA) currently being used to screen patients with type 1 diabetes (T1D) and genetically at-risk individuals for CD. We selected 183 T1D patients with 60 patients having received biopsy and analyzed 396 sequential samples from 73 young children longitudinally followed up with TGA seroconversion, with 27 undergoing biopsy. In addition, 112 age-matched healthy control subjects were included in the study. With the 99th percentile of specificity, the ECL assay detected significantly more TGA positivity among patients with T1D (133/183) than RIA (114/183) and more of the sequential samples (34%) from 73 children than RIA (18%). The TGA assay performed by ECL was positive in all 59 subjects with villous atrophy. Among 73 longitudinally followed up children, ECL assay had earlier detection of TGA on 34 children by a mean of 2.5 years. In conclusion, the new TGA assay by ECL has a higher sensitivity than the current RIA assay and may better predict the onset of CD.
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The progress of luminescent assay in clinical diagnosis and treatment of diabetes mellitus. J Electroanal Chem (Lausanne) 2016. [DOI: 10.1016/j.jelechem.2016.07.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Affiliation(s)
- Zhiyuan Zhao
- 1 Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine , Aurora, Colorado
- 2 Department of Endocrinology, Second Hospital of Jilin University , Changchun, Jilin, China
| | - Liping Yu
- 1 Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine , Aurora, Colorado
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Endesfelder D, Hagen M, Winkler C, Haupt F, Zillmer S, Knopff A, Bonifacio E, Ziegler AG, Zu Castell W, Achenbach P. A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. Diabetologia 2016; 59:2172-80. [PMID: 27400691 DOI: 10.1007/s00125-016-4050-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 06/15/2016] [Indexed: 12/30/2022]
Abstract
AIMS/HYPOTHESIS Progression to type 1 diabetes in children and adolescents is not uniform. Based on individual genetic background and environment, islet autoimmunity may develop at variable age, exhibit different autoantibody profiles and progress to clinical diabetes at variable rates. Here, we aimed to quantify the qualitative dynamics of sequential islet autoantibody profiles in order to identify longitudinal patterns that stratify progression rates to type 1 diabetes in multiple-autoantibody-positive children. METHODS Qualitative changes in antibody status on follow-up and progression rate to diabetes were analysed in 88 children followed from birth in the prospective BABYDIAB study who developed multiple autoantibodies against insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and/or zinc transporter 8 (ZnT8A). An algorithm was developed to define similarities in sequential autoantibody profiles and hierarchical clustering was performed to group children with similar profiles. RESULTS We defined nine clusters that distinguished children with respect to their sequential profiles of IAA, GADA, IA-2A and ZnT8A. Progression from first autoantibody appearance to clinical diabetes between clusters ranged from 6% (95% CI [0, 16.4]) to 73% (28.4, 89.6) within 5 years. Delayed progression was observed in children who were positive for only two autoantibodies, and for a cluster of 12 children who developed three or four autoantibodies but were IAA-negative in their last samples, nine of whom lost IAA positivity during follow-up. Among all children who first seroconverted to IAA positivity and developed at least two other autoantibodies (n = 57), the 10 year risk of diabetes was 23% (0, 42.9) in those who became IAA-negative during follow-up compared with 76% (58.7, 85.6) in those who remained IAA-positive (p = 0.004). CONCLUSIONS/INTERPRETATION The novel clustering approach provides a tool for stratification of islet autoantibody-positive individuals that has prognostic relevance, and new opportunities in elucidating disease mechanisms. Our data suggest that losing IAA reactivity is associated with delayed progression to type 1 diabetes in multiple-islet-autoantibody-positive children.
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Affiliation(s)
- David Endesfelder
- Scientific Computing Research Unit, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
| | - Michael Hagen
- Scientific Computing Research Unit, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
| | - Christiane Winkler
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Forschergruppe Diabetes e.V., Neuherberg, Germany
| | - Florian Haupt
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Stephanie Zillmer
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Annette Knopff
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Ezio Bonifacio
- Forschergruppe Diabetes e.V., Neuherberg, Germany
- DFG Research Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Technische Universität Dresden, Dresden, Germany
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Forschergruppe Diabetes e.V., Neuherberg, Germany
| | - Wolfgang Zu Castell
- Scientific Computing Research Unit, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
- Department of Mathematics, Technische Universität München, München, Germany.
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany.
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, München, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Forschergruppe Diabetes e.V., Neuherberg, Germany.
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Fouts A, Pyle L, Yu L, Miao D, Michels A, Krischer J, Sosenko J, Gottlieb P, Steck AK. Do Electrochemiluminescence Assays Improve Prediction of Time to Type 1 Diabetes in Autoantibody-Positive TrialNet Subjects? Diabetes Care 2016; 39:1738-44. [PMID: 27456836 PMCID: PMC5033080 DOI: 10.2337/dc16-0302] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 06/28/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To explore whether electrochemiluminescence (ECL) assays can help improve prediction of time to type 1 diabetes in the TrialNet autoantibody-positive population. RESEARCH DESIGN AND METHODS TrialNet subjects who were positive for one or more autoantibodies (microinsulin autoantibody, GAD65 autoantibody [GADA], IA-2A, and ZnT8A) with available ECL-insulin autoantibody (IAA) and ECL-GADA data at their initial visit were analyzed; after a median follow-up of 24 months, 177 of these 1,287 subjects developed diabetes. RESULTS Univariate analyses showed that autoantibodies by radioimmunoassays (RIAs), ECL-IAA, ECL-GADA, age, sex, number of positive autoantibodies, presence of HLA DR3/4-DQ8 genotype, HbA1c, and oral glucose tolerance test (OGTT) measurements were all significantly associated with progression to diabetes. Subjects who were ECL positive had a risk of progression to diabetes within 6 years of 58% compared with 5% for the ECL-negative subjects (P < 0.0001). Multivariate Cox proportional hazards models were compared, with the base model including age, sex, OGTT measurements, and number of positive autoantibodies by RIAs. The model with positivity for ECL-GADA and/or ECL-IAA was the best, and factors that remained significantly associated with time to diabetes were area under the curve (AUC) C-peptide, fasting C-peptide, AUC glucose, number of positive autoantibodies by RIAs, and ECL positivity. Adding ECL to the Diabetes Prevention Trial risk score (DPTRS) improved the receiver operating characteristic curves with AUC of 0.83 (P < 0.0001). CONCLUSIONS ECL assays improved the ability to predict time to diabetes in these autoantibody-positive relatives at risk for developing diabetes. These findings might be helpful in the design and eligibility criteria for prevention trials in the future.
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Affiliation(s)
- Alexandra Fouts
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Laura Pyle
- Department of Pediatrics, University of Colorado Denver, Aurora, CO Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Aaron Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Jeffrey Krischer
- Pediatrics Epidemiology Center, University of South Florida, Tampa, FL
| | - Jay Sosenko
- University of Miami School of Medicine, Miami, FL
| | - Peter Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
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Gesualdo PD, Bautista KA, Waugh KC, Yu L, Norris JM, Rewers MJ, Baxter J. Feasibility of screening for T1D and celiac disease in a pediatric clinic setting. Pediatr Diabetes 2016; 17:441-8. [PMID: 26251221 PMCID: PMC4979315 DOI: 10.1111/pedi.12301] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 07/02/2015] [Accepted: 07/06/2015] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Type 1 diabetes (T1D) or celiac disease (CD) develops in at least 2% of the general population. Early detection of disease-specific autoimmunity and subsequent monitoring would be possible if screening tests were more widely available. Currently, screening for islet autoimmunity is available only in a research setting, and CD-specific autoimmunity screening is limited to those in high-risk groups. This study assessed the feasibility of incorporating T1D and CD autoantibody screening into a pediatric practice. METHODS Patient engagement strategies, blood collection preference, blood sample volume, rate of autoantibody detection in the general population, and parental satisfaction were assessed. Over 5 weeks, research staff recruited 200 patients, aged 2-6 yr from two pediatric practices in the Denver area to be screened for islet autoantibodies (IAs) and the transglutaminase antibody. RESULTS Of the 765 parents approached, 200 (26%) completed the same-day screening. Of the 565 subjects who did not complete the screening, 345 expressed interest, but were unable to make a participation decision. A finger stick, compared with a venous draw, was the preferred method of sample collection. Both methods yielded sufficient blood volume for autoantibody determination. IAs or the transglutaminase antibody were detected in 11 subjects. Parents expressed satisfaction with all aspects of participation. CONCLUSIONS The results of this study suggest that it is feasible to conduct this type of screening in a pediatric clinic. Such screening could lead to increased disease awareness and the possible benefits that can result from early detection.
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Affiliation(s)
- Patricia D. Gesualdo
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
| | - Kimberly A. Bautista
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
| | - Kathleen C. Waugh
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
| | - Liping Yu
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, 13001 East 17th Place, Campus Box B119, Aurora, CO 80045
| | - Marian J. Rewers
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
| | - Judith Baxter
- University of Colorado Denver, Barbara Davis Center for Diabetes, 1775 Aurora Court, Campus Box F527, Aurora, CO 80045
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Abstract
PURPOSE OF REVIEW There are an increasing number of markers that are used to predict the occurrence of type 1 diabetes (T1D), and to study the progression of pathologic changes prior to diagnosis. This review discusses some of those markers, particularly markers for which data are available that pertain to the progression to T1D. RECENT FINDINGS A study of birth cohorts showed that young children who develop multiple autoantibodies are at a particularly high risk for developing T1D, and that there appears to be a typical sequence for autoantibody development. The measurement of autoantibodies by electrochemiluminescence can increase the prediction accuracy for T1D. A new marker of changes in glucose over 6 months (PS6 M) has potential utility as an endpoint in short-term prevention trials. Markers which combine C-peptide and glucose, such as the Diabetes Prevention Trial-Type 1 Risk Score and the Index60, can increase the accuracy of prediction, and can potentially be utilized as prediagnostic endpoints. β-cell death measurements could have substantial utility in future T1D research. SUMMARY Markers are highly useful for studying the prediction of and progression to T1D. Moreover, markers can possibly be utilized to diagnose T1D at an earlier stage of disease.
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Affiliation(s)
- Jay M. Sosenko
- Division of Endocrinology, University of Miami, Address: PO Box 016960 (D110), Miami, FL 33101, Phone: 305-243-6146, Fax: 305-243-4484,
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Steck AK, Fouts A, Miao D, Zhao Z, Dong F, Sosenko J, Gottlieb P, Rewers MJ, Yu L. ECL-IAA and ECL-GADA Can Identify High-Risk Single Autoantibody-Positive Relatives in the TrialNet Pathway to Prevention Study. Diabetes Technol Ther 2016; 18:410-4. [PMID: 26991969 PMCID: PMC4931768 DOI: 10.1089/dia.2015.0316] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Relatives with single positive islet autoantibodies have a much lower risk of progression to diabetes than those with multiple autoantibodies. MATERIALS AND METHODS TrialNet subjects positive for single autoantibody to insulin (mIAA) (n = 50) or single autoantibody to glutamic acid decarboxylase (GADA) (n = 50) were analyzed using new electrochemiluminescence (ECL) assays (ECL-IAA and ECL-GADA, respectively) at their initial visit and longitudinally over time. Affinity assays were performed on a subset of single autoantibody-positive subjects at initial and most recent visits. RESULTS After a mean follow-up of 5.3 years, 20 subjects developed type 1 diabetes. Among either single GADA or single mIAA subjects, those who were positive in the ECL assay showed higher affinity at the initial visit, and affinity results stayed consistent over time. No converting events from low to high or high to low affinity were seen over time. CONCLUSIONS Confirmed positivity for ECL is associated with high affinity and can help staging of risk for type 1 diabetes in single autoantibody-positive subjects.
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Affiliation(s)
- Andrea K. Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Alexandra Fouts
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Fran Dong
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Jay Sosenko
- University of Miami School of Medicine, Miami, Florida
| | - Peter Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Marian J. Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
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42
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Steck AK, Dong F, Waugh K, Frohnert BI, Yu L, Norris JM, Rewers MJ. Predictors of slow progression to diabetes in children with multiple islet autoantibodies. J Autoimmun 2016; 72:113-7. [PMID: 27255734 DOI: 10.1016/j.jaut.2016.05.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 05/18/2016] [Accepted: 05/23/2016] [Indexed: 01/04/2023]
Abstract
Although most children with multiple islet autoantibodies develop type 1 diabetes, rate of progression is highly variable. The goal of this study was to explore potential factors involved in rate of progression to diabetes in children with multiple islet autoantibodies. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 118 children with multiple islet autoantibodies for progression to diabetes. After excluding 27 children currently diabetes-free but followed for <10 years, the study population was grouped into: rapid progressors (N = 39) who developed diabetes in <5 years; moderate progressors (N = 25), diagnosed with diabetes within 5-10 years; and slow progressors (N = 27), diabetes-free for >10 years. Islet autoimmunity appeared at 4.0 ± 3.5, 3.2 ± 1.8 and 5.8 ± 3.1 years of age in rapid, moderate and slow progressors, respectively (p = 0.006). Insulin autoantibody levels were lower in slow progressors compared to moderate and rapid progressors. The groups did not differ by gender, ethnicity, family history, susceptibility HLA and non-HLA genes. The rate of development of individual islet autoantibodies including mIAA, GADA, IA-2A and ZnT8A were all slower in the slow versus moderate/rapid progressors. In multivariate analyses, older age at seroconversion and lower initial mIAA levels independently predicted slower progression to diabetes. Later onset of islet autoimmunity and lower autoantibody levels predicted slower progression to diabetes among children with multiple islet autoantibodies. These factors may need to be considered in the design of trials to prevent type 1 diabetes.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
| | - Fran Dong
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kathleen Waugh
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Brigitte I Frohnert
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jill M Norris
- Colorado School of Public Health, University of Colorado Denver, Aurora, CO, USA
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
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43
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Kodama K, Zhao Z, Toda K, Yip L, Fuhlbrigge R, Miao D, Fathman CG, Yamada S, Butte AJ, Yu L. Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes. Diabetes 2016; 65:1341-9. [PMID: 26983959 PMCID: PMC4839207 DOI: 10.2337/db15-1308] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 02/22/2016] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D-binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D.
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Affiliation(s)
- Keiichi Kodama
- Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - Kyoko Toda
- Biomedical Research Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| | - Linda Yip
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Rebecca Fuhlbrigge
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - C Garrison Fathman
- Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Satoru Yamada
- Diabetes Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan
| | - Atul J Butte
- Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
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44
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Tsai CT, Robinson P, Spencer C, Bertozzi CR. Ultrasensitive Antibody Detection by Agglutination-PCR (ADAP). ACS CENTRAL SCIENCE 2016; 2:139-147. [PMID: 27064772 PMCID: PMC4819452 DOI: 10.1021/acscentsci.5b00340] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Indexed: 05/14/2023]
Abstract
Antibodies are widely used biomarkers for the diagnosis of many diseases. Assays based on solid-phase immobilization of antigens comprise the majority of clinical platforms for antibody detection, but can be undermined by antigen denaturation and epitope masking. These technological hurdles are especially troublesome in detecting antibodies that bind nonlinear or conformational epitopes, such as anti-insulin antibodies in type 1 diabetes patients and anti-thyroglobulin antibodies associated with thyroid cancers. Radioimmunoassay remains the gold standard for these challenging antibody biomarkers, but the limited multiplexability and reliance on hazardous radioactive reagents have prevented their use outside specialized testing facilities. Here we present an ultrasensitive solution-phase method for detecting antibodies, termed antibody detection by agglutination-PCR (ADAP). Antibodies bind to and agglutinate synthetic antigen-DNA conjugates, enabling ligation of the DNA strands and subsequent quantification by qPCR. ADAP detects zepto- to attomoles of antibodies in 2 μL of sample with a dynamic range spanning 5-6 orders of magnitude. Using ADAP, we detected anti-thyroglobulin autoantibodies from human patient plasma with a 1000-fold increased sensitivity over an FDA-approved radioimmunoassay. Finally, we demonstrate the multiplexability of ADAP by simultaneously detecting multiple antibodies in one experiment. ADAP's combination of simplicity, sensitivity, broad dynamic range, multiplexability, and use of standard PCR protocols creates new opportunities for the discovery and detection of antibody biomarkers.
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Affiliation(s)
- Cheng-ting Tsai
- Department
of Chemistry, University of California, Berkeley, California 94720, United States
| | - Peter
V. Robinson
- Department
of Chemistry, University of California, Berkeley, California 94720, United States
| | - Carole
A. Spencer
- USC
Endocrine Laboratories, Department of Medicine, University of Southern California, Los Angeles, California 91105, United States
| | - Carolyn R. Bertozzi
- Department of Chemistry and Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, United States
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45
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Zhao Z, Miao D, Michels A, Steck A, Dong F, Rewers M, Yu L. A multiplex assay combining insulin, GAD, IA-2 and transglutaminase autoantibodies to facilitate screening for pre-type 1 diabetes and celiac disease. J Immunol Methods 2016; 430:28-32. [PMID: 26809048 DOI: 10.1016/j.jim.2016.01.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 01/20/2016] [Accepted: 01/21/2016] [Indexed: 01/02/2023]
Abstract
At the current time, multiple candidate interventions are being proposed to abrogate or slow progression to type 1 diabetes (T1D) among islet autoantibody (iAb) positive subjects, but mass screening for eligible subjects and the general population remains a laborious and inefficient process. We have recently developed and extensively validated nonradioactive iAb assays using electrochemiluminescense (ECL) detection with an excellent sensitivity and specificity compared to the gold-standard radioassays. Using ECL detection on a platform from MesoScale Discovery (MSD) allows the measurement of four antibodies in a single well using a small blood volume (6 μl). In the present study using a MSD QuickPlex 4-Spot plate, we successfully combined three iAb to insulin (IAA), GAD65 (GADA), and IA-2 (IA-2A) with tissue transglutaminase autoantibodies (TGA) in a single well of a 96 well plate. We tested 40 new onset T1D patients, all positive for at least one iAb and a half of them positive for TGA by radioassay, as well as 50 healthy controls. The multiplex assay retained 100% sensitivity and 100% specificity for all four autoantibodies in terms of positivity identified in patients versus normal controls compared to the corresponding standard radioassays and our single ECL assays. The multiplex ECL assay was able to identify more positivity than current radioassays for IAA and TGA. The development of this multiplex assay will facilitate high-throughput screening for T1D and celiac disease risk in the general population.
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Affiliation(s)
- Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Dongmei Miao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Aaron Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Andrea Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Fran Dong
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, United States.
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46
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Abstract
Two fundamental aspects for precisely predicting the risk of developing type 1 diabetes by islet autoantibodies are assay sensitivity and disease specificity. We have recently developed electrochemiluminescent (ECL) insulin autoantibody (IAA) and GAD65 autoantibody (GADA) assays. ECL assays are sensitive, able to identify the initiation of islet autoimmunity earlier in life among high-risk young children before clinical onset of diabetes and are more disease specific because they are able to discriminate high-affinity, high-risk diabetes specific islet autoantibodies from low-affinity, low-risk autoantibodies.
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Affiliation(s)
- Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Building 500-13001 E. 17th Place, Campus Box C290, Room E1354, Aurora, CO, 80045, USA.
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47
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Abstract
Type 1 diabetes (T1D) is a chronic inflammatory disease, caused by the immune mediated destruction of insulin-producing β-cells in the islets of the pancreas (Ziegler and Nepom, Immunity 32(4):468-478, 2010). Semiquantitative assays with high specificity and sensitivity for T1D are now available to detect antibodies to the four major islet autoantigens: glutamate decarboxylase (GADA) (Baekkeskov et al., Nature 347(6289):151-156, 1990), the protein tyrosine phosphatase-like proteins IA-2 (IA-2A) and IA-2β (Notkins et al., Diabetes Metab Rev 14(1):85-93, 1998), zinc transporter 8 (ZnT8A) (Wenzlau et al., Proc Natl Acad Sci U S A 104(43):17040-17045, 2007), and insulin (IAA) (Palmer, Diabetes Metab Rev 3(4):1005-1015, 1987). More than 85 % of cases of newly diagnosed or future T1D can be identified by testing for antibodies to GADA and/or IA-2A/IAA, with 98 % specificity (Bingley et al., Diabet Care 24(2):398, 2001). Overall, radioimmunoassay (RIA) is considered the de facto gold standard format for the measurement of T1D autoantibodies (Bottazzo et al., Lancet 2(7892):1279-1283, 1974; Schlosser et al., Diabetologia 53(12):2611-2620, 2010). Here we describe current methods for autoantibody measurement using RIA. These fluid phase assays use radiolabeled ligands and immunoprecipitation to quantify autoantibodies to GAD, IA-2, ZnT8, and insulin (Bonifacio et al., J Clin Endocrinol Metab 95(7):3360-3367, 2010; Long et al., Clin Endocrinol Metab 97(2):632-637, 2012; Williams et al., J Autoimmun 10(5):473-478, 1997).
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Affiliation(s)
- Rebecca Wyatt
- Diabetes and Metabolism Unit, School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, UK
| | - Alistair J K Williams
- Diabetes and Metabolism Unit, School of Clinical Sciences, Southmead Hospital, University of Bristol, Bristol, UK.
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48
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Kanatsuna N, Delli A, Andersson C, Nilsson AL, Vaziri-Sani F, Larsson K, Carlsson A, Cedervall E, Jönsson B, Neiderud J, Elding Larsson H, Ivarsson SA, Törn C, Fex M, Lernmark Å. Doubly Reactive INS-IGF2 Autoantibodies in Children with Newly Diagnosed Autoimmune (type 1) Diabetes. Scand J Immunol 2015; 82:361-9. [PMID: 26073034 DOI: 10.1111/sji.12325] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 04/28/2015] [Indexed: 01/30/2023]
Abstract
The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.
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Affiliation(s)
- N Kanatsuna
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - A Delli
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - C Andersson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - A-L Nilsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.,Department of Pediatrics, Östersund Hospital, Östersund, Sweden
| | - F Vaziri-Sani
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - K Larsson
- Department of Pediatrics, Kristianstad Hospital, Kristianstad, Sweden
| | - A Carlsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - E Cedervall
- Department of Pediatrics, Ängelholm Hospital, Ängelholm, Sweden
| | - B Jönsson
- Department of Pediatrics, Ystad Hospital, Ystad, Sweden
| | - J Neiderud
- Department of Pediatrics, Helsingborg Hospital, Helsingborg, Sweden
| | - H Elding Larsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - S-A Ivarsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - C Törn
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - M Fex
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
| | - Å Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden
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49
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Simmons KM, Michels AW. Alternate Ways to Quantify Antibodies. Diabetes Technol Ther 2015; 17:854-6. [PMID: 26544921 PMCID: PMC4677111 DOI: 10.1089/dia.2015.0328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Kimber M Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado , Aurora, Colorado
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado , Aurora, Colorado
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50
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Michels A, Zhang L, Khadra A, Kushner JA, Redondo MJ, Pietropaolo M. Prediction and prevention of type 1 diabetes: update on success of prediction and struggles at prevention. Pediatr Diabetes 2015; 16. [PMID: 26202050 PMCID: PMC4592445 DOI: 10.1111/pedi.12299] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is the archetypal example of a T cell-mediated autoimmune disease characterized by selective destruction of pancreatic β cells. The pathogenic equation for T1DM presents a complex interrelation of genetic and environmental factors, most of which have yet to be identified. On the basis of observed familial aggregation of T1DM, it is certain that there is a decided heritable genetic susceptibility for developing T1DM. The well-known association of T1DM with certain human histocompatibility leukocyte antigen (HLA) alleles of the major histocompatibility complex (MHC) was a major step toward understanding the role of inheritance in T1DM. Type 1 diabetes is a polygenic disease with a small number of genes having large effects (e.g., HLA) and a large number of genes having small effects. Risk of T1DM progression is conferred by specific HLA DR/DQ alleles [e.g., DRB1*03-DQB1*0201 (DR3/DQ2) or DRB1*04-DQB1*0302 (DR4/DQ8)]. In addition, the HLA allele DQB1*0602 is associated with dominant protection from T1DM in multiple populations. A concordance rate lower than 100% between monozygotic twins indicates a potential involvement of environmental factors on disease development. The detection of at least two islet autoantibodies in the blood is virtually pre-diagnostic for T1DM. The majority of children who carry these biomarkers, regardless of whether they have an a priori family history of the disease, will develop insulin-requiring diabetes. Facilitating pre-diagnosis is the timing of seroconversion which is most pronounced in the first 2 yr of life. Unfortunately the significant progress in improving prediction of T1DM has not yet been paralleled by safe and efficacious intervention strategies aimed at preventing the disease. Herein we summarize the chequered history of prediction and prevention of T1DM, describing successes and failures alike, and thereafter examine future trends in the exciting, partially explored field of T1DM prevention.
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Affiliation(s)
- Aaron Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
| | - Li Zhang
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
| | - Anmar Khadra
- Department of Physiology, McGill University, Montreal, QC Canada
| | - Jake A. Kushner
- Division of Diabetes Pediatric Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
| | - Maria J. Redondo
- Division of Diabetes Pediatric Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
| | - Massimo Pietropaolo
- Division of Diabetes, Endocrinology and Metabolism, McNair Medical Institute, Baylor College of Medicine, Houston, Texas,To Whom Correspondence May be Addressed: Massimo Pietropaolo, M.D., Division of Diabetes, Endocrinology and Metabolism, Alkek Building for Biomedical Research, R 609, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030
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