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Papadimitriou DT, Dermitzaki E, Christopoulos P, Papagianni M, Kleanthous K, Marakaki C, Papadimitriou A, Mastorakos G. Secondary Prevention of Diabetes Type 1 with Oral Calcitriol and Analogs, the PRECAL Study. CHILDREN (BASEL, SWITZERLAND) 2023; 10:862. [PMID: 37238410 PMCID: PMC10217040 DOI: 10.3390/children10050862] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/04/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023]
Abstract
Screening for Type 1 Diabetes (T1D, incidence 1:300) with T1D autoantibodies (T1Ab) at ages 2 and 6, while sensitive, lacks a preventive strategy. Cholecalciferol 2000 IU daily since birth reduced T1D by 80% at 1 year. T1D-associated T1Ab negativized within 0.6 years with oral calcitriol in 12 children. To further investigate secondary prevention of T1D with calcitriol and its less calcemic analog, paricalcitol, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). In total, 50 high-risk children were included: 44 were positive for T1Ab, and 6 had predisposing for T1D HLA genotypes. Nine T1Ab+ patients had variable impaired glucose tolerance (IGT), four had pre-T1D (3 T1Ab+, 1 HLA+), nine had T1Ab+ new-onset T1D not requiring insulin at diagnosis. T1Ab, thyroid/anti-transglutaminase Abs, glucose/calcium metabolism were determined prior and q3-6 months on calcitriol, 0.05 mcg/Kg/day, or paricalcitol 1-4 mcg × 1-3 times/day p.o. while on cholecalciferol repletion. Available data on 42 (7 dropouts, 1 follow-up < 3 months) patients included: all 26 without pre-T1D/T1D followed for 3.06 (0.5-10) years negativized T1Ab (15 +IAA, 3 IA2, 4 ICA, 2 +GAD, 1 +IAA/+GAD, 1 +ICA/+GAD) within 0.57 (0.32-1.3) years or did not develop to T1D (5 +HLA, follow-up 3 (1-4) years). From four pre-T1D cases, one negativized T1Ab (follow-up 1 year), one +HLA did not progress to T1D (follow-up 3.3 years) and two +T1Ab patients developed T1D in 6 months/3 years. Three out of nine T1D cases progressed immediately to overt disease, six underwent complete remission for 1 year (1 month-2 years). Five +T1Ab patients relapsed and negativized again after resuming therapy. Four (aged <3 years) negativized anti-TPO/TG, and two anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Secondary prevention of T1D with calcitriol and paricalcitol seems possible and reasonably safe, if started soon enough after seroconversion.
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Affiliation(s)
- Dimitrios T. Papadimitriou
- Second Department of Obstetrics and Gynecology, Aretaieion University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, 15125 Marousi, Greece
| | - Eleni Dermitzaki
- Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, 15125 Marousi, Greece
| | - Panagiotis Christopoulos
- Second Department of Obstetrics and Gynecology, Aretaieion University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Maria Papagianni
- Department of Nutrition and Dietetics, University of Thessaly, 42132 Trikala, Greece
- Unit of Endocrinology, Diabetes and Metabolism, Third Department of Pediatrics, Aristotle University of Thessaloniki, Hippokrateion Hospital of Thessaloniki, 54642 Thessaloniki, Greece
| | - Kleanthis Kleanthous
- Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, 15125 Marousi, Greece
| | - Chrysanthi Marakaki
- Department of Pediatric-Adolescent Endocrinology and Diabetes, Athens Medical Center, 15125 Marousi, Greece
| | - Anastasios Papadimitriou
- Pediatric Endocrinology Unit, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Haidari, Greece
| | - George Mastorakos
- Second Department of Obstetrics and Gynecology, Aretaieion University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
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2
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Michalek DA, Onengut-Gumuscu S, Repaske DR, Rich SS. Precision Medicine in Type 1 Diabetes. J Indian Inst Sci 2023; 103:335-351. [PMID: 37538198 PMCID: PMC10393845 DOI: 10.1007/s41745-023-00356-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 01/04/2023] [Indexed: 03/09/2023]
Abstract
Type 1 diabetes is a complex, chronic disease in which the insulin-producing beta cells in the pancreas are sufficiently altered or impaired to result in requirement of exogenous insulin for survival. The development of type 1 diabetes is thought to be an autoimmune process, in which an environmental (unknown) trigger initiates a T cell-mediated immune response in genetically susceptible individuals. The presence of islet autoantibodies in the blood are signs of type 1 diabetes development, and risk of progressing to clinical type 1 diabetes is correlated with the presence of multiple islet autoantibodies. Currently, a "staging" model of type 1 diabetes proposes discrete components consisting of normal blood glucose but at least two islet autoantibodies (Stage 1), abnormal blood glucose with at least two islet autoantibodies (Stage 2), and clinical diagnosis (Stage 3). While these stages may, in fact, not be discrete and vary by individual, the format suggests important applications of precision medicine to diagnosis, prevention, prognosis, treatment and monitoring. In this paper, applications of precision medicine in type 1 diabetes are discussed, with both opportunities and barriers to global implementation highlighted. Several groups have implemented components of precision medicine, yet the integration of the necessary steps to achieve both short- and long-term solutions will need to involve researchers, patients, families, and healthcare providers to fully impact and reduce the burden of type 1 diabetes.
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Affiliation(s)
- Dominika A. Michalek
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA
| | - Suna Onengut-Gumuscu
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA USA
| | - David R. Repaske
- Division of Endocrinology, Department of Pediatrics, University of Virginia, Charlottesville, VA USA
| | - Stephen S. Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA USA
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA USA
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3
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Ang GY. Age of onset of diabetes and all-cause mortality. World J Diabetes 2020; 11:95-99. [PMID: 32313608 PMCID: PMC7156298 DOI: 10.4239/wjd.v11.i4.95] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 02/19/2020] [Accepted: 02/24/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus continues to present a large social, financial and health system burden across the world. The relationship between age of onset of the different types of diabetes and all-cause mortality is uncertain. In this review paper, the relationship between age of onset of the different types of diabetes and all-cause mortality will be reviewed and an update of the current evidence will be presented. There is strong evidence of the relationship between age of onset of type 2 diabetes mellitus (T2DM) and all-cause mortality, good evidence of the relationship between age of onset of T1DM and all-cause mortality and no evidence of the relationship between age of onset of gestational diabetes or prediabetes and all-cause mortality. Further research is needed to look at whether aggressive management of earlier onset of T2DM can help to reduce premature mortality.
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Affiliation(s)
- Gary Yee Ang
- Health Services and Outcomes Research, National Healthcare Group, Singapore 138543, Singapore
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Yahaya T, Salisu T. Genes predisposing to type 1 diabetes mellitus and pathophysiology: a narrative review. MEDICAL JOURNAL OF INDONESIA 2020; 29:100-9. [DOI: 10.13181/mji.rev.203732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Accepted: 01/23/2020] [Indexed: 02/08/2023] Open
Abstract
The possibility of targeting the causal genes along with the mechanisms of pathogenically complex diseases has led to numerous studies on the genetic etiology of some diseases. In particular, studies have added more genes to the list of type 1 diabetes mellitus (T1DM) suspect genes, necessitating an update for the interest of all stakeholders. Therefore this review articulates T1DM suspect genes and their pathophysiology. Notable electronic databases, including Medline, Scopus, PubMed, and Google-Scholar were searched for relevant information. The search identified over 73 genes suspected in the pathogenesis of T1DM, with human leukocyte antigen, insulin gene, and cytotoxic T lymphocyte-associated antigen 4 accounting for most of the cases. Mutations in these genes, along with environmental factors, may produce a defective immune response in the pancreas, resulting in β-cell autoimmunity, insulin deficiency, and hyperglycemia. The mechanisms leading to these cellular reactions are gene-specific and, if targeted in diabetic individuals, may lead to improved treatment. Medical practitioners are advised to formulate treatment procedures that target these genes in patients with T1DM.
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Do D, Schnittker J. Utilization of Medications With Cognitive Impairment Side Effects and the Implications for Older Adults' Cognitive Function. J Aging Health 2020; 32:1165-1177. [PMID: 31904296 DOI: 10.1177/0898264319895842] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Objectives: Many medications have cognitive impairment, memory loss, amnesia, or dementia as side effects ("cognitive side effects" hereafter), but little is known about trends in the prevalence of these medications or their implications for population-level cognitive impairment. Method: We use data from the National Health and Nutrition Examination Survey (1999-2016) to describe trends in the use of medications with cognitive side effects among adults aged 60+ (N = 16,937) and their implications for cognitive functioning (measured using word learning and recall, animal fluency, and digit symbol substitution assessments). Results: Between 1999 to 2000 and 2015 to 2016, the prevalence of older adults taking one, two, and at least three medications with cognitive side effects increased by 10.2%, 57.3%, and 298.7%, respectively. Compared to non-users, respondents who simultaneously used three or more medications with cognitive side effects scored 0.22 to 0.27 standard deviations lower in word learning and recall (p = .02), digit symbol substitution (p < .01), and the average standardized score of the three assessments (p < .001). Limitation: Dosage of medications associated with cognitive side effects was not measured. Discussion: Concurrent use of medications with cognitive side effects among older adults has increased dramatically over the past two decades. The use of such medications is associated with cognitive impairment and may explain for disparities in cognitive function across subgroups. These findings highlight the need for cognitive screenings among patients who consume medications with cognitive side effects. They also highlight the synergic effects of polypharmacy and potential drug-drug interactions that result in cognitive deficits.
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Affiliation(s)
- Duy Do
- University of Pennsylvania, Philadelphia, USA
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Yamamura S, Fukui T, Mori Y, Hayashi T, Yamamoto T, Ohara M, Fukase A, Sasamori H, Kobayashi T, Hirano T. Circulating anti-glutamic acid decarboxylase-65 antibody titers are positively associated with the capacity of insulin secretion in acute-onset type 1 diabetes with short duration in a Japanese population. J Diabetes Investig 2019; 10:1480-1489. [PMID: 30919585 PMCID: PMC7663970 DOI: 10.1111/jdi.13052] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/19/2019] [Accepted: 03/21/2019] [Indexed: 12/15/2022] Open
Abstract
Aims/Introduction To elucidate the relationship between titers of islet autoantibodies, the C‐X‐C motif chemokine 10 – a circulating chemokine that activates T‐helper 1 cells leading to β‐cell destruction – and β‐cell function in type 1 diabetes. Materials and Methods In total, 58 type 1 diabetes patients positive for glutamic decarboxylase‐65 autoantibodies (GADA)‐radioimmunoassay (mean age 54.1 years; 27 acute‐onset cases and 31 slowly progressive cases) were enrolled; serum C‐X‐C motif chemokine 10 (n = 50), zinc transporter 8 autoantibodies (n = 50) and GADA (n = 58) by an enzyme‐linked immunosorbent assay, and insulinoma‐associated antigen‐2 autoantibodies by radioimmunoassay (n = 50) were measured. The ratio of 100 × random C‐peptide (ng/mL)‐to‐plasma glucose levels (mg/dL; C‐peptide index [CPI]) was measured. Results The CPI significantly decreased in both groups with the progression of disease duration. GADA titers by radioimmunoassay and enzyme‐linked immunosorbent assay were strongly correlated with the CPI in acute‐onset type 1 diabetes patients with a shorter disease duration (≤10 years), but not in those with a longer duration or slowly progressive type 1 diabetes. Neither insulinoma‐associated antigen‐2 nor zinc transporter 8 autoantibodies titers were correlated with the CPI. Serum C‐X‐C motif chemokine 10 levels in both groups were significantly higher than in non‐diabetic controls, and persisted at high levels even in those with chronic duration. Conclusions Among islet autoantibodies, the intensity of the humoral immune response, as defined by GADA titers, reflected the degree of residual β‐cell function in acute‐onset type 1 diabetes patients with short duration. Prolonged disease activity might accelerate β‐cell impairment in both subtypes of type 1 diabetes.
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Affiliation(s)
- So Yamamura
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Tomoyasu Fukui
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Yusaku Mori
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Toshiyuki Hayashi
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Takeshi Yamamoto
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Makoto Ohara
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Ayako Fukase
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | | | - Tetsuro Kobayashi
- Division of Immunology and Molecular Medicine, Okinaka Memorial Institute for Medical Research, Tokyo, Japan
| | - Tsutomu Hirano
- Division of Diabetes, Department of Medicine, Metabolism and Endocrinology, Showa University School of Medicine, Tokyo, Japan
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Affiliation(s)
- Parth Narendran
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
- Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
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Church D, Cardoso L, Kay RG, Williams CL, Freudenthal B, Clarke C, Harris J, Moorthy M, Karra E, Gribble FM, Reimann F, Burling K, Williams AJK, Munir A, Jones TH, Führer D, Moeller LC, Cohen M, Khoo B, Halsall D, Semple RK. Assessment and Management of Anti-Insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome. J Clin Endocrinol Metab 2018; 103:3845-3855. [PMID: 30085133 PMCID: PMC6179165 DOI: 10.1210/jc.2018-00972] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 07/26/2018] [Indexed: 01/01/2023]
Abstract
Context Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting Observational study in the UK Severe Insulin Resistance Service. Patients Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main Outcome Measures Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.
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Affiliation(s)
- David Church
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom
| | - Luís Cardoso
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Academic Endocrine Unity, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Richard G Kay
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
| | - Claire L Williams
- Diabetes & Metabolism, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol, United Kingdom
| | - Bernard Freudenthal
- Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom
| | - Catriona Clarke
- Department of Clinical Biochemistry, Western General Hospital, NHS Lothian, Edinburgh, United Kingdom
| | - Julie Harris
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Myuri Moorthy
- Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom
| | - Efthmia Karra
- Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom
| | - Fiona M Gribble
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Frank Reimann
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
| | - Keith Burling
- Core Biochemical Assay Laboratory, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom
| | - Alistair J K Williams
- Diabetes & Metabolism, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol, United Kingdom
| | - Alia Munir
- Department of Endocrinology, Royal Hallamshire Hospital, Sheffield, United Kingdom
| | - T Hugh Jones
- Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital, NHS Foundation Trust, Barnsley, United Kingdom
| | - Dagmar Führer
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Lars C Moeller
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Mark Cohen
- Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom
| | - Bernard Khoo
- Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom
| | - David Halsall
- Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom
| | - Robert K Semple
- University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge, United Kingdom
- National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom
- University of Edinburgh Centre for Cardiovascular Science, Queen’s Medical Research Institute, Edinburgh, United Kingdom
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Risk of beta-cell autoimmunity presence for progression to type 1 diabetes: A systematic review and meta-analysis. J Autoimmun 2018; 86:9-18. [DOI: 10.1016/j.jaut.2017.09.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 09/20/2017] [Accepted: 09/25/2017] [Indexed: 12/18/2022]
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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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Incani M, Serafini C, Satta C, Perra L, Scano F, Frongia P, Ricciardi R, Ripoli C, Soro M, Strazzera A, Zampetti S, Buzzetti R, Cavallo MG, Cossu E, Baroni MG. High prevalence of diabetes-specific autoimmunity in first-degree relatives of Sardinian patients with type 1 diabetes. Diabetes Metab Res Rev 2017; 33. [PMID: 27726307 DOI: 10.1002/dmrr.2864] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 09/16/2016] [Accepted: 10/07/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND The incidence of type 1 diabetes mellitus (T1DM) in Sardinia is among the highest in the world (44.8 cases/100,000 person-years). Recommendations of the Immunology of Diabetes Society advise evaluating autoantibody positivity in first-degree relatives (FDRs) of patients with T1DM, for their higher risk to develop the disease. The aim of this study was to determine the prevalence of beta-cell autoimmunity in FDRs of T1DM patients in Sardinia. METHODS A total of 188 Sardinian families were recruited in collaboration between diabetes and pediatric units of university and district hospitals in Sardinia. The recruitment involved 188 patients with diagnosed T1DM and all their available FDRs (n = 447). Autoantibodies (Aabs) against GAD, IA2, insulin, and ZnT8 were measured in all subjects. Human leukocyte antigen (HLA) risk genotypes (HLA-DR and DQ loci) were analyzed in 43 Aabs-positive FDR. RESULTS The prevalence of Aabs (any type of autoantibody, single or multiple) in FDR was 11.9% (53/447). Of those with autoantibodies, 62.3% (33/53) were positive to only 1 autoantibody, 22.6% (12/53) had 2 autoantibodies, 7.55% (4/53) had 3 autoantibodies, and 7.55% (4/53) had all 4 autoantibodies. Typing of HLA-DR and DQ loci showed that 89% of FDR carried moderate- to high-risk genotypes, with only 5 FDR with low-risk genotypes. CONCLUSIONS The prevalence of T1DM autoantibodies in FDRs of T1DM patients was very high (11.9%) in the Sardinian population, higher than in other populations from the United States and Europe, and similar to that observed in Finland. Autoantibody positivity strongly associated with HLA risk. This study provides evidence of the high risk of T1DM in FDR of T1DM patients in Sardinia and warrants longitudinal follow-up to estimate the risk of progression to T1DM in high-risk populations.
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Affiliation(s)
- M Incani
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - C Serafini
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - C Satta
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - L Perra
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - F Scano
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - P Frongia
- Paediatric Unit, San Michele Hospital, Cagliari, Italy
| | - R Ricciardi
- Paediatric Unit, San Michele Hospital, Cagliari, Italy
| | - C Ripoli
- Diabetes Paediatric Unit, San Michele Hospital, Cagliari, Italy
| | - M Soro
- Paediatric Unit, San Martino Hospital, Oristano, Italy
| | - A Strazzera
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - S Zampetti
- Endocrinology, Department Experimental Medicine, Sapienza University of Rome, Italy
| | - R Buzzetti
- Endocrinology, Department Experimental Medicine, Sapienza University of Rome, Italy
| | - M G Cavallo
- Internal Medicine Unit, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Italy
| | - E Cossu
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
| | - M G Baroni
- Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Italy
- Endocrinology, Department Experimental Medicine, Sapienza University of Rome, Italy
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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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Steck AK, Vehik K, Bonifacio E, Lernmark A, Ziegler AG, Hagopian WA, She J, Simell O, Akolkar B, Krischer J, Schatz D, Rewers MJ. Predictors of Progression From the Appearance of Islet Autoantibodies to Early Childhood Diabetes: The Environmental Determinants of Diabetes in the Young (TEDDY). Diabetes Care 2015; 38:808-13. [PMID: 25665818 PMCID: PMC4407751 DOI: 10.2337/dc14-2426] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 01/05/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. RESULTS Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]). The mean GADA level did not significantly affect the risk of diabetes. CONCLUSIONS In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Kendra Vehik
- Pediatric Epidemiology Center, University of South Florida, Tampa, FL
| | | | - Ake Lernmark
- Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany; Klinikum rechts der Isar, Technische Universität München, München, Germany; and Forschergruppe Diabetes e.V., Neuherberg, Germany
| | | | - JinXiong She
- Medical College of Georgia, Georgia Regents University, Augusta, GA
| | - Olli Simell
- Department of Pediatrics, University of Turku, Turku, Finland
| | - Beena Akolkar
- Division of Diabetes, Endocrinology, & Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Jeffrey Krischer
- Pediatric Epidemiology Center, University of South Florida, Tampa, FL
| | | | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
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14
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Diaz-Valencia PA, Bougnères P, Valleron AJ. Global epidemiology of type 1 diabetes in young adults and adults: a systematic review. BMC Public Health 2015; 15:255. [PMID: 25849566 PMCID: PMC4381393 DOI: 10.1186/s12889-015-1591-y] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/27/2015] [Indexed: 12/24/2022] Open
Abstract
Background Although type 1 diabetes (T1D) can affect patients of all ages, most epidemiological studies of T1D focus on disease forms with clinical diagnosis during childhood and adolescence. Clinically, adult T1D is difficult to discriminate from certain forms of Type 2 Diabetes (T2D) and from Latent Autoimmune Diabetes in Adults (LADA). We searched the information available worldwide on the incidence of T1D among individuals over 15 years of age, and which diagnostic criteria should be used use to qualify T1D in adults. We then studied the variation of T1D incidence with age in adults, and compared it to the incidence in the <15 years-old. Methods A systematic review of the literature was performed to retrieve original papers in English, French and Spanish published up to November 6, 2014, reporting the incidence of T1D among individuals aged over 15 years. The study was carried out according to the PRISMA recommendations. Results We retrieved information reporting incidence of T1D among individuals aged more than 15 years in 35 countries, and published in 70 articles between 1982 and 2014. Specific anti-beta-cell proteins or C-peptide detection were performed in 14 of 70 articles (20%). The most frequent diagnostic criteria used were clinical symptoms and immediate insulin therapy. Country-to-country variations of incidence in those aged >15 years paralleled those of children in all age groups. T1D incidence was larger in males than in females in 44 of the 54 (81%) studies reporting incidence by sex in people >15 years of age. The overall mean male-to-female ratio in the review was 1.47 (95% CI = 1.33-1.60, SD = 0.49, n = 54, p = <0.0001). Overall, T1D incidence decreased in adulthood, after the age of 14 years. Conclusions Few studies on epidemiology of T1D in adults are available worldwide, as compared to those reporting on children with T1D. The geographical variations of T1D incidence in adults parallel those reported in children. As opposed to what is known in children, the incidence is generally larger in males than in females. There is an unmet need to evaluate the incidence of autoimmune T1D in adults, using specific autoantibody detection, and to better analyze epidemiological specificities – if any – of adult T1D. PROSPERO registration number CRD42012002369. Electronic supplementary material The online version of this article (doi:10.1186/s12889-015-1591-y) contains supplementary material, which is available to authorized users.
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Woittiez NJC, Roep BO. Impact of disease heterogeneity on treatment efficacy of immunotherapy in Type 1 diabetes: different shades of gray. Immunotherapy 2015; 7:163-74. [DOI: 10.2217/imt.14.104] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes results from selective destruction of insulin-producing pancreatic β-cells by a progressive autoimmune process. Type 1 diabetes proves very heterogeneous in pathology, disease progression and efficacy of therapeutic intervention. Indeed, several immunotherapies that appear ineffective for the entire treated patient population in fact look promising in subgroups of patients. It therefore seems inconceivable that one standard therapy will provide the golden bullet of disease intervention. Instead, personalized medicine may improve immune intervention efficacy rates. We discuss the effect of disease heterogeneity on treatment outcome of immunotherapies, identifying apparent gaps in our understanding of treatment efficacy in subgroups of Type 1 diabetic patients as well as identifying future opportunities for immunotherapy.
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Affiliation(s)
- Nicky JC Woittiez
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, E3-Q, LUMC, PO Box 9600, NL-2300RC Leiden, The Netherlands
| | - Bart O Roep
- Department of Immunohematology & Blood Transfusion, Leiden University Medical Center, E3-Q, LUMC, PO Box 9600, NL-2300RC Leiden, The Netherlands
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Chen YG, Cabrera SM, Jia S, Kaldunski ML, Kramer J, Cheong S, Geoffrey R, Roethle MF, Woodliff JE, Greenbaum CJ, Wang X, Hessner MJ. Molecular signatures differentiate immune states in type 1 diabetic families. Diabetes 2014; 63:3960-73. [PMID: 24760139 PMCID: PMC4207392 DOI: 10.2337/db14-0214] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Mechanisms associated with type 1 diabetes (T1D) development remain incompletely defined. Using a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially interleukin (IL)-1-dependent signatures associated with preonset and recent onset (RO) T1D relative to unrelated healthy control subjects (uHC). To better understand inherited susceptibility in T1D families, we conducted cross-sectional and longitudinal analyses of healthy autoantibody-negative (AA(-)) high HLA-risk siblings (HRS) (DR3 and/or DR4) and AA(-) low HLA-risk siblings (LRS) (non-DR3/non-DR4). Signatures, scored with a novel ontology-based algorithm, and confirmatory studies differentiated the RO T1D, uHC, HRS, and LRS plasma milieus. Relative to uHC, T1D family members exhibited an elevated inflammatory state, consistent with innate receptor ligation that was independent of HLA, AA, or disease status and included elevated plasma IL-1α, IL-12p40, CCL2, CCL3, and CCL4 levels. Longitudinally, signatures of T1D progressors exhibited increasing inflammatory bias. Conversely, HRS possessing decreasing AA titers revealed emergence of an IL-10/transforming growth factor-β-mediated regulatory state that paralleled temporal increases in peripheral activated CD4(+)/CD45RA(-)/FoxP3(high) regulatory T-cell frequencies. In AA(-) HRS, the familial innate inflammatory state also was temporally supplanted by immunoregulatory processes, suggesting a mechanism underlying the decline in T1D susceptibility with age.
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Affiliation(s)
- Yi-Guang Chen
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Susanne M Cabrera
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Shuang Jia
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Mary L Kaldunski
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Joanna Kramer
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Sami Cheong
- Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI
| | - Rhonda Geoffrey
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Mark F Roethle
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
| | - Jeffrey E Woodliff
- Flow Cytometry and Cell Separation Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN
| | | | - Xujing Wang
- Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
| | - Martin J Hessner
- The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin, Milwaukee, WI
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Tripathi P, Moinuddin, Dixit K, Mir AR, Habib S, Alam K, Ali A. Peroxynitrite modified DNA presents better epitopes for anti-DNA autoantibodies in diabetes type 1 patients. Cell Immunol 2014; 290:30-38. [PMID: 24859014 DOI: 10.1016/j.cellimm.2014.04.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 04/12/2014] [Accepted: 04/25/2014] [Indexed: 12/14/2022]
Abstract
Peroxynitrite (ONOO(-)), formed by the reaction between nitric oxide (NO) and superoxide (O2(-)), has been implicated in the etiology of numerous disease processes. Peroxynitrite interacts with DNA via direct oxidative reactions or via indirect radical-mediated mechanism. It can inflict both oxidative and nitrosative damages on DNA bases, generating abasic sites, resulting in the single strand breaks. Plasmid pUC 18 isolated from Escherichiacoli was modified with peroxynitrite, generated by quenched flow process. Modifications incurred in plasmid DNA were characterized by ultraviolet and fluorescence spectroscopy, circular dichroism, HPLC and melting temperature studies. Binding characteristics and specificity of antibodies from diabetes patients were analyzed by direct binding and inhibition ELISA. Peroxynitrite modification of pUC 18 plasmid resulted in the formation of strand breaks and base modification. The major compound formed when peroxynitrite reacted with DNA was 8-nitroguanine, a specific marker for peroxynitrite induced DNA damage in inflamed tissues. The concentration of 8-nitroguanine was found to be 3.8 μM. Sera from diabetes type 1 patients from different age groups were studied for their binding to native and peroxynitrite modified plasmid. Direct binding and competitive-inhibition ELISA results showed higher recognition of peroxynitrite modified plasmid, as compared to the native form, by auto-antibodies present in diabetes patients. The preferential recognition of modified plasmid by diabetes autoantibodies was further reiterated by gel shift assay. Experimentally induced anti-peroxynitrite-modified plasmid IgG was used as a probe to detect nitrosative lesions in the DNA isolated from diabetes patients.
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Affiliation(s)
- Prashant Tripathi
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Moinuddin
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India.
| | - Kiran Dixit
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Abdul Rouf Mir
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Safia Habib
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Khursheed Alam
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
| | - Asif Ali
- Department of Biochemistry, Jawaharlal Nehru Medical College, AMU, Aligarh, India
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18
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Papadimitriou DT, Marakaki C, Fretzayas A, Nicolaidou P, Papadimitriou A. Negativation of type 1 diabetes-associated autoantibodies to glutamic acid decarboxylase and insulin in children treated with oral calcitriol. J Diabetes 2013; 5:344-348. [PMID: 23302101 DOI: 10.1111/1753-0407.12023] [Citation(s) in RCA: 16] [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: 10/28/2012] [Revised: 12/16/2012] [Accepted: 12/19/2012] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Based on recent knowledge of the possible involvement of 1,25-dihydroxyvitamin D in the pathogenesis of type 1 diabetes (T1D) and the results of its administration in animal models, we conducted a clinical trial by treating high-risk children, positive for T1D autoantibodies, with oral calcitriol. METHODS The present prospective trial was performed on 12 children (1.5-13 years old) who were investigated for the potential risk of T1D because of an already diagnosed association of celiac disease and autoimmune thyroiditis (four girls), autoimmune thyroiditis at a very young age (two girls, two boys), a diagnosis of T1D in siblings (two boys), and impaired glucose tolerance (IGT; one boy, one girl). Serum autoantibody levels, including islet cell autoantibodies, anti-glutamic acid decarboxylase (GAD) 65, insulin autoantibodies (IAA), and anti-tyrosine phosphatase, and markers of calcium metabolism were evaluated prior to and at 6-monthly intervals after the initiation of 0.25 μg/day calcitriol for 1-3 years. RESULTS In all children, persistent negativation of the anti-GAD65 antibodies and IAA was observed within 0.4-2.1 years. Of the two children with IGT, the boy proved to have maturity onset diabetes of the young (MODY) 2, whereas the glycemic profile was normalized in the girl. CONCLUSIONS Despite the small number of subjects and the absence of a control group in the present study, 0.25 μg/day calcitriol effectively negativates anti-GAD65 antibodies and IAA after a median time of 6 months. This simple, safe, and low-cost strategy may prove effective in the prevention of T1D in the future.
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19
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Mallone R, Roep BO. Biomarkers for immune intervention trials in type 1 diabetes. Clin Immunol 2013; 149:286-96. [PMID: 23510725 DOI: 10.1016/j.clim.2013.02.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 02/09/2013] [Indexed: 02/07/2023]
Abstract
After many efforts to improve and standardize assays for detecting immune biomarkers in type 1 diabetes (T1D), methods to identify and monitor such correlates of insulitis are coming of age. The ultimate goal is to use these correlates to predict disease progression before onset and regression following therapeutic intervention, which would allow performing smaller and shorter pilot clinical trials with earlier endpoints than those offered by preserved β-cell function or improved glycemic control. Here, too, progress has been made. With the emerging insight that T1D represents a heterogeneous disease, the next challenge is to define patient subpopulations that qualify for personalized medicine or that should be enrolled for immune intervention, to maximize clinical benefit and decrease collateral damage by ineffective or even adverse immune therapeutics. This review discusses the current state of the art, setting the stage for future efforts to monitor disease heterogeneity, progression and therapeutic intervention in T1D.
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Affiliation(s)
- Roberto Mallone
- Cochin Institute, INSERM U1016, DeAR Lab Avenir, Paris, France; Paris Descartes University, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Assistance Publique Hôpitaux de Paris, Hôtel Dieu, Service de Diabétologie, Paris, France.
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20
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Xu P, Beam CA, Cuthbertson D, Sosenko JM, Skyler JS, Krischer JP. Prognostic accuracy of immunologic and metabolic markers for type 1 diabetes in a high-risk population: receiver operating characteristic analysis. Diabetes Care 2012; 35:1975-80. [PMID: 22787174 PMCID: PMC3447832 DOI: 10.2337/dc12-0183] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 04/18/2012] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To establish and compare the prognostic accuracy of immunologic and metabolic markers in predicting onset of type 1 diabetes in those with high risk in a prospective study. RESEARCH DESIGN AND METHODS A total of 339 subjects from the Diabetes Prevention Trial-Type 1 (DPT-1) parenteral study, who were islet cell antibody (ICA)-positive, with low first-phase insulin response (FPIR) and/or abnormal glucose tolerance at baseline, were followed until clinical diabetes onset or study end (5-year follow-up). The prognostic performance of biomarkers was estimated using receiver operating characteristic (ROC) curve analysis and compared with nonparametric testing of ROC curve areas. Pearson correlation was used to assess the relationship between the markers. RESULTS Individually, insulin autoantibody titer, ICA512A titer, peak C-peptide, 2-h glucose, FPIR, and FPIR/homeostasis model assessment of insulin resistance provided modest but significant prognostic values for 5-year risk with a similar level of area under ROC curve ranging between 0.61 and 0.67. The combination of 2-h glucose, peak C-peptide, and area under the curve C-peptide significantly improved the prognostic accuracy compared with any solitary index (P < 0.05) with an area under ROC curve of 0.76 (95% CI 0.70-0.81). The addition of antibody titers and/or intravenous glucose tolerance test (IVGTT) markers did not increase the prognostic accuracy further (P = 0.46 and P = 0.66, respectively). CONCLUSIONS The combination of metabolic markers derived from the oral glucose tolerance test improved accuracy in predicting progression to type 1 diabetes in a population with ICA positivity and abnormal metabolism. The results indicate that the autoimmune activity may not alter the risk of type 1 diabetes after metabolic function has deteriorated. Future intervention trials may consider eliminating IVGTT measurements as an effective cost-reduction strategy for prognostic purposes.
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Affiliation(s)
- Ping Xu
- Department of Pediatrics, College of Medicine, University of South Florida, Tampa, Florida, USA.
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Steck AK, Johnson K, Barriga KJ, Miao D, Yu L, Hutton JC, Eisenbarth GS, Rewers MJ. Age of islet autoantibody appearance and mean levels of insulin, but not GAD or IA-2 autoantibodies, predict age of diagnosis of type 1 diabetes: diabetes autoimmunity study in the young. Diabetes Care 2011; 34:1397-9. [PMID: 21562325 PMCID: PMC3114355 DOI: 10.2337/dc10-2088] [Citation(s) in RCA: 149] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2010] [Accepted: 03/14/2011] [Indexed: 02/06/2023]
Abstract
OBJECTIVE We evaluated predictors of progression to diabetes in children with high-risk HLA genotypes and persistent islet autoantibodies. RESEARCH DESIGN AND METHODS The Diabetes Autoimmunity Study in the Young (DAISY) followed 2,542 children with autoantibodies measured to GAD, IA-2, and insulin. RESULTS Persistent islet autoantibodies developed in 169 subjects, and 55 of those progressed to diabetes. Children expressing three autoantibodies showed a linear progression to diabetes with 74% cumulative incidence by the 10-year follow-up compared with 70% with two antibodies and 15% with one antibody (P < 0.0001). Both age of appearance of first autoantibody and insulin autoantibody (IAA) levels, but not GAD or IA-2 autoantibodies, were major determinants of the age of diabetes diagnosis (r = 0.79, P < 0.0001). CONCLUSIONS In the DAISY cohort, 89% of children who progressed to diabetes expressed two or more autoantibodies. Age of diagnosis of diabetes is strongly correlated with age of appearance of first autoantibody and IAA levels.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA.
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22
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Petrich de Marquesini LG, Fu J, Connor KJ, Bishop AJ, McLintock NE, Pope C, Wong FS, Dayan CM. IFN-gamma and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes. Diabetologia 2010; 53:1451-60. [PMID: 20369219 DOI: 10.1007/s00125-010-1739-3] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2009] [Accepted: 02/08/2010] [Indexed: 01/13/2023]
Abstract
AIMS/HYPOTHESIS Islet antibody-negative first-degree relatives of type 1 diabetes patients have a very low risk of developing diabetes. We studied the balance between IFN-gamma (proinflammatory) and IL-10 (regulatory) T cell responses in these participants. METHODS Peripheral blood T cells from adult (18-50 years old, n = 40) DRB1*0401-positive first-degree relatives negative for GAD and tyrosine phosphatase-like insulinoma antigen 2 (IA-2) antibodies were tested for IFN-gamma and IL-10 responses in a sensitive cytokine enzyme-linked immunospot assay against a panel of seven peptide epitopes derived from IA-2 and proinsulin. Comparison was made with HLA-matched newly diagnosed type 1 diabetic patients (n = 42) and healthy controls (n = 39). RESULTS First-degree relatives and newly diagnosed type 1 diabetic patients displayed a similar frequency of IFN-gamma responses to the peptide panel and both were significantly greater than in healthy controls (relatives 9.6%, patients 11.8%, controls 4.0%, p = 0.003). First-degree relatives and newly diagnosed type 1 diabetic patients also showed similar frequencies of IL-10 responses, which were significantly lower than in healthy controls (relatives 7.1%, patients 9.0%, controls 15.8%, p = 0.003). However, individual IL-10 responses of first-degree relatives were similar in size to those in healthy controls and larger than those in newly diagnosed type 1 diabetic patients (relatives median 29 spot-forming cells/1 x 10(6) peripheral blood mononuclear cells, controls 33, patients 11, p = 0.02). CONCLUSIONS/INTERPRETATION Taken together, these results suggest that antibody-negative first-degree relatives have a balance of proinflammatory and regulatory T cells, which is intermediate between that of newly diagnosed type 1 diabetic patients and healthy controls. This suggests that even a moderate regulatory response may be sufficient to prevent the development of clinical type 1 diabetes in genetically predisposed individuals.
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Affiliation(s)
- L G Petrich de Marquesini
- Henry Wellcome Laboratory for Integrative Neuroscience and Endocrinology, Dorothy Hodgkin Building, Clinical Science at South Bristol, University of Bristol, Whitson St, Bristol, BS1 3NY, UK
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23
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Ziegler AG, Nepom GT. Prediction and pathogenesis in type 1 diabetes. Immunity 2010; 32:468-78. [PMID: 20412757 PMCID: PMC2861716 DOI: 10.1016/j.immuni.2010.03.018] [Citation(s) in RCA: 223] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 03/15/2010] [Accepted: 03/30/2010] [Indexed: 12/11/2022]
Abstract
A combination of genetic and immunological features is useful for prediction of autoimmune diabetes. Patterns of immune response correspond to the progression from a preclinical phase of disease to end-stage islet damage, with biomarkers indicating transition from susceptibility to active autoimmunity, and to a final loss of immune regulation. Here, we review the markers that provide evidence for immunological checkpoint failure and that also provide tools for assessment of individualized disease risk. When viewed in the context of genetic variation that influences immune response thresholds, progression from susceptibility to overt disease displays predictable modalities of clinical presentation resulting from a sequential series of failed homeostatic checkpoints for selection and activation of immunity.
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Affiliation(s)
- Anette-G Ziegler
- Prof. Dr. med. Anette-G Ziegler, Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Kölner Platz 1, 80804 München, Germany;
| | - Gerald T Nepom
- Gerald T Nepom, MD, PhD, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101-2795, USA;
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Roep BO, Kleijwegt FS, van Halteren AGS, Bonato V, Boggi U, Vendrame F, Marchetti P, Dotta F. Islet inflammation and CXCL10 in recent-onset type 1 diabetes. Clin Exp Immunol 2010; 159:338-43. [PMID: 20059481 DOI: 10.1111/j.1365-2249.2009.04087.x] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Type 1 diabetes results from a T cell-mediated destruction of insulin-producing pancreatic beta cells. Little is known on local factors contributing to migration of T cells to pancreatic tissue. We recently demonstrated evidence of viral infection in beta cells in several recent-onset type 1 diabetes patients. Islet inflammation was analysed in a series of new- or recent-onset type 1 diabetic patients and non-diabetic control subjects. Autoimmune T cell reactivity was studied in lymphocytes derived from pancreas-draining lymph nodes of one recent-onset type 1 diabetes patient in partial clinical remission. Insulitic lesions were characterized by presence of beta cells, elevated levels of the chemokine CXCL10 and infiltration of lymphocytes expressing the corresponding chemokine receptor CXCR3 in all pancreatic lesions of type 1 diabetes patients, regardless of enterovirus infection of beta cells. CXCR3 and CXCL10 were undetectable in pancreata of non-diabetic control subjects. T cells isolated from draining lymph nodes of a recent-onset patient with virally infected beta cells and in clinical remission reacted with multiple islet autoantigens and displayed a mixed interferon (IFN)-gamma/interleukin (IL)-10 cytokine pattern. Our data point to CXCL10 as an important cytokine in distressed islets that may contribute to inflammation leading to insulitis and beta cell destruction, regardless of local viral infection. We demonstrate further pro- and anti-inflammatory islet autoreactivity, indicating that different adaptive and innate immune responses may contribute to insulitis and beta cell destruction.
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Affiliation(s)
- B O Roep
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
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Siljander HT, Simell S, Hekkala A, Lähde J, Simell T, Vähäsalo P, Veijola R, Ilonen J, Simell O, Knip M. Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population. Diabetes 2009; 58:2835-42. [PMID: 19755526 PMCID: PMC2780879 DOI: 10.2337/db08-1305] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE As data on the predictive characteristics of diabetes-associated autoantibodies for type 1 diabetes in the general population are scarce, we assessed the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs), autoantibodies against GAD, and/or islet antigen 2 for type 1 diabetes in children with HLA-defined disease predisposition recruited from the general population. RESEARCH DESIGN AND METHODS We observed 7,410 children from birth (median 9.2 years) for beta-cell autoimmunity and diabetes. If a child developed ICA positivity or diabetes, the three other antibodies were measured in all samples available from that individual. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample. RESULTS Pre-diabetic ICA positivity was observed in 1,173 subjects (15.8%), 155 of whom developed type 1 diabetes. With ICA screening, 86% of 180 progressors (median age at diagnosis 5.0 years) were identified. Positivity for four antibodies was associated with the highest disease sensitivity (54.4%) and negative predictive values (98.3%) and the lowest negative likelihood ratio (0.5). The combination of persistent ICA and IAA positivity resulted in the highest positive predictive value (91.7%), positive likelihood ratio (441.8), cumulative disease risk (100%), and specificity (100%). Young age at seroconversion, high ICA level, multipositivity, and persistent positivity for IAA were significant risk markers for type 1 diabetes. CONCLUSIONS Within the general population, the combination of HLA and autoantibody screening resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with type 1 diabetes.
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Affiliation(s)
- Heli T.A. Siljander
- Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Satu Simell
- Department of Pediatrics, University of Turku, Turku, Finland
| | - Anne Hekkala
- Department of Pediatrics, University of Oulu, Oulu, Finland
| | - Jyrki Lähde
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Tuula Simell
- Department of Pediatrics, University of Turku, Turku, Finland
| | - Paula Vähäsalo
- Department of Pediatrics, University of Oulu, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, University of Oulu, Oulu, Finland
| | - Jorma Ilonen
- Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland
- Immunogenetics Laboratory, University of Turku, Turku, Finland
| | - Olli Simell
- Department of Pediatrics, University of Turku, Turku, Finland
| | - Mikael Knip
- Hospital for Children and Adolescents and Folkhälsan Research Center, University of Helsinki, Helsinki, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Corresponding author: Mikael Knip,
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Bingley PJ, Williams AJK. Validation of Autoantibody Assays in Type 1 Diabetes: Workshop Programme. Autoimmunity 2009; 37:257-60. [PMID: 15518037 DOI: 10.1080/08916930410001710677] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Polly J Bingley
- Department of Clinical Science at North Bristol, University of Bristol, UK.
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Ramachandran N, Anderson KS, Raphael JV, Hainsworth E, Sibani S, Montor WR, Pacek M, Wong J, Eljanne M, Sanda MG, Hu Y, Logvinenko T, LaBaer J. Tracking humoral responses using self assembling protein microarrays. Proteomics Clin Appl 2008; 2:1518-27. [PMID: 21136799 PMCID: PMC3158030 DOI: 10.1002/prca.200800034] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2008] [Indexed: 11/07/2022]
Abstract
The humoral immune response is a highly specific and adaptive sensor for changes in the body's protein milieu, which responds to novel structures of both foreign and self antigens. Although Igs represent a major component of human serum and are vital to survival, little is known about the response specificity and determinants that govern the human immunome. Historically, antigen-specific humoral immunity has been investigated using individually produced and purified target proteins, a labor-intensive process that has limited the number of antigens that have been studied. Here, we present the development of methods for applying self-assembling protein microarrays and a related method for producing 96-well formatted macroarrays for monitoring the humoral response at the proteome scale. Using plasmids encoding full-length cDNAs for over 850 human proteins and 1700 pathogen proteins, we demonstrate that these microarrays are highly sensitive, specific, reproducible, and can simultaneously measure immunity to thousands of proteins without a priori protein purification. Using this approach, we demonstrate the detection of humoral immunity to known and novel self-antigens, cancer antigens, autoimmune antigens, as well as pathogen-derived antigens. This represents a powerful and versatile tool for monitoring the immunome in health and disease.
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Affiliation(s)
- Niroshan Ramachandran
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Karen S. Anderson
- Cancer Vaccine Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston MA 02115
| | - Jacob v. Raphael
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Eugenie Hainsworth
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
- Technology & Engineering Center, Harvard Medical School, 240 Longwood Avenue, Boston, MA, 02115
| | - Sahar Sibani
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Wagner R. Montor
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Marcin Pacek
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Jessica Wong
- Cancer Vaccine Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney St, Boston MA 02115
| | - Mariam Eljanne
- Division of Urology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
| | - Martin G. Sanda
- Division of Urology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215
| | - Yanhui Hu
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
| | - Tanya Logvinenko
- Institute for Clinical Research and Health Policy Studies, Tufts New England Medical Center, Boston, MA 02110
| | - Joshua LaBaer
- Harvard Institute of Proteomics, Harvard Medical School, 320 Charles Street, Cambridge, MA 0214
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Siljander HT, Veijola R, Reunanen A, Virtanen SM, Akerblom HK, Knip M. Prediction of type 1 diabetes among siblings of affected children and in the general population. Diabetologia 2007; 50:2272-5. [PMID: 17768605 DOI: 10.1007/s00125-007-0799-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2007] [Accepted: 07/09/2007] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS To compare the predictive characteristics of autoantibodies to GAD (GADA) and islet antigen 2 (IA-2A) for type 1 diabetes between siblings of affected children and children from the general population. METHODS Seven-hundred and fifty-five siblings and 3,475 population-derived children were screened for GADA and IA-2A and observed for type 1 diabetes for 15 years. Sensitivity and cumulative disease risks from GADA, IA-2A and double positivity were compared between the cohorts. RESULTS Fifty-six siblings (7.4%) tested positive for GADA, 39 (5.2%) for IA-2A and 29 (3.8%) for both autoantibodies. Thirty-four population derived participants (1.0%) had GADA, 22 (0.6%) had IA-2A and 7 (0.2%) had double positivity. Fifty-one siblings (6.8%) and 15 participants in the population cohort (0.4%) progressed to type 1 diabetes. The predictive sensitivity of GADA was 68% (95% CI 53-81%) among siblings and 50% (95% CI 23-77%) in the general population, while the corresponding values were 58 (95% CI 43-72%) and 43% (95% CI 18-71%) for IA-2A. Double-autoantibody positivity had a sensitivity of 48% (95% CI 34-63%) among siblings and 36% (95% CI 13-65%) in the population cohort. Cumulative disease risks from GADA, IA-2A and double positivity were, respectively, 61% (95% CI 48-74%), 74% (95% CI 61-88%) and 83% (95% CI 69-97%) among siblings compared with those of 24% (95% CI 9-38%), 32% (95% CI 12-51%) and 86% (95% CI 60-100%) in the general population. CONCLUSIONS/INTERPRETATION There were no significant differences in the disease-predictive sensitivity of GADA and IA-2A positivity or their combination between siblings and the population cohort, whereas, for each antibody, positivity was associated with a higher cumulative disease risk among siblings. Double-antibody positivity conferred similar cumulative disease risk both among siblings and in the general population.
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Affiliation(s)
- H T Siljander
- Hospital for Children and Adolescents, University of Helsinki, P.O. Box 22 (Stenbäckinkatu 11), 00014 Helsinki, Finland
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de Leiva A, Mauricio D, Corcoy R. Diabetes-related autoantibodies and gestational diabetes. Diabetes Care 2007; 30 Suppl 2:S127-33. [PMID: 17596460 DOI: 10.2337/dc07-s204] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Alberto de Leiva
- Servei d'Endocrinologia i Nutrició, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Avinguda Sant Antoni M. Claret, 167, 08025, Barcelona, Spain.
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30
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Stene LC, Witsø E, Torjesen PA, Rasmussen T, Magnus P, Cinek O, Wetlesen T, Rønningen KS. Islet autoantibody development during follow-up of high-risk children from the general Norwegian population from three months of age: design and early results from the MIDIA study. J Autoimmun 2007; 29:44-51. [PMID: 17560077 DOI: 10.1016/j.jaut.2007.04.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2007] [Revised: 04/13/2007] [Accepted: 04/16/2007] [Indexed: 01/19/2023]
Abstract
We describe the design of the MIDIA study and present serial islet autoantibody data from 3 months of age in the 526 first enrolled children from the general population carrying the type 1 diabetes high-risk HLA-DRB1*0401-DQA1*03-DQB1*0302/DRB1*0301-DQA1*05-DQB1*02 genotype. Blood samples were obtained from children at ages 3, 6, 9 and 12 months and annually thereafter to a median age of 12 months. Autoantibodies to insulin, glutamic acid decarboxylase and insulinoma-associated antigen-2 were measured with radiobinding assays. About 25,000 general population newborns were genotyped, and among 526 children with the high-risk HLA genotype, 2104 samples were assayed. Fourteen children were positive in at least two consecutive samples, including 12 who were positive for > or =2 autoantibodies at least once, of which five developed type 1 diabetes at median age 15.3 months. Seven of 14 persistently positive children seroconverted before 9 months, including two before 6 months of age. The estimated cumulative probability of multiple autoantibody positivity at 5 years was 7.3% (95% confidence interval: 3.5-12.4%). Thus, persistent islet autoimmunity is not uncommon in the first year of life in children from the general population carrying the high-risk HLA genotype, and may develop as early as at 6 months of age.
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Affiliation(s)
- Lars C Stene
- Division of Epidemiology, Norwegian Institute of Public Health, NO-0403 Oslo, Norway.
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31
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. AMNELD, . SMAELD, . HAA, . HR. Assessment of Interleukin 18 in Children with Type 1 Diabetes and Their Relatives: Its Relation to Autoantibodies. JOURNAL OF MEDICAL SCIENCES 2006. [DOI: 10.3923/jms.2006.603.608] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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32
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SANJEEVI CB. Preface. Ann N Y Acad Sci 2006. [DOI: 10.1111/j.1749-6632.2002.tb02940.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Abstract
Type 1 diabetes results from the autoimmune destruction of the insulin producing pancreatic beta-cells. For years, the notion that T-lymphocytes played a crucial role in the disorder's formation was considered such sound dogma, that interest in B-lymphocytes and autoantibodies as pathogenic variables was largely relegated to second-class status. However, much of our knowledge regarding the pathogenesis and natural history of this disease has been afforded by analysis of subjects having type 1 diabetes associated autoantibodies. While autoantibodies to more than two dozen autoantigens have been associated with this disease, a majority of interest has been directed at four autoantibodies; islet cell cytoplasmic (ICA), insulin (IAA), glutamic acid decarboxylase (GADA), and IA2/ICA512 autoantigen (IA2A). These autoantibodies, combined with other metabolic and genetic markers, are extremely effective for predicting eventual development of type 1 diabetes in otherwise healthy individuals. These autoantibodies have also aided in our understanding of disease heterogeneity and suggest that the autoimmune processes underlying type 1 diabetes initiate in the earliest stages of life (e.g., initial autoantibody formation at 9-18 months of age). Additional improvements are needed to more accurately define the time to disease onset, response to therapeutic intervention, the pathogenic features of the autoimmune response, and perhaps even the quantity of residual beta cell function.
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Affiliation(s)
- Clive H Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Health Science Center, 1600 SW Archer Road, Gainesville, FL 32610, USA
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Casu A, Trucco M, Pietropaolo M. A look to the future: prediction, prevention, and cure including islet transplantation and stem cell therapy. Pediatr Clin North Am 2005; 52:1779-804. [PMID: 16301093 DOI: 10.1016/j.pcl.2005.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by the almost complete absence of insulin secretion, which is secondary to an autoimmune destruction or dysfunction of the insulin-producing cells of the pancreatic islets of Langerhans. Because T1DM is an autoimmune disease with a long preclinical course, the predictive testing of individuals before the clinical onset of the disease has provided a real opportunity for the identification of risk markers and the design of therapeutic intervention. With such a high degree of predictability using a combination of immunologic markers, strategies to prevent T1DM may become possible. A number of novel therapeutic strategies are under investigation in newly diagnosed T1DM patients and might ultimately be applied to prevent T1DM.
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Affiliation(s)
- Anna Casu
- Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3460 Fifth Avenue, Pittsburgh, PA 15213, USA
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35
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Abstract
Predicting type 1 diabetes mellitus (T1DM) is a prerequisite for disease prevention. Prediction is currently performed on three levels, which include the genetic susceptibility for disease, the identification of preclinical T1DM by way of circulating islet autoantibodies, and the use of metabolic tests to stage preclinical disease into late or early prediabetes. Combinations of genetic markers such as HLA genotype, INS genotype, and if and how much family history of T1DM is present can stratify disease risk more than 1000-fold, and can be used for selection of first-degree relatives of patients with T1DM for primary intervention trials. Measurement of autoantibodies in genetically at-risk subjects identifies future cases of T1DM. Further stratification of diabetes risk in autoantibody-positive subjects can be made on the basis of autoantibody characteristics that correspond to the magnitude of the autoantibody response.
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Affiliation(s)
- Peter Achenbach
- Diabetes Research Institute, Koelner Platz 1, Munich 80804, Germany
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36
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Rapoport MJ, Bistritzer T, Aharoni D, Weiss M, Ramot Y, Buchs A, Bloch K, Vardi P. TH1/TH2 cytokine secretion of first degree relatives of T1DM patients. Cytokine 2005; 30:219-27. [PMID: 15927845 DOI: 10.1016/j.cyto.2005.01.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2004] [Revised: 12/04/2004] [Accepted: 01/25/2005] [Indexed: 11/22/2022]
Abstract
Th1/Th2 cytokine imbalance has been demonstrated in Type 1 diabetes (T1DM) patients. We characterized the peak levels, secretory pattern and total cytokine production of the Th1 cytokines (IL-2 and IFN gamma) and Th2 cytokines (IL-4 and IL-10), by stimulated peripheral blood mononuclear cells of twenty six first-degree relatives of T1DM patients, and eleven matched controls. At enrollment, first degree relatives demonstrated a significant increase in peak and overall secretion of IL-2; P<0.01 and P<0.005 respectively and IL-4 cytokine; P<0.05 and P<0.01 respectively, as compared to normal controls. Their mean IFN gamma secretion increased significantly, P<0.05, after one year while their higher IL-2 and IL-4 secretion remained unchanged. Ab-negative and Ab-positive relatives demonstrated a similar cytokine secretion pattern. Four relatives all Ab positive, developed diabetes: Peak IL-4 levels were low in three and markedly decreased within one year in one of these relatives, while peak IL-2 and IFN gamma levels were elevated in all of them. These data demonstrate that secretion of both Th1 and Th2 cytokines is increased in first-degree relatives of T1DM patients independently of their diabetes-associated autoantibodies. The presence of low IL-4 and elevated IL-2 and IFN gamma levels in autoAb positive relatives is associated with progression to overt disease.
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Affiliation(s)
- Micha J Rapoport
- Diabetes and Endocrinology Unit, Assaf Harofeh Medical Center Zerifin affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Zerifin 70300, Israel.
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Abstract
Type 1 diabetes mellitus is preceded by autoimmunity against the insulin-producing islet beta cells. Autoantibodies against islet antigens such as insulin, glutamic acid decarboxylase, and the protein tyrosine phosphatase-like molecule IA-2 are found in most patients with type 1 diabetes and are now established markers for the clinical diagnosis and the preclinical phase of this disease. The development of islet autoantibodies and diabetes is influenced by genetic and environmental factors, and the detection and characterization of islet autoantibodies in euglycemic members of affected families identifies some individuals who have a markedly elevated risk for type 1 diabetes. This ability to accurately predict diabetes risk in non-diabetic subjects will prove very useful for targeted recruitment of participants of interventional studies aimed at preventing the progression to type 1 diabetes in subjects at risk.
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Affiliation(s)
- Peter Achenbach
- Diabetes Research Institute and 3rd Medical Department Academic, Hospital München-Schwabing, Koelner Platz 1, 80804 Munich, Germany
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38
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Roep BO, Atkinson M, von Herrath M. Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol 2005; 4:989-97. [PMID: 15573133 DOI: 10.1038/nri1502] [Citation(s) in RCA: 149] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Without a doubt, rodent models have been instrumental in describing pathways that lead to pancreatic beta-cell destruction, evaluating potential causes of type 1 diabetes and providing proof-of-principle for the potential of immune-based interventions. However, despite more than two decades of productive research, we are still yet to define an initiating autoantigen for the human disease, to determine the precise mechanisms of beta-cell destruction in humans and to design interventions that prevent or cure type 1 diabetes. In this Perspective article, we propose that a major philosophical change would benefit this field, a proposition that is based on evaluation of situations in which rodent models have provided useful guidance and in which they have led to disappointments.
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Affiliation(s)
- Bart O Roep
- Bart O. Roep is at the Leiden University Medical Center, Department of Immunohematology and Blood Transfusion, Leiden NL-2300 RC, The Netherlands.
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Devendra D, Galloway TS, Horton SJ, Wilkin TJ. Exploring the idiotypes of insulin antibodies as markers for remission in Type 1 diabetes. Diabet Med 2004; 21:1316-24. [PMID: 15569135 DOI: 10.1111/j.1464-5491.2004.01344.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIMS Complete or partial remission can occur in newly diagnosed Type 1 diabetes patients. We created idiotype-specific reagents to explore the idiotypes of insulin antibodies (IA) in a patient in remission, and to compare with a patient who was not. METHODS Phage display was used to create a library of phagotopes specific to insulin binding in four sera. Sera from a Type 1 diabetes subject deemed to have undergone remission were taken at diagnosis and again during remission. Sera from a non-remitter were taken at diagnosis and after 3 months on insulin. Phagotopes from the four sera were randomly selected and tested for insulin specificity in a radiobinding assay by using sera from remitters and non-remitters. RESULTS IA-binding phagotope selected from serum during remission displaced insulin binding in all nine IA(+) remitters and all 10 IA(+) non-remitters. IA-binding phagotope selected from the non-remission patient (3 months after insulin therapy) displaced insulin binding in 8/9 IA(+) remitters and 8/10 IA(+) non-remitters. The consensus peptide sequences adduced from the phages were identical for both these phagotopes. Phagotopes derived from insulin autoantibody-positive individuals at diagnosis were unable to displace insulin binding in the IA(+) sera 3 months later, whether in remission or not. CONCLUSIONS We have established the principle of using phage display in the investigation of insulin antibodies during remission in Type 1 diabetes. The immunological characteristics of IA 3 months after the introduction of insulin treatment were different from those at diagnosis of Type 1 diabetes (IAA). Using phage display technology, it was not possible to distinguish insulin antibodies according to remission status.
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Affiliation(s)
- D Devendra
- Department of Endocrinology & Metabolism, Peninsula Medical School, Plymouth campus, Plymouth, UK.
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40
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Abstract
AIMS/HYPOTHESIS Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to type 1 diabetes. METHODS Islet-antibody-positive first-degree relatives of type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR. RESULTS Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase. CONCLUSIONS/INTERPRETATION Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin-glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes.
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Fourlanos S, Narendran P, Byrnes GB, Colman PG, Harrison LC. Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 2004; 47:1661-7. [PMID: 15480539 DOI: 10.1007/s00125-004-1507-3] [Citation(s) in RCA: 167] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2003] [Accepted: 07/12/2004] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Glucose homeostasis is determined by an interplay between insulin secretion and insulin action. In type 1 diabetes, autoimmune destruction of pancreatic beta cells leads to impaired insulin secretion. However, the contribution of impaired insulin action (insulin resistance) to the development of type 1 diabetes has received little attention. We investigated whether insulin resistance was a risk factor for progression to type 1 diabetes. METHODS Islet-antibody-positive first-degree relatives of type 1 diabetes probands were followed for 4.0 years (median). Insulin secretion was measured as first-phase insulin response (FPIR) to intravenous glucose. Insulin resistance was estimated by homeostasis model assessment of insulin resistance (HOMA-R). We compared subjects who progressed (n=43) and subjects who did not progress (n=61) to diabetes, including 21 pairs matched for age, sex, islet antibodies and FPIR. RESULTS Progressors had higher insulin resistance relative to insulin secretion at baseline (median HOMA-R : FPIR 0.033 vs 0.013, p<0.0001). According to Cox proportional hazards analysis, islet antibody number, FPIR, fasting plasma glucose, fasting serum insulin, HOMA-R and log(HOMA-R : FPIR) were each predictive of progression to diabetes. However, log(HOMA-R : FPIR) (hazard ratio 2.57 per doubling, p<0.001) was the only metabolic variable independently associated with progression. In the matched comparison, progressors had higher fasting glucose, fasting insulin, HOMA-R and HOMA-R : FPIR, both at baseline and during the follow-up pre-clinical phase. CONCLUSIONS/INTERPRETATION Relatives positive for islet antibodies who progress most rapidly to diabetes have a subtle disturbance of insulin-glucose homeostasis years before the onset of symptoms, distinguished by greater insulin resistance for their level of insulin secretion. Taking steps to reduce this insulin resistance could therefore delay the development of type 1 diabetes.
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Affiliation(s)
- S Fourlanos
- Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia
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Manfredi M, McCullough MJ, Vescovi P, Al-Kaarawi ZM, Porter SR. Update on diabetes mellitus and related oral diseases. Oral Dis 2004; 10:187-200. [PMID: 15196139 DOI: 10.1111/j.1601-0825.2004.01019.x] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Diabetes mellitus (DM) is a group of complex multisystem metabolic disorders characterized by a relative or absolute insufficiency of insulin secretion and/or concomitant resistance to the metabolic action of insulin on target tissues. The chronic hyperglycaemia of diabetes is associated with long-term systemic dysfunction. The present article summarizes current knowledge of DM and details the oral and dental implications of this common endocrine disorder.
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Affiliation(s)
- M Manfredi
- Oral Medicine Department, Eastman Dental Institute, UCL, London, UK.
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Gale EAM, Bingley PJ, Emmett CL, Collier T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 2004; 363:925-31. [PMID: 15043959 DOI: 10.1016/s0140-6736(04)15786-3] [Citation(s) in RCA: 346] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Results of studies in animals and human beings suggest that type 1 diabetes is preventable. Nicotinamide prevents autoimmune diabetes in animal models, possibly through inhibition of the DNA repair enzyme poly-ADP-ribose polymerase and prevention of beta-cell NAD depletion. We aimed to assess whether high dose nicotinamide prevents or delays clinical onset of diabetes in people with a first-degree family history of type 1 diabetes. METHOD We did a randomised double-blind placebo-controlled trial of nicotinamide in 552 relatives with confirmed islet cell antibody (ICA) levels of 20 Juvenile Diabetes Federation (JDF) units or more, and a non-diabetic oral glucose tolerance test. Participants were recruited from 18 European countries, Canada, and the USA, and were randomly allocated oral modified release nicotinamide (1.2 g/m2) or placebo for 5 years. Random allocation was done with a pseudorandom number generator and we used size balanced blocks of four and stratified by age and national group. Primary outcome was development of diabetes, as defined by WHO criteria. Analysis was done on an intention-to-treat basis. FINDINGS There was no difference in the development of diabetes between the treatment groups. Of 159 participants who developed diabetes in the course of the trial, 82 were taking nicotinamide and 77 were on placebo. The unadjusted hazard ratio for development of diabetes was 1.07 (95% CI 0.78-1.45; p=0.69), and the hazard ratio adjusted for age-at-entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73-1.38; p=0.97). Of 168 (30.4%) participants who withdrew from the trial, 83 were on placebo. The number of serious adverse events did not differ between treatment groups. Nicotinamide treatment did not affect growth in children or first-phase insulin secretion. INTERPRETATION Large-scale controlled trials of interventions designed to prevent the onset of type 1 diabetes are feasible, but nicotinamide was ineffective at the dose we used.
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Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJK, Bingley PJ, Bonifacio E, Ziegler AG. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes 2004; 53:384-92. [PMID: 14747289 DOI: 10.2337/diabetes.53.2.384] [Citation(s) in RCA: 198] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Family history of type 1 diabetes and autoantibodies to the islet antigens insulin (IAA), glutamate decarboxylase (GADA), and the protein tyrosine phosphatase-like protein IA-2 (IA-2A) are strong predictors of type 1 diabetes, but the rate of progression to diabetes in multiple islet autoantibody-positive relatives varies widely. We asked whether detailed characterization of islet autoantibodies that included determination of titer, epitope specificity, and IgG subclass would improve diabetes prediction in a large cohort of autoantibody-positive relatives. The study shows a strong association between risk and high titer, broad antibody responses to IA-2 and insulin. The highest risks were associated with high-titer IA-2A and IAA, IgG2, IgG3, and/or IgG4 subclass of IA-2A and IAA, and antibodies to the IA-2-related molecule IA-2beta. Using models based on these antibody characteristics, autoantibody-positive relatives can be classified into groups with risks of diabetes ranging from 7 to 89% within 5 years.
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Affiliation(s)
- Peter Achenbach
- Diabetes Research Institute and 3rd Medical Department, Hospital München-Schwabing, Munich, Germany
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Abstract
The clinical manifestation of type 1 diabetes mellitus is preceded by an asymptomatic prodromal period called prediabetes or preclinical diabetes. It may last from a few months to several years, during which the autoimmune destruction of the insulin-producing beta-cells in the pancreas progresses. The genes on the human leukocyte antigen (HLA) and insulin gene region are major genetic determinants for genetic disease susceptibility, while dietary compounds and viral infections are the most likely environmental factors contributing to the etiopathogenesis. T cells are thought to be the effector cells for the beta-cell destruction, and glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin represent the three major autoantigens. Autoantibodies are early detectable markers of an ongoing disease process and are used to diagnose prediabetes. Among first-degree relatives of patients with type 1 diabetes, the risk for clinical disease can be graded from <5% in those with one or no antibodies to >90% in individuals who carry the HLA-DQB1*02/0302 risk genotype and are positive for multiple autoantibodies. beta-Cell function may also be tested in autoantibody-positive individuals and low first-phase insulin response is highly predictive for rapid progression to the clinical disease. However, dynamic course and individual variation of the disease process complicates the disease prediction, and it is not known whether all individuals with signs of prediabetes will inevitably progress to clinical type 1 diabetes. Until clinically applicable prevention for the condition exists, the screening for the risk markers of type 1 diabetes should actively be undertaken only in the context of research projects. Several major national and international multicenter studies are ongoing to test the potential of various agents (e.g. insulin and nicotinamide) or early elimination of dietary compounds (e.g. cow's milk proteins) to delay or prevent the onset of clinical type 1 diabetes.
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Affiliation(s)
- Petri Kulmala
- Department of Pediatrics, University of Oulu, Oulu, Finland.
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Abstract
The aims of the first proficiency evaluation of the Diabetes Antibody Standardization Program (DASP) were to assess general implementation of assay methods and to evaluate the new World Health Organization (WHO) reference reagent for autoantibodies to GAD and IA-2. Forty-six laboratories in 13 countries received coded sera from 50 patients with newly diagnosed type 1 diabetes and 50 blood donor control subjects, together with the WHO reference reagent and diluent serum. Results were analyzed using receiver operator characteristic (ROC) curves. Sensitivity was adjusted to 90% specificity in workshop controls. The median adjusted sensitivity for GADA (45 laboratories) was 84% (range 62-96%), for IA-2A (43 laboratories) was 58% (50-74%), and for insulin autoantibody (IAA; 23 laboratories) was 36% (13-66%). ROC curve analysis showed all GADA and IA-2A assays, and 18/23 IAA assays found significant differences between patients and control subjects. There was good concordance between laboratories in ranking of samples by GADA and IA-2A levels or if results were expressed in relation to the WHO reference reagent. Assays that achieved the highest sensitivity for IAA were also concordant in ranking samples, but overall concordance for IAA was poor. Differences in assay protocols between laboratories must be addressed so that all centers and kit manufacturers can perform to the same high standard.
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Affiliation(s)
- Polly J Bingley
- Division of Medicine, Medical School Unit, University of Bristol, Southmead Hospital, Bristol BS10 5NB, U.K.
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Roep BO. The role of T-cells in the pathogenesis of Type 1 diabetes: from cause to cure. Diabetologia 2003; 46:305-21. [PMID: 12687328 DOI: 10.1007/s00125-003-1089-5] [Citation(s) in RCA: 242] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2003] [Revised: 03/06/2003] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus results from a T-cell mediated autoimmune destruction of the pancreatic beta cells in genetically predisposed individuals. The knowledge of the immunopathogenesis has increased enormously in the last two decades. The contribution of T-cells in the pathogenesis is beyond doubt. Therapies directed against T-cells have been shown to halt the disease process and prevent recurrent beta-cell destruction after islet transplantation. Less is known about the nature and function of these T-cells, the cause of the loss of tolerance to islet autoantigens, why the immune system apparently fails to suppress autoreactivity, and whether (or which) autoantigen(s) are critically involved in the initiation or progression of the disease. The contribution of dendritic cells in directing the immune response is clear, while the contribution of B-cells and autoantibodies is subject to reconsideration. Autoreactive T-cells have proven to be valuable tools to study pathogenic or diabetes-related processes. Measuring T-cell autoreactivity has also provided critical information to determine the fate of islet allografts transplanted to Type 1 diabetic patients. Cellular autoimmunity is a difficult study subject, but it has been a worthwhile quest to unravel the role of T-cells in the pathogenesis of Type 1 diabetes. The challenge for the future is to determine which factors contribute to the loss of tolerance to beta-cell antigens, and to define what measures T-cells can provide to suppress autoreactivity, since it is becoming increasingly evident that T-cells provide a two-edged sword: some T-cells could be pathogenic, but others can regulate the disease process and thus form new targets for immunointervention.
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Affiliation(s)
- Bart O Roep
- Dept. Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
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Vogt RF, Meredith N, Henderson LO, Hannon WH. Newborn screening and type 1 diabetes: historical perspective and current activities at the CDC Division of Laboratory Sciences. Diabetes Technol Ther 2003; 5:1017-21. [PMID: 14709205 DOI: 10.1089/152091503322641079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Robert F Vogt
- Newborn Screening Branch, Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341, USA
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Gross JL, Silveiro SP, Camargo JL, Reichelt AJ, Azevedo MJD. Diabetes Melito: Diagnóstico, Classificação e Avaliação do Controle Glicêmico. ACTA ACUST UNITED AC 2002. [DOI: 10.1590/s0004-27302002000100004] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Diabetes e alterações da tolerância à glicose são freqüentes na população adulta e estão associados a um aumento da mortalidade por doença cardiovascular e complicações microvasculares. O diagnóstico destas situações deve ser feito precocemente, utilizando métodos sensíveis e acurados, já que mudanças no estilo de vida e a correção da hiperglicemia podem retardar o aparecimento do diabetes ou de suas complicações. O teste oral de tolerância à glicose é o método de referência, considerando-se a presença de diabetes ou tolerância à glicose diminuída quando a glicose plasmática de 2h após a ingestão de 75g de glicose for > ou = 200mg/dl ou > ou = 140 e <200mg/dl, respectivamente. Quando este teste não puder ser realizado, utiliza-se a medida da glicose plasmática em jejum, considerando-se como diabetes ou glicose alterada em jejum quando os valores forem > ou = 126mg/dl ou > ou = 110 e <126mg/dl, respectivamente. A medida da glico-hemoglobina não deve ser utilizada para o diagnóstico, mas é o método de referência para avaliar o grau de controle glicêmico a longo prazo. A classificação etiológica proposta atualmente para o diabetes melito inclui 4 categorias: diabetes melito tipo 1, diabetes melito tipo 2, outros tipos específicos de diabetes e diabetes gestacional. A classificação do paciente é usualmente feita em bases clínicas, mas a medida de auto-anticorpos e do peptídeo C pode ser útil em alguns casos.
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Abstract
BACKGROUND Diabetes mellitus is estimated to have a worldwide prevalence of 4.6% and afflict 200 million people. The prevalence is accelerating rapidly and the disease has reached epidemic proportions. While type 1 diabetes usually has a dramatic clinical onset, almost half of all those individuals with type 2 diabetes have not been diagnosed. This observation, coupled with the presence of complications at diagnosis and the significant reduction of microvascular complications obtained with tight glycemic control, has led to the recommendation that screening for diabetes be instituted. The American Diabetes Association recommends that adults aged 45 years or more should be evaluated for diabetes by measuring fasting plasma glucose concentrations. CONCLUSIONS The rationale for screening, evidence that tight glycemic control reduces complications, and the possible roles of Hb A(1c) and autoantibodies in screening strategies are addressed in this review.
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Affiliation(s)
- Roger A Greenberg
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02215, USA
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