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Jaakkola MK, Kukkonen-Macchi A, Suomi T, Elo LL. Longitudinal pathway analysis using structural information with case studies in early type 1 diabetes. Sci Rep 2025; 15:15393. [PMID: 40316626 PMCID: PMC12048611 DOI: 10.1038/s41598-025-98492-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 04/11/2025] [Indexed: 05/04/2025] Open
Abstract
Pathway analysis is a frequent step in studies involving gene or protein expression data, but most of the available pathway methods are designed for simple case versus control studies of two sample groups without further complexity. The few available methods allowing the pathway analysis of more complex study designs cannot use pathway structures or handle the situation where the variable of interest is not defined for all samples. Such scenarios are common in longitudinal studies with so long follow up time that healthy controls are required to identify the effect of normal aging apart from the effect of disease development, which is not defined for controls. To address the need, we introduce a new method for Pathway Analysis of Longitudinal data (PAL), which is suitable for complex study designs, such as longitudinal data. The main advantages of PAL are the use of pathway structures and the suitability of the approach for study settings beyond currently available tools. We demonstrate the performance of PAL with simulated data and three longitudinal datasets related to the early development of type 1 diabetes, which involve different study designs and only subtle biological signals, and include both transcriptomic and proteomic data. An R package implementing PAL is publicly available at https://github.com/elolab/PAL .
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Affiliation(s)
- Maria K Jaakkola
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Department of Mathematics and Statistics, University of Turku, Turku, Finland
| | - Anu Kukkonen-Macchi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Tomi Suomi
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
| | - Laura L Elo
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
- Institute of Biomedicine, University of Turku, Turku, Finland.
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Calhoun P, Spanbauer C, Steck AK, Frohnert BI, Herman MA, Keymeulen B, Veijola R, Toppari J, Desouter A, Gorus F, Atkinson M, Wilson DM, Pietropaolo S, Beck RW. Continuous glucose monitor metrics from five studies identify participants at risk for type 1 diabetes development. Diabetologia 2025; 68:930-939. [PMID: 39934369 DOI: 10.1007/s00125-025-06362-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 12/12/2024] [Indexed: 02/13/2025]
Abstract
AIMS/HYPOTHESIS We aimed to assess whether continuous glucose monitor (CGM) metrics can accurately predict stage 3 type 1 diabetes diagnosis in those with islet autoantibodies (AAb). METHODS Baseline CGM data were collected from participants with ≥1 positive AAb type from five studies: ASK (n=79), BDR (n=22), DAISY (n=18), DIPP (n=8) and TrialNet Pathway to Prevention (n=91). Median follow-up time was 2.6 years (quartiles: 1.5 to 3.6 years). A participant characteristics-only model, a CGM metrics-only model and a full model combining characteristics and CGM metrics were compared. RESULTS The full model achieved a numerically higher performance predictor estimate (C statistic=0.74; 95% CI 0.66, 0.81) for predicting stage 3 type 1 diabetes diagnosis compared with the characteristics-only model (C statistic=0.69; 95% CI 0.60, 0.77) and the CGM-only model (C statistic=0.68; 95% CI 0.61, 0.75). Greater percentage of time >7.8 mmol/l (p<0.001), HbA1c (p=0.02), having a first-degree relative with type 1 diabetes (p=0.02) and testing positive for IA-2 AAb (p<0.001) were associated with greater risk of type 1 diabetes diagnosis. Additionally, being male (p=0.06) and having a negative GAD AAb (p=0.09) were selected but not found to be significant. Participants classified as having low (n=79), medium (n=98) or high (n=41) risk of stage 3 type 1 diabetes diagnosis using the full model had a probability of developing symptomatic disease by 2 years of 5%, 13% and 48%, respectively. CONCLUSIONS/INTERPRETATION CGM metrics can help predict disease progression and classify an individual's risk of type 1 diabetes diagnosis in conjunction with other factors. CGM can also be used to better assess the risk of type 1 diabetes progression and define eligibility for potential prevention trials.
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Affiliation(s)
| | | | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Brigitte I Frohnert
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark A Herman
- Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Bart Keymeulen
- Department of Diabetes and Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Belgian Diabetes Registry, Brussels, Belgium
| | - Riitta Veijola
- Department of Paediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jorma Toppari
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Aster Desouter
- Department of Diabetes and Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Belgian Diabetes Registry, Brussels, Belgium
| | - Frans Gorus
- Department of Diabetes and Endocrinology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium
- Diabetes Research Center, Vrije Universiteit Brussel (VUB), Brussels, Belgium
- Belgian Diabetes Registry, Brussels, Belgium
| | - Mark Atkinson
- Diabetes Institute, University of Florida, Gainesville, FL, USA
| | - Darrell M Wilson
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Susan Pietropaolo
- Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Roy W Beck
- Jaeb Center for Health Research, Tampa, FL, USA
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Lernmark Å, Agardh D, Akolkar B, Gesualdo P, Hagopian WA, Haller MJ, Hyöty H, Johnson SB, Elding Larsson H, Liu E, Lynch KF, McKinney EF, McIndoe R, Melin J, Norris JM, Rewers M, Rich SS, Toppari J, Triplett E, Vehik K, Virtanen SM, Ziegler AG, Schatz DA, Krischer J. Looking back at the TEDDY study: lessons and future directions. Nat Rev Endocrinol 2025; 21:154-165. [PMID: 39496810 PMCID: PMC11825287 DOI: 10.1038/s41574-024-01045-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/26/2024] [Indexed: 11/06/2024]
Abstract
The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1-3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2-4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.
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Affiliation(s)
- Åke Lernmark
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.
| | - Daniel Agardh
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
| | - Beena Akolkar
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Patricia Gesualdo
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, USA
| | - William A Hagopian
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Michael J Haller
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Suzanne Bennett Johnson
- Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, FL, USA
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
| | - Edwin Liu
- Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kristian F Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Eoin F McKinney
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Richard McIndoe
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Jessica Melin
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
| | - Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Jorma Toppari
- Department of Paediatrics, Turku University Hospital, Turku, Finland
- Institute of Biomedicine, Research Centre for Integrated Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Eric Triplett
- University of Florida, Department of Microbiology and Cell Science, Gainesville, FL, USA
| | - Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Suvi M Virtanen
- Center for Child Health Research, Tampere University and University Hospital and Research, Tampere, Finland
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München and e.V., Munich, Germany
| | - Desmond A Schatz
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Ebekozien O, Echouffo-Tcheugui JB, Ekhlaspour L, Gaglia JL, Garg R, Khunti K, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Selvin E, Stanton RC, Bannuru RR. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S27-S49. [PMID: 39651986 PMCID: PMC11635041 DOI: 10.2337/dc25-s002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/12/2024] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Jacobsen LM, Atkinson MA, Sosenko JM, Gitelman SE. Time to reframe the disease staging system for type 1 diabetes. Lancet Diabetes Endocrinol 2024; 12:924-933. [PMID: 39608963 PMCID: PMC12019770 DOI: 10.1016/s2213-8587(24)00239-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 06/16/2024] [Accepted: 07/25/2024] [Indexed: 11/30/2024]
Abstract
In 2015, introduction of a disease staging system offered a framework for benchmarking progression to clinical type 1 diabetes. This model, based on islet autoantibodies (stage 1) and dysglycaemia (stage 2) before type 1 diabetes diagnosis (stage 3), has facilitated screening and identification of people at risk. Yet, there are many limitations to this model as the stages combine a very heterogeneous group of individuals; do not have high specificity for type 1 diabetes; can occur without persistence (ie, reversion to an earlier risk stage); and exclude age and other influential risk factors. The current staging system also infers that individuals at risk of type 1 diabetes progress linearly from stage 1 to stage 2 and subsequently stage 3, whereas such movements are often more complex. With the approval of teplizumab by the US Food and Drug Administration in 2022 to delay type 1 diabetes in people at stage 2, there is a need to refine the definition and accuracy of type 1 diabetes staging. Theoretically, we propose that a type 1 diabetes risk calculator should incorporate any available demographic, genetic, autoantibody, metabolic, and immune data that could be continuously updated. Additionally, we call to action for the field to increase the breadth of knowledge regarding type 1 diabetes risk in non-relatives, adults, and individuals from minority populations.
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Affiliation(s)
- Laura M Jacobsen
- Department of Paediatrics and Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA.
| | - Mark A Atkinson
- Department of Paediatrics and Department of Pathology, Immunology and Laboratory Medicine, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Jay M Sosenko
- Division of Endocrinology, University of Miami, Miami, FL, USA
| | - Stephen E Gitelman
- Department of Paediatrics, Diabetes Center, University of California San Francisco, San Francisco, California, USA
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Quinn LM, Dias RP, Bidder C, Bhowmik S, Bumke K, Ganapathi J, Gorman S, Hind E, Karandikar S, Kumar K, Lipscomb N, McGovern S, Puthi VR, Randell T, Watts G, Narendran P. Presentation and characteristics of children with screen-detected type 1 diabetes: learnings from the ELSA general population pediatric screening study. BMJ Open Diabetes Res Care 2024; 12:e004480. [PMID: 39327068 PMCID: PMC11429353 DOI: 10.1136/bmjdrc-2024-004480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
INTRODUCTION We describe the identification and management of general population screen-detected type 1 diabetes (T1D) and share learnings for best practice. RESEARCH DESIGN AND METHODS Children diagnosed with T1D through a general population screening initiative, the EarLy Surveillance for Autoimmune diabetes (ELSA) study, were reviewed and described.Parents provided written, informed consent for inclusion in the case series. RESULTS 14 children with insulin requiring (stage 3) T1D are described. These cases offer unique insights into the features of screen-detected T1D. T1D is identified sooner through screening programs, characterized by absent/short symptom duration, median presenting glycated hemoglobin 6.6% (49 mmol/mol) and insulin requirements<0.5 units/kg/day. ELSA identified four children at stage 3 and another 4 progressed within 4 months of ELSA completion, including two single seropositive children. Six children developed stage 3 T1D prior to ELSA completion, including two children (14%, n=2/14) with diabetic ketoacidosis prior to confirmed antibody status. CONCLUSIONS There are three main learnings from this case series. First, T1D identified through screening is at an earlier stage of its natural history and requires personalized insulin regimens with lower total daily insulin doses. Second, single autoantibody seropositivity can rapidly progress to stage 3. Finally, insulin requirement can manifest at any stage of the T1D screening pathway, and therefore early education around symptom recognition is essential for families participating in screening programs.
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Affiliation(s)
- Lauren M Quinn
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Renuka P Dias
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
- Department of Paediatric Endocrinology, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Birmingham, UK
| | - Christopher Bidder
- Department of Child health, Swansea Bay University Health Board, Morriston Hospital, Swansea, UK
| | | | - Kerstin Bumke
- Paediatric Department, University Hospital Wishaw, Wishaw, UK
| | | | - Shaun Gorman
- Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK
| | - Edward Hind
- North Hampshire Hospital, Basingstoke, Hampshire, UK
| | | | - Kiran Kumar
- Burton Hospitals NHS Foundation Trust, Derby, UK
| | - Nicholas Lipscomb
- Department of Paediatrics, South West Acute Hospital, Enniskillen, UK
| | | | - Vijith R Puthi
- Department of Paediatrics, Peterborough City Hospital, Peterborough, UK
| | | | | | - Parth Narendran
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Diabetes, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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Karavanaki K, Korona A, Karanasios S, Kossiva L. Predictors of the clinical severity of T1DM presentation at diagnosis in children and adolescents with type 1 diabetes mellitus (T1DM). Hormones (Athens) 2024; 23:395-405. [PMID: 38150136 PMCID: PMC11436423 DOI: 10.1007/s42000-023-00518-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 12/11/2023] [Indexed: 12/28/2023]
Abstract
PURPOSE We aimed to assess factors associated with the presence and severity of ketoacidosis (DKA) at pediatric type 1 diabetes (T1DM) diagnosis, in relation to pancreatic, associated and familial autoimmunity. METHODS Antibodies against pancreatic beta-cells, organ specific autoantibodies (thyroid, celiac, and parietal) and family history of autoimmunity were retrospectively evaluated in 116 T1DM patients aged 11.9 ± 4.6 (mean ± SD) years, with disease duration 7.62 ± 3.67 years (mean ± SD). RESULTS Most patients (67.2%) presented with DKA at diagnosis. Younger children (< 2 years) had tenfold risk of DKA, compared to older children (12.1-15 years) (OR = 10.8, 95% CI: 1.0-116.9, P = 0.05). Fasting c-peptide levels were lower in the DKA group (OR = 0.26, 95% CI = 0.07-0.89, P = 0.033). The number of anti-pancreatic antibodies at disease onset did not show any significant correlations with the presence (p = 0.889) or severity of DKA (p = 0.863). All patients with multiple autoimmunity (> 2 autoimmune diseases plus T1DM) presented with DKA. Familial autoimmunity acted protectively against DKA manifestation (OR = 0.40, 95% CI = 0.16-1.0, P = 0.051). CONCLUSIONS Among newly diagnosed T1DM patients, 67.2% presented with DKA. Younger age, lower c-peptide and the presence of associated autoimmunity were predictive factors of the presence and severity of DKA at diagnosis. High degree of suspicion, due to family history, may prevent DKA development and severity.
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Affiliation(s)
- Kyriaki Karavanaki
- Diabetic Clinic, 2nd Department of Pediatrics, 'P. & A. Kyriakou' Children's Hospital, National and Kapodistrian University of Athens, Thivon & Levadeias Str, 115 27, Athens, Greece
| | - Anastasia Korona
- Diabetic Clinic, 2nd Department of Pediatrics, 'P. & A. Kyriakou' Children's Hospital, National and Kapodistrian University of Athens, Thivon & Levadeias Str, 115 27, Athens, Greece
| | - Spyridon Karanasios
- Diabetic Clinic, 2nd Department of Pediatrics, 'P. & A. Kyriakou' Children's Hospital, National and Kapodistrian University of Athens, Thivon & Levadeias Str, 115 27, Athens, Greece
| | - Lydia Kossiva
- Diabetic Clinic, 2nd Department of Pediatrics, 'P. & A. Kyriakou' Children's Hospital, National and Kapodistrian University of Athens, Thivon & Levadeias Str, 115 27, Athens, Greece.
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Aung NL. Plasma Glucose. Clin Diabetes 2024; 42:574-578. [PMID: 39429450 PMCID: PMC11486848 DOI: 10.2337/cd24-0074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
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Joglekar MV, Kaur S, Pociot F, Hardikar AA. Prediction of progression to type 1 diabetes with dynamic biomarkers and risk scores. Lancet Diabetes Endocrinol 2024; 12:483-492. [PMID: 38797187 DOI: 10.1016/s2213-8587(24)00103-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/31/2024] [Accepted: 04/02/2024] [Indexed: 05/29/2024]
Abstract
Identifying biomarkers of functional β-cell loss is an important step in the risk stratification of type 1 diabetes. Genetic risk scores (GRS), generated by profiling an array of single nucleotide polymorphisms, are a widely used type 1 diabetes risk-prediction tool. Type 1 diabetes screening studies have relied on a combination of biochemical (autoantibody) and GRS screening methodologies for identifying individuals at high-risk of type 1 diabetes. A limitation of these screening tools is that the presence of autoantibodies marks the initiation of β-cell loss, and is therefore not the best biomarker of progression to early-stage type 1 diabetes. GRS, on the other hand, represents a static biomarker offering a single risk score over an individual's lifetime. In this Personal View, we explore the challenges and opportunities of static and dynamic biomarkers in the prediction of progression to type 1 diabetes. We discuss future directions wherein newer dynamic risk scores could be used to predict type 1 diabetes risk, assess the efficacy of new and emerging drugs to retard, or prevent type 1 diabetes, and possibly replace or further enhance the predictive ability offered by static biomarkers, such as GRS.
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Affiliation(s)
- Mugdha V Joglekar
- School of Medicine, Western Sydney University, Sydney, NSW, Australia
| | | | - Flemming Pociot
- Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
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Warncke K, Tamura R, Schatz DA, Veijola R, Steck AK, Akolkar B, Hagopian W, Krischer JP, Lernmark Å, Rewers MJ, Toppari J, McIndoe R, Ziegler AG, Vehik K, Haller MJ, Elding Larsson H. The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study. J Endocr Soc 2024; 8:bvae103. [PMID: 38867880 PMCID: PMC11167566 DOI: 10.1210/jendso/bvae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Indexed: 06/14/2024] Open
Abstract
Context The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.
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Affiliation(s)
- Katharina Warncke
- TUM School of Medicine, Department of Pediatrics, Technical University of Munich, 81675 Munich, Germany
- German Center for Environmental Health, Institute of Diabetes Research, Helmholtz Munich, 80939 Munich, Germany
| | - Roy Tamura
- Health Informatics Institute, University of South Florida, Tampa, FL 33612, USA
| | - Desmond A Schatz
- Diabetes Center of Excellence, University of Florida, Gainesville, FL 32610, USA
| | - Riitta Veijola
- Department of Pediatrics, Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90014 Oulu, Finland
| | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Beena Akolkar
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA
| | - William Hagopian
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jeffrey P Krischer
- Health Informatics Institute, University of South Florida, Tampa, FL 33612, USA
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skane University Hospital, 21428 Malmö, Sweden
| | - Marian J Rewers
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jorma Toppari
- Department of Pediatrics, University of Turku and Turku University Hospital, 20520 Turku, Finland
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, 20520 Turku, Finland
| | - Richard McIndoe
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Anette-G Ziegler
- German Center for Environmental Health, Institute of Diabetes Research, Helmholtz Munich, 80939 Munich, Germany
- German Center for Diabetes Research (DZD), 85764 Munich-Neuherberg, Germany
- Forschergruppe Diabetes, School of Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany
- Forschergruppe Diabetes e.V. at Helmholtz Munich, German Research Center for Environmental Health, 80939 Munich, Germany
| | - Kendra Vehik
- Health Informatics Institute, University of South Florida, Tampa, FL 33612, USA
| | - Michael J Haller
- Department of Pediatrics, Diabetes Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Helena Elding Larsson
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, 20502 Malmö, Sweden
- Department of Paediatrics, Skåne University Hospital, 20502 Malmö, Sweden
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11
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Shields BM, Carlsson A, Patel K, Knupp J, Kaur A, Johnston D, Colclough K, Larsson HE, Forsander G, Samuelsson U, Hattersley A, Ludvigsson J. Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis. Sci Rep 2024; 14:10589. [PMID: 38719926 PMCID: PMC11079008 DOI: 10.1038/s41598-024-60160-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis.
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Affiliation(s)
- Beverley M Shields
- The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
| | | | - Kashyap Patel
- The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Julieanne Knupp
- The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Akaal Kaur
- Faculty of Medicine, Imperial College London, London, UK
| | - Des Johnston
- Faculty of Medicine, Imperial College London, London, UK
| | - Kevin Colclough
- Exeter Genomics Laboratory, The Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Helena Elding Larsson
- Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
- Department of Pediatrics, Skånes University Hospital, Malmö, Sweden
| | - Gun Forsander
- Department of Paediatrics, Institute for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Paediatrics, Sahlgrenska University Hospital, Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Ulf Samuelsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Linköping University, Linköping, Sweden
| | - Andrew Hattersley
- The Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Johnny Ludvigsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Linköping University, Linköping, Sweden.
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12
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Jacobsen LM. Prompt Recognition of New-Onset Type 1 Diabetes Is Everyone's Responsibility-Even on Weekends. Diabetes Care 2024; 47:646-648. [PMID: 38527124 DOI: 10.2337/dci23-0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Affiliation(s)
- Laura M Jacobsen
- Departments of Pediatrics and Pathology, Diabetes Institute, University of Florida, Gainesville, FL
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13
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ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Ekhlaspour L, Gaglia JL, Hilliard ME, Johnson EL, Khunti K, Lingvay I, Matfin G, McCoy RG, Perry ML, Pilla SJ, Polsky S, Prahalad P, Pratley RE, Segal AR, Seley JJ, Selvin E, Stanton RC, Gabbay RA. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47:S20-S42. [PMID: 38078589 PMCID: PMC10725812 DOI: 10.2337/dc24-s002] [Citation(s) in RCA: 469] [Impact Index Per Article: 469.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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14
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Galderisi A, Carr ALJ, Martino M, Taylor P, Senior P, Dayan C. Quantifying beta cell function in the preclinical stages of type 1 diabetes. Diabetologia 2023; 66:2189-2199. [PMID: 37712956 PMCID: PMC10627950 DOI: 10.1007/s00125-023-06011-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/08/2023] [Indexed: 09/16/2023]
Abstract
Clinically symptomatic type 1 diabetes (stage 3 type 1 diabetes) is preceded by a pre-symptomatic phase, characterised by progressive loss of functional beta cell mass after the onset of islet autoimmunity, with (stage 2) or without (stage 1) measurable changes in glucose profile during an OGTT. Identifying metabolic tests that can longitudinally track changes in beta cell function is of pivotal importance to track disease progression and measure the effect of disease-modifying interventions. In this review we describe the metabolic changes that occur in the early pre-symptomatic stages of type 1 diabetes with respect to both insulin secretion and insulin sensitivity, as well as the measurable outcomes that can be derived from the available tests. We also discuss the use of metabolic modelling to identify insulin secretion and sensitivity, and the measurable changes during dynamic tests such as the OGTT. Finally, we review the role of risk indices and minimally invasive measures such as those derived from the use of continuous glucose monitoring.
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Affiliation(s)
| | - Alice L J Carr
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Mariangela Martino
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Peter Taylor
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Peter Senior
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
| | - Colin Dayan
- Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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15
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Simmons KM, Sims EK. Screening and Prevention of Type 1 Diabetes: Where Are We? J Clin Endocrinol Metab 2023; 108:3067-3079. [PMID: 37290044 PMCID: PMC11491628 DOI: 10.1210/clinem/dgad328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 05/10/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
A diagnosis of type 1 diabetes (T1D) and the subsequent requirement for exogenous insulin treatment is associated with considerable acute and chronic morbidity and a substantial effect on patient quality of life. Importantly, a large body of work suggests that early identification of presymptomatic T1D can accurately predict clinical disease, and when paired with education and monitoring, can yield improved health outcomes. Furthermore, a growing cadre of effective disease-modifying therapies provides the potential to alter the natural history of early stages of T1D. In this mini review, we highlight prior work that has led to the current landscape of T1D screening and prevention, as well as challenges and next steps moving into the future of these rapidly evolving areas of patient care.
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Affiliation(s)
- Kimber M Simmons
- Barbara Davis Center for Diabetes, Division of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA
| | - Emily K Sims
- Division of Pediatric Endocrinology and Diabetology, Herman B Wells Center for Pediatric Research; Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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16
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Quinn LM, Narendran P, Randell MJ, Bhavra K, Boardman F, Greenfield SM, Litchfield I. General population screening for paediatric type 1 diabetes-A qualitative study of UK professional stakeholders. Diabet Med 2023; 40:e15131. [PMID: 37151184 DOI: 10.1111/dme.15131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/09/2023]
Abstract
AIMS Identifying children at risk of type 1 diabetes allows education for symptom recognition and monitoring to reduce the risk of diabetic ketoacidosis at presentation. We aimed to explore stakeholder views towards paediatric general population screening for type 1 diabetes in the United Kingdom (UK). METHODS Qualitative interviews were undertaken with 25 stakeholders, including diabetes specialists, policymakers and community stakeholders who could be involved in a future type 1 diabetes screening programme in the UK. A thematic framework analysis was performed using the National Screening Committee's evaluative criteria as the overarching framework. RESULTS Diabetic ketoacidosis prevention was felt to be a priority and proposed benefits of screening included education, monitoring and helping the family to better prepare for a future with type 1 diabetes. However, diabetes specialists were cautious about general population screening because of lack of evidence for public acceptability. Concerns were raised about the harms of living with risk, provoking health anxiety and threatening the child's right to an 'open future'. Support systems that met the clinical and psychological needs of the family living with risk were considered essential. Stakeholders were supportive of research into general population screening and acknowledged this would be a priority if an immunoprevention agent were licensed in the UK. CONCLUSIONS Although stakeholders suggested the harms of UK paediatric general population screening currently outweigh the benefits, this view would potentially be altered if prevention therapies were licensed. In this case, an evidence-based screening strategy would need to be formulated and public acceptability explored.
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Affiliation(s)
- Lauren M Quinn
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Parth Narendran
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Department of Diabetes, University Hospitals of Birmingham, Birmingham, UK
| | | | | | | | - Sheila M Greenfield
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Ian Litchfield
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
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17
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Nigrovic LE, Kuppermann N, Ghetti S, Schunk JE, Stoner MJ, Rewers A, McManemy JK, Quayle KS, Trainor JL, Tzimenatos L, Bennett JE, Kwok MY, Myers SR, Brown KM, Casper TC, Olsen CS, Glaser NS. Emergency Department Presentations of Diabetic Ketoacidosis in a Large Cohort of Children. Pediatr Diabetes 2023; 2023:6693226. [PMID: 40303236 PMCID: PMC12017173 DOI: 10.1155/2023/6693226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/02/2023] [Accepted: 08/05/2023] [Indexed: 05/02/2025] Open
Abstract
Background Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of childhood diabetes. However, the influence of demographic factors on presentation are not well-defined. Methods We included children from 12 centers who were <18 years with DKA (glucose > 300 mg/dL, serum pH < 7.25, or serum bicarbonate <15 mEq/L) enrolled in the Pediatric Emergency Care Applied Research Network (PECARN) Fluid Therapies Under Investigation in DKA (FLUID) Trial. Data were also collected for children who presented to the centers during the enrollment period but were not enrolled due to disease or treatment-related reasons. We compared demographic, clinical, and biochemical findings among children with newly and previously diagnosed diabetes and children in different age groups. Results Of the 1,679 DKA episodes in 1,553 children, 799 (47.5%) episodes occurred in children with newly diagnosed diabetes and 396 (23.6%) were severe (pH < 7.1). Newly diagnosed children <6 years of age were not more likely to have severe DKA in terms of pH, but had more severe hypocarbia and higher blood urea nitrogen levels, factors previously associated with the risk of cerebral injury. Lower socioeconomic status (SES) (based on family income and maternal education level) were associated with more severe DKA in new onset children, and recurrent DKA in the previously diagnosed children. Conclusions Greater efforts are needed to identify the children with diabetes early and to prevent recurrent DKA, particularly among children in low-SES groups. Young children with DKA may need more intensive monitoring due to higher risk of cerebral injury.
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Affiliation(s)
- Lise E. Nigrovic
- Division of Emergency Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Nathan Kuppermann
- Department of Emergency Medicine, University of California Davis Health, School of Medicine, Sacramento, CA, USA
- Department of Pediatrics, University of California Davis Health, School of Medicine, Sacramento, CA, USA
| | - Simona Ghetti
- Department of Psychology, University of California Davis, Davis, CA, USA
| | - Jeff E. Schunk
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Michael J. Stoner
- Division of Emergency Medicine, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Arleta Rewers
- Section of Emergency Medicine, Department of Pediatrics, University of Colorado-Denver, School of Medicine, Aurora, CO, USA
| | - Julie K. McManemy
- Division of Emergency Medicine, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Kimberly S. Quayle
- Division of Emergency Medicine, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
| | - Jennifer L. Trainor
- Division of Emergency Medicine, Department of Pediatrics, Ann & Robert H, Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Leah Tzimenatos
- Department of Emergency Medicine, University of California Davis Health, School of Medicine, Sacramento, CA, USA
| | - Jonathan E. Bennett
- Division of Emergency Medicine, Nemours Children's Hospital, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Maria Y. Kwok
- Division of Emergency Medicine, Department of Pediatrics, New York Presbyterian Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Sage R. Myers
- Division of Emergency Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Kathleen M. Brown
- Division of Emergency Medicine, Department of Pediatrics, Children's National Medical Center, The George Washington School of Medicine and Health Sciences, Washington, DC, USA
| | - T. Charles Casper
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Cody S. Olsen
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Nicole S. Glaser
- Department of Pediatrics, University of California Davis Health, School of Medicine, Sacramento, CA, USA
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18
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Colella M, Charitos IA, Ballini A, Cafiero C, Topi S, Palmirotta R, Santacroce L. Microbiota revolution: How gut microbes regulate our lives. World J Gastroenterol 2023; 29:4368-4383. [PMID: 37576701 PMCID: PMC10415973 DOI: 10.3748/wjg.v29.i28.4368] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/16/2023] [Accepted: 07/10/2023] [Indexed: 07/26/2023] Open
Abstract
The human intestine is a natural environment ecosystem of a complex of diversified and dynamic microorganisms, determined through a process of competition and natural selection during life. Those intestinal microorganisms called microbiota and are involved in a variety of mechanisms of the organism, they interact with the host and therefore are in contact with the organs of the various systems. However, they play a crucial role in maintaining host homeostasis, also influencing its behaviour. Thus, microorganisms perform a series of biological functions important for human well-being. The host provides the microorganisms with the environment and nutrients, simultaneously drawing many benefits such as their contribution to metabolic, trophic, immunological, and other functions. For these reasons it has been reported that its quantitative and qualitative composition can play a protective or harmful role on the host health. Therefore, a dysbiosis can lead to an association of unfavourable factors which lead to a dysregulation of the physiological processes of homeostasis. Thus, it has pre-viously noted that the gut microbiota can participate in the pathogenesis of autoimmune diseases, chronic intestinal inflammation, diabetes mellitus, obesity and atherosclerosis, neurological disorders (e.g., neurological diseases, autism, etc.) colorectal cancer, and more.
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Affiliation(s)
- Marica Colella
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Ioannis Alexandros Charitos
- Maugeri Clinical Scientific Research Institutes (IRCCS) of Pavia - Division of Pneumology and Respiratory Rehabilitation, Scientific Institute of Bari, Bari 70124, Italy
| | - Andrea Ballini
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia 71122, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Concetta Cafiero
- Area of Molecular Pathology, Anatomic Pathology Unit, Fabrizio Spaziani Hospital, Frosinone 03100, Italy
| | - Skender Topi
- Department of Clinical Disciplines, School of Technical Medical Sciences, University of Elbasan “A. Xhuvani”, Elbasan 3001, Albania
| | - Raffaele Palmirotta
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Luigi Santacroce
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, University of Bari “Aldo Moro”, Bari 70124, Italy
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19
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Marzinotto I, Pittman DL, Williams AJK, Long AE, Achenbach P, Schlosser M, Akolkar B, Winter WE, Lampasona V. Islet Autoantibody Standardization Program: interlaboratory comparison of insulin autoantibody assay performance in 2018 and 2020 workshops. Diabetologia 2023; 66:897-912. [PMID: 36759347 PMCID: PMC10036445 DOI: 10.1007/s00125-023-05877-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023]
Abstract
AIMS/HYPOTHESIS The Islet Autoantibody Standardization Program (IASP) aims to improve the performance of immunoassays measuring autoantibodies in type 1 diabetes and the concordance of results across laboratories. IASP organises international workshops distributing anonymised serum samples to participating laboratories and centralises the collection and analysis of results. In this report, we describe the results of assays measuring IAA submitted to the IASP 2018 and 2020 workshops. METHODS The IASP distributed uniquely coded sera from individuals with new-onset type 1 diabetes, multiple islet autoantibody-positive individuals, and diabetes-free blood donors in both 2018 and 2020. Serial dilutions of the anti-insulin mouse monoclonal antibody HUI-018 were also included. Sensitivity, specificity, area under the receiver operating characteristic curve (ROC-AUC), partial ROC-AUC at 95% specificity (pAUC95) and concordance of qualitative/quantitative results were compared across assays. RESULTS Results from 45 IAA assays of seven different formats and from 37 IAA assays of six different formats were submitted to the IASP in 2018 and 2020, respectively. The median ROC-AUC was 0.736 (IQR 0.617-0.803) and 0.790 (IQR 0.730-0.836), while the median pAUC95 was 0.016 (IQR 0.004-0.021) and 0.023 (IQR 0.014-0.026) in the 2018 and 2020 workshops, respectively. Assays largely differed in AUC (IASP 2018 range 0.232-0.874; IASP 2020 range 0.379-0.924) and pAUC95 (IASP 2018 and IASP 2020 range 0-0.032). CONCLUSIONS/INTERPRETATION Assay formats submitted to this study showed heterogeneous performance. Despite the high variability across laboratories, the in-house radiobinding assay (RBA) remains the gold standard for IAA measurement. However, novel non-radioactive IAA immunoassays showed a good performance and, if further improved, might be considered valid alternatives to RBAs.
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Affiliation(s)
- Ilaria Marzinotto
- San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy
| | - David L Pittman
- Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Alistair J K Williams
- Diabetes and Metabolism, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Anna E Long
- Diabetes and Metabolism, Translational Health Sciences, University of Bristol, Bristol, UK
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany.
| | - Michael Schlosser
- Department of General Surgery, Visceral, Thoracic and Vascular Surgery, University Medical Center Greifswald, Greifswald, Germany
- Institute of Pathophysiology, Research Group of Predictive Diagnostics, University Medical Center Greifswald, Karlsburg, Germany
| | - Beena Akolkar
- Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - William E Winter
- Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Vito Lampasona
- San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
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20
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Ghalwash M, Anand V, Lou O, Martin F, Rewers M, Ziegler AG, Toppari J, Hagopian WA, Veijola R. Islet autoantibody screening in at-risk adolescents to predict type 1 diabetes until young adulthood: a prospective cohort study. THE LANCET. CHILD & ADOLESCENT HEALTH 2023; 7:261-268. [PMID: 36681087 PMCID: PMC10038928 DOI: 10.1016/s2352-4642(22)00350-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/21/2022] [Accepted: 11/23/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10-18 years with an increased risk of developing type 1 diabetes. METHODS Data were harmonised from prospective studies from Finland (the Diabetes Prediction and Prevention study), Germany (the BABYDIAB study), and the USA (Diabetes Autoimmunity Study in the Young and the Diabetes Evaluation in Washington study). Autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2 were measured at each follow-up visit. Children who were lost to follow-up or diagnosed with type 1 diabetes before 10 years of age were excluded. Inverse probability censoring weighting was used to include data from remaining participants. Sensitivity and the positive predictive value of these autoantibodies, tested at one or two ages, to predict type 1 diabetes by the age of 18 years were the main outcomes. FINDINGS Of 20 303 children with an increased type 1 diabetes risk, 8682 were included for the analysis with inverse probability censoring weighting. 1890 were followed up to 18 years of age or developed type 1 diabetes between the ages of 10 years and 18 years, and their median follow-up was 18·3 years (IQR 14·5-20·3). 442 (23·4%) of 1890 adolescents were positive for at least one islet autoantibody, and 262 (13·9%) developed type 1 diabetes. Time from seroconversion to diabetes diagnosis increased by 0·64 years (95% CI 0·34-0·95) for each 1-year increment of diagnosis age (Pearson's correlation coefficient 0·88, 95% CI 0·50-0·97, p=0·0020). The median interval between the last prediagnostic sample and diagnosis was 0·3 years (IQR 0·1-1·3) in the 227 participants who were autoantibody positive and 6·8 years (1·6-9·9) for the 35 who were autoantibody negative. Single screening at the age of 10 years was 90% (95% CI 86-95) sensitive, with a positive predictive value of 66% (60-72) for clinical diabetes. Screening at two ages (10 years and 14 years) increased sensitivity to 93% (95% CI 89-97) but lowered the positive predictive value to 55% (49-60). INTERPRETATION Screening of adolescents at risk for type 1 diabetes only once at 10 years of age for islet autoantibodies was highly effective to detect type 1 diabetes by the age of 18 years, which in turn could enable prevention of diabetic ketoacidosis and participation in secondary prevention trials. FUNDING JDRF International.
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Affiliation(s)
- Mohamed Ghalwash
- Center for Computational Health, IBM Research, Yorktown Heights, NY, USA; Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Vibha Anand
- Center for Computational Health, IBM Research, Cambridge, MA, USA
| | | | | | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado, Denver, CO, USA
| | - Anette-G Ziegler
- Forschergruppe Diabetes and Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany der TU München, Munich, Germany
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland; Department of Pediatrics, Turku University Hospital, Turku, Finland
| | | | - Riitta Veijola
- Department of Pediatrics, Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.
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21
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ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46:S19-S40. [PMID: 36507649 PMCID: PMC9810477 DOI: 10.2337/dc23-s002] [Citation(s) in RCA: 1194] [Impact Index Per Article: 597.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Ghalwash M, Dunne JL, Lundgren M, Rewers M, Ziegler AG, Anand V, Toppari J, Veijola R, Hagopian W. Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study. Lancet Diabetes Endocrinol 2022; 10:589-596. [PMID: 35803296 PMCID: PMC10040253 DOI: 10.1016/s2213-8587(22)00141-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 01/08/2023]
Abstract
BACKGROUND Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years. METHODS We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes. FINDINGS Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79-86) and PPV of 79% (95% CI 75-80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2-5·99 year or 6-15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood. INTERPRETATION Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics. FUNDING Juvenile Diabetes Research Foundation.
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Affiliation(s)
- Mohamed Ghalwash
- Center for Computational Health, IBM Research, Yorktown Heights, NY, USA; Faculty of Science, Ain Shams University, Cairo, Egypt
| | | | - Markus Lundgren
- Department of Clinical Sciences Malmö, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado, Denver, CO, USA
| | - Anette-G Ziegler
- Forschegruppe Diabetes and Institute of Diabetes Research, Helmholtz Zentrum München, German Research Centre for Environmental Health, Munich-Neuherberg, Germany der TU München, Munich, Germany
| | - Vibha Anand
- Center for Computational Health, IBM Research, Yorktown Heights, NY, USA
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland; Department of Paediatrics, Turku University Hospital, Turku, Finland
| | - Riitta Veijola
- Department of Paediatrics, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - William Hagopian
- Pacific Northwest Research Institute, Seattle, WA, USA; Department of Medicine, University of Washington, Seattle, WA, USA.
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Webb-Robertson BJM, Nakayasu ES, Frohnert BI, Bramer LM, Akers SM, Norris JM, Vehik K, Ziegler AG, Metz TO, Rich SS, Rewers MJ. Integration of Infant Metabolite, Genetic, and Islet Autoimmunity Signatures to Predict Type 1 Diabetes by Age 6 Years. J Clin Endocrinol Metab 2022; 107:2329-2338. [PMID: 35468213 PMCID: PMC9282254 DOI: 10.1210/clinem/dgac225] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Indexed: 02/08/2023]
Abstract
CONTEXT Biomarkers that can accurately predict risk of type 1 diabetes (T1D) in genetically predisposed children can facilitate interventions to delay or prevent the disease. OBJECTIVE This work aimed to determine if a combination of genetic, immunologic, and metabolic features, measured at infancy, can be used to predict the likelihood that a child will develop T1D by age 6 years. METHODS Newborns with human leukocyte antigen (HLA) typing were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY). TEDDY ascertained children in Finland, Germany, Sweden, and the United States. TEDDY children were either from the general population or from families with T1D with an HLA genotype associated with T1D specific to TEDDY eligibility criteria. From the TEDDY cohort there were 702 children will all data sources measured at ages 3, 6, and 9 months, 11.4% of whom progressed to T1D by age 6 years. The main outcome measure was a diagnosis of T1D as diagnosed by American Diabetes Association criteria. RESULTS Machine learning-based feature selection yielded classifiers based on disparate demographic, immunologic, genetic, and metabolite features. The accuracy of the model using all available data evaluated by the area under a receiver operating characteristic curve is 0.84. Reducing to only 3- and 9-month measurements did not reduce the area under the curve significantly. Metabolomics had the largest value when evaluating the accuracy at a low false-positive rate. CONCLUSION The metabolite features identified as important for progression to T1D by age 6 years point to altered sugar metabolism in infancy. Integrating this information with classic risk factors improves prediction of the progression to T1D in early childhood.
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Affiliation(s)
- Bobbie-Jo M Webb-Robertson
- Correspondence: Bobbie-Jo Webb-Robertson, PhD, Biological Sciences Division, Pacific Northwest National Laboratory, 902 Battelle Blvd, MSIN: J4-18, Richland, WA 99352, USA.
| | - Ernesto S Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352,USA
| | - Brigitte I Frohnert
- Barbara Davis Center for Childhood Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Lisa M Bramer
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352,USA
| | - Sarah M Akers
- Computing & Analytics Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA
| | - Jill M Norris
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
| | - Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, USA
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Kilinikum rechts der Isar, Technische Universität München, 80333 Munich, Germany
- Forschergruppe Diabetes e.V., 85764 Neuherberg, Germany
| | - Thomas O Metz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352,USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908,USA
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, USA
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24
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Kossiva L, Korona A, Kafassi N, Karanasios S, Karavanaki K. Familial autoimmunity in pediatric patients with type 1 diabetes (T1D) and its associations with the severity of clinical presentation at diabetes diagnosis and with coexisting autoimmunity. Hormones (Athens) 2022; 21:277-285. [PMID: 35254657 PMCID: PMC8900107 DOI: 10.1007/s42000-022-00358-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 02/22/2022] [Indexed: 11/05/2022]
Abstract
PURPOSE The aim was to evaluate the impact of familial autoimmunity on the age and severity of type 1 diabetes (T1D) presentation and on the coexistence of other autoimmune diseases. METHODS We retrospectively evaluated the medical records of 121 children/adolescents (male: 63) followed in our Diabetic Clinic from 2002 to 2016. RESULTS Seventy-six patients (62.8%) had at least one relative with an autoimmune disease, Hashimoto's thyroiditis (49.5%) and T1D (22.3%) being the commonest. Children with familial autoimmunity were younger at T1D diagnosis (mean age ± SD) (6.766 ± 3.75). Median fasting c-peptide levels at presentation were not related to familial autoimmunity. Patients with familial autoimmunity more often exhibited GADA autoantibody positivity at diagnosis. The larger the number of the patient's relatives diagnosed with an autoimmune disease, the higher were the patient's GADA levels (Spearman's rho test = 0.19, p = 0.049). Children with a first-degree relative with autoimmunity had a coexisting autoimmune disorder at a significantly higher percentage (p = 0.016). Family history of autoimmunity was negatively associated with the presence of diabetic ketoacidosis (DKA) (p = 0.024). Patients with a relative with T1D less frequently exhibited DKA at diagnosis (12.8 vs. 87.2%, p = 0.003). The presence of DKA was associated with younger age (p = 0.05) and lower c-peptide levels (p = 0.033). CONCLUSIONS Familial autoimmunity was present in 62.8% of children with T1D, autoimmune thyroiditis and T1D being the two most frequent familial autoimmune diseases. Familial autoimmunity reduced the risk of DKA at diagnosis, but these patients were younger and had higher levels of pancreatic autoantibodies and a greater risk of developing additional autoimmune diseases.
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Affiliation(s)
- Lydia Kossiva
- Diabetic Clinic, Department of Pediatrics, National and Kapodistrian University of Athens, A. Kyriakou' Children's Hospital, 'P. &, 2nd, Athens, Greece.
| | - Anastasia Korona
- Diabetic Clinic, Department of Pediatrics, National and Kapodistrian University of Athens, A. Kyriakou' Children's Hospital, 'P. &, 2nd, Athens, Greece
| | | | - Spyridon Karanasios
- Diabetic Clinic, Department of Pediatrics, National and Kapodistrian University of Athens, A. Kyriakou' Children's Hospital, 'P. &, 2nd, Athens, Greece
| | - Kyriaki Karavanaki
- Diabetic Clinic, Department of Pediatrics, National and Kapodistrian University of Athens, A. Kyriakou' Children's Hospital, 'P. &, 2nd, Athens, Greece
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Huang Y, Chen J, Xu L, Tang NS. Bayesian Joint Modeling of Multivariate Longitudinal and Survival Data With an Application to Diabetes Study. Front Big Data 2022; 5:812725. [PMID: 35574573 PMCID: PMC9094046 DOI: 10.3389/fdata.2022.812725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/24/2022] [Indexed: 11/15/2022] Open
Abstract
Joint models of longitudinal and time-to-event data have received a lot of attention in epidemiological and clinical research under a linear mixed-effects model with the normal assumption for a single longitudinal outcome and Cox proportional hazards model. However, those model-based analyses may not provide robust inference when longitudinal measurements exhibit skewness and/or heavy tails. In addition, the data collected are often featured by multivariate longitudinal outcomes which are significantly correlated, and ignoring their correlation may lead to biased estimation. Under the umbrella of Bayesian inference, this article introduces multivariate joint (MVJ) models with a skewed distribution for multiple longitudinal exposures in an attempt to cope with correlated multiple longitudinal outcomes, adjust departures from normality, and tailor linkage in specifying a time-to-event process. We develop a Bayesian joint modeling approach to MVJ models that couples a multivariate linear mixed-effects (MLME) model with the skew-normal (SN) distribution and a Cox proportional hazards model. Our proposed models and method are evaluated by simulation studies and are applied to a real example from a diabetes study.
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Affiliation(s)
- Yangxin Huang
- College of Public Health, University of South Florida, Tampa, FL, United States
- *Correspondence: Yangxin Huang
| | - Jiaqing Chen
- Department of Statistics, College of Science, Wuhan University of Technology, Wuhan, China
| | - Lan Xu
- College of Public Health, University of South Florida, Tampa, FL, United States
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26
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Jacobsen LM, Vehik K, Veijola R, Warncke K, Toppari J, Steck AK, Gesualdo P, Akolkar B, Lundgren M, Hagopian WA, She JX, Rewers M, Ziegler AG, Krischer JP, Larsson HE, Haller MJ. Heterogeneity of DKA Incidence and Age-Specific Clinical Characteristics in Children Diagnosed With Type 1 Diabetes in the TEDDY Study. Diabetes Care 2022; 45:624-633. [PMID: 35043162 PMCID: PMC8918232 DOI: 10.2337/dc21-0422] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Accepted: 12/11/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Environmental Determinants of Diabetes in the Young (TEDDY) study is uniquely capable of investigating age-specific differences associated with type 1 diabetes. Because age is a primary driver of heterogeneity in type 1 diabetes, we sought to characterize by age metabolic derangements prior to diagnosis and clinical features associated with diabetic ketoacidosis (DKA). RESEARCH DESIGN AND METHODS The 379 TEDDY children who developed type 1 diabetes were grouped by age at onset (0-4, 5-9, and 10-14 years; n = 142, 151, and 86, respectively) with comparisons of autoantibody profiles, HLAs, family history of diabetes, presence of DKA, symptomatology at onset, and adherence to TEDDY protocol. Time-varying analysis compared those with oral glucose tolerance test data with TEDDY children who did not progress to diabetes. RESULTS Increasing fasting glucose (hazard ratio [HR] 1.09 [95% CI 1.04-1.14]; P = 0.0003), stimulated glucose (HR 1.50 [1.42-1.59]; P < 0.0001), fasting insulin (HR 0.89 [0.83-0.95]; P = 0.0009), and glucose-to-insulin ratio (HR 1.29 [1.16-1.43]; P < 0.0001) were associated with risk of progression to type 1 diabetes. Younger children had fewer autoantibodies with more symptoms at diagnosis. Twenty-three children (6.1%) had DKA at onset, only 1 (0.97%) of 103 with and 22 (8.0%) of 276 children without a first-degree relative (FDR) with type 1 diabetes (P = 0.008). Children with DKA were more likely to be nonadherent to study protocol (P = 0.047), with longer duration between their last TEDDY evaluation and diagnosis (median 10.2 vs. 2.0 months without DKA; P < 0.001). CONCLUSIONS DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes.
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Affiliation(s)
| | - Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Riitta Veijola
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Katharina Warncke
- Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes e.V., Neuherberg, Germany
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, Centre for Population Health Research, University of Turku, Turku, Finland
| | - Andrea K. Steck
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Patricia Gesualdo
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Beena Akolkar
- Diabetes Division, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD
| | - Markus Lundgren
- Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
| | | | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Anette-G. Ziegler
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Jeffrey P. Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Helena Elding Larsson
- Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden
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27
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Steck AK, Dong F, Geno Rasmussen C, Bautista K, Sepulveda F, Baxter J, Yu L, Frohnert BI, Rewers MJ. CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study. Diabetes Care 2022; 45:365-371. [PMID: 34880069 DOI: 10.2337/dc21-0602] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 11/15/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish continuous glucose monitoring (CGM) metrics that could predict imminent progression to diabetes. RESEARCH DESIGN AND METHODS In the Autoimmunity Screening for Kids study, 91 children who were persistently islet autoantibody positive (median age 11.5 years; 48% non-Hispanic White; 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range 0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range 0.4-29) months. RESULTS Compared with children who did not progress to clinical diabetes (nonprogressors), those who did (progressors) had significantly higher average sensor glucose levels (119 vs. 105 mg/dL, P < 0.001) and increased glycemic variability (SD 27 vs. 16, coefficient of variation, 21 vs. 15, mean of daily differences 24 vs. 16, and mean amplitude of glycemic excursions 43 vs. 26, all P < 0.001). For progressors, 21% of the time was spent with glucose levels >140 mg/dL (TA140) and 8% of time >160 mg/dL, compared with 3% and 1%, respectively, for nonprogressors. In survival analyses, the risk of progression to diabetes in 1 year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. Performance of prediction by receiver operating curve analyses showed area under the curve of ≥0.89 for both individual and combined CGM metric models. CONCLUSIONS TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year in autoantibody-positive children. CGM should be included in the ongoing monitoring of high-risk children and could be used as potential entry criterion for prevention trials.
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Abstract
The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Abstract
This article summarizes clinical observations and management strategies in pediatric type 1 diabetes (T1D) during the coronavirus disease 2019 (COVID-19) pandemic. Despite initial fears that children with diabetes would, similar to adults with diabetes, be at risk for severe COVID-19, most pediatric patients with a history of T1D who developed COVID-19 had mild disease or were asymptomatic similar to their peers without diabetes. The article also summarizes the use of telemedicine to provide ongoing care for pediatric patients with T1D during the COVID-19 pandemic. Finally, the article highlights important lessons learned about management of pediatric diabetes during the COVID-19 pandemic.
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30
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Smith LB, Lynch KF, Driscoll KA, Johnson SB. Parental monitoring for type 1 diabetes in genetically at-risk young children: The TEDDY study. Pediatr Diabetes 2021; 22:717-728. [PMID: 33704891 PMCID: PMC8771863 DOI: 10.1111/pedi.13173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Revised: 10/15/2020] [Accepted: 11/08/2020] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE We examined parental diabetes monitoring behaviors in a cohort of children at increased genetic risk for type 1 diabetes. We hypothesized that being informed of a positive islet autoantibody (IA) would increase monitoring behaviors. RESEARCH DESIGN AND METHODS The Environmental Determinants of Diabetes in the Young (TEDDY) study follows 8676 children with high-risk human leucocyte antigen-DQ genotypes from birth to age 15, including general population (GP) children and those with a first-degree relative (FDR) with diabetes. Data on parental monitoring behaviors were solicited yearly. Serum samples were tested for IA and parents were informed of child results. We examined parental monitoring behaviors during the first 7 years of TEDDY. RESULTS In IA- children, the most common monitoring behavior was participating in TEDDY study tasks; up to 49.8% and 44.2% of mothers and fathers, respectively, reported this. Among FDRs, 7%-10% reported watching for diabetes symptoms and 7%-9% reported monitoring the child's glucose, for mothers and fathers, respectively. After IA+ notification, all monitoring behaviors significantly increased in GP parents; only glucose monitoring increased in FDR parents and these behaviors continued for up to 4 years. FDR status, accurate diabetes risk perception, and anxiety were associated with glucose monitoring in IA+ and IA- cohorts. CONCLUSIONS Many parents view TEDDY participation as a way to monitor for type 1 diabetes, a benefit of enrollment in a longitudinal study with no prevention offered. IA+ notification increases short- and long-term monitoring behaviors. For IA- and IA+ children, FDR parents engage in glucose monitoring, even when not instructed to do so.
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Affiliation(s)
- Laura B. Smith
- Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Kristian F. Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Kimberly A. Driscoll
- Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida, USA
| | - Suzanne Bennett Johnson
- Department of Medical Humanities and Social Sciences, Florida State University College of Medicine, Tallahassee, Florida, USA
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Akil AAS, Yassin E, Al-Maraghi A, Aliyev E, Al-Malki K, Fakhro KA. Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era. J Transl Med 2021; 19:137. [PMID: 33794915 PMCID: PMC8017850 DOI: 10.1186/s12967-021-02778-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/08/2021] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The type 1 diabetes patient cohort is highly heterogeneous, with individuals presenting with disease at different stages and severities, arising from distinct etiologies, and overlaying varied genetic backgrounds. At present, the “one-size-fits-all” treatment for type 1 diabetes is exogenic insulin substitution therapy, but this approach fails to achieve optimal blood glucose control in many individuals. With advances in our understanding of early-stage diabetes development, diabetes stratification, and the role of genetics, type 1 diabetes is a promising candidate for a personalized medicine approach, which aims to apply “the right therapy at the right time, to the right patient”. In the case of type 1 diabetes, great efforts are now being focused on risk stratification for diabetes development to enable pre-clinical detection, and the application of treatments such as gene therapy, to prevent pancreatic destruction in a sub-set of patients. Alongside this, breakthroughs in stem cell therapies hold great promise for the regeneration of pancreatic tissues in some individuals. Here we review the recent initiatives in the field of personalized medicine for type 1 diabetes, including the latest discoveries in stem cell and gene therapy for the disease, and current obstacles that must be overcome before the dream of personalized medicine for all type 1 diabetes patients can be realized.
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Affiliation(s)
- Ammira Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.
| | - Esraa Yassin
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Aljazi Al-Maraghi
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Elbay Aliyev
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Khulod Al-Malki
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar
| | - Khalid A Fakhro
- Department of Human Genetics-Precision Medicine Program, Sidra Medicine, P.O. Box 26999, Doha, Qatar.,Department of Genetic Medicine, Weill Cornell Medicine, P.O. Box 24144, Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar
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32
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Abstract
Type 1 diabetes (T1D) is an autoimmune disease that resulted from the severe destruction of the insulin-producing β cells in the pancreases of individuals with a genetic predisposition. Genome-wide studies have identified HLA and other risk genes associated with T1D susceptibility in humans. However, evidence obtained from the incomplete concordance of diabetes incidence among monozygotic twins suggests that environmental factors also play critical roles in T1D pathogenesis. Epigenetics is a rapidly growing field that serves as a bridge to link T1D risk genes and environmental exposures, thereby modulating the expression of critical genes relevant to T1D development beyond the changes of DNA sequences. Indeed, there is compelling evidence that epigenetic changes induced by environmental insults are implicated in T1D pathogenesis. Herein, we sought to summarize the recent progress in terms of epigenetic mechanisms in T1D initiation and progression, and discuss their potential as biomarkers and therapeutic targets in the T1D setting.
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33
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Steck AK, Liu X, Krischer JP, Haller MJ, Veijola R, Lundgren M, Ahmed S, Akolkar B, Toppari J, Hagopian WA, Rewers MJ, Elding Larsson H. Factors Associated With the Decline of C-Peptide in a Cohort of Young Children Diagnosed With Type 1 Diabetes. J Clin Endocrinol Metab 2021; 106:e1380-e1388. [PMID: 33035311 PMCID: PMC8244121 DOI: 10.1210/clinem/dgaa715] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Indexed: 12/30/2022]
Abstract
CONTEXT Understanding factors involved in the rate of C-peptide decline is needed to tailor therapies for type 1 diabetes (T1D). OBJECTIVE Evaluate factors associated with rate of C-peptide decline after a T1D diagnosis in young children. DESIGN Observational study. SETTING Academic centers. PARTICIPANTS A total of 57 participants from the Environmental Determinants of Diabetes in the Young (TEDDY) study who were enrolled at 3 months of age and followed until T1D, and 56 age-matched children diagnosed with T1D in the community. INTERVENTION A mixed meal tolerance test was used to measure the area under the curve (AUC) C-peptide at 1, 3, 6, 12, and 24 months postdiagnosis. OUTCOME Factors associated with rate of C-peptide decline during the first 2 years postdiagnosis were evaluated using mixed effects models, adjusting for age at diagnosis and baseline C-peptide. RESULTS Adjusted slopes of AUC C-peptide decline did not differ between TEDDY subjects and community controls (P = 0.21), although the former had higher C-peptide baseline levels. In univariate analyses combining both groups (n = 113), younger age, higher weight and body mass index z-scores, female sex, an increased number increased number of islet autoantibodies, and IA-2A or ZnT8A positivity at baseline were associated with a higher rate of C-peptide loss. Younger age, female sex, and higher weight z-score remained significant in multivariate analysis (all P < 0.02). At 3 months after diagnosis, higher HbA1c became an additional independent factor associated with a higher rate of C-peptide decline (P < 0.01). CONCLUSION Younger age at diagnosis, female sex, higher weight z-score, and HbA1c were associated with a higher rate of C-peptide decline after T1D diagnosis in young children.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Xiang Liu
- Health Informatics Institute, University of South Florida, Tampa, Florida
| | - Jeffrey P Krischer
- Health Informatics Institute, University of South Florida, Tampa, Florida
| | - Michael J Haller
- Department of Pediatrics, University of Florida, Gainesville, Florida
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Markus Lundgren
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
| | - Simi Ahmed
- Immunology of T1D, JDRF International, New York, New York
| | - Beena Akolkar
- Division of Diabetes, Endocrinology and Metabolism, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
- Pacific Diabetes Research Institute, Seattle, Washington
| | | | - Marian J Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden
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Balzano-Nogueira L, Ramirez R, Zamkovaya T, Dailey J, Ardissone AN, Chamala S, Serrano-Quílez J, Rubio T, Haller MJ, Concannon P, Atkinson MA, Schatz DA, Triplett EW, Conesa A. Integrative analyses of TEDDY Omics data reveal lipid metabolism abnormalities, increased intracellular ROS and heightened inflammation prior to autoimmunity for type 1 diabetes. Genome Biol 2021; 22:39. [PMID: 33478573 PMCID: PMC7818777 DOI: 10.1186/s13059-021-02262-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 01/04/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time. RESULTS We identify a multi-omics signature that was predictive of islet autoimmunity (IA) as early as 1 year before seroconversion. At this time, abnormalities in lipid metabolism, decreased capacity for nutrient absorption, and intracellular ROS accumulation are detected in children progressing towards IA. Additionally, extracellular matrix remodeling, inflammation, cytotoxicity, angiogenesis, and increased activity of antigen-presenting cells are observed, which may contribute to beta cell destruction. Our results indicate that altered molecular homeostasis is present in IA-developing children months before the actual detection of islet autoantibodies, which opens an interesting window of opportunity for therapeutic intervention. CONCLUSIONS The approach employed herein for assessment of the TEDDY cohort showcases the utilization of multi-omics data for the modeling of complex, multifactorial diseases, like T1D.
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Affiliation(s)
- Leandro Balzano-Nogueira
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Ricardo Ramirez
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Tatyana Zamkovaya
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Jordan Dailey
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Alexandria N Ardissone
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Srikar Chamala
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Joan Serrano-Quílez
- Gene Expression and RNA Metabolism Laboratory, Instituto de Biomedicina de Valencia (CSIC), Jaume Roig, 11, 46010, Valencia, Spain
| | - Teresa Rubio
- Laboratory of Neurobiology, Prince Felipe Research Center, Valencia, Spain
| | - Michael J Haller
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Patrick Concannon
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL, USA
- University of Florida Genetics Institute, Gainesville, FL, USA
| | - Mark A Atkinson
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Desmond A Schatz
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Eric W Triplett
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA
| | - Ana Conesa
- Microbiology and Cell Science Department, Institute for Food and Agricultural Sciences, University of Florida, Gainesville, USA.
- University of Florida Genetics Institute, Gainesville, FL, USA.
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Andersson Svärd A, Kaur S, Trôst K, Suvitaival T, Lernmark Å, Maziarz M, Pociot F, Overgaard AJ. Characterization of plasma lipidomics in adolescent subjects with increased risk for type 1 diabetes in the DiPiS cohort. Metabolomics 2020; 16:109. [PMID: 33033923 PMCID: PMC7544716 DOI: 10.1007/s11306-020-01730-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 09/25/2020] [Indexed: 10/25/2022]
Abstract
INTRODUCTION Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet beta cells resulting in total loss of insulin production. Recent studies have suggested that the destruction may be interrelated to plasma lipids. OBJECTIVES Specific lipids have previously been shown to be decreased in children who develop T1D before four years of age. Disturbances of plasma lipids prior to clinical diagnosis of diabetes, if true, may provide a novel way to improve prediction, and monitor disease progression. METHODS A lipidomic approach was utilized to analyze plasma from 67 healthy adolescent subjects (10-15 years of age) with or without islet autoantibodies but all with increased genetic risk for T1D. The study subjects were enrolled at birth in the Diabetes Prediction in Skåne (DiPiS) study and after 10-15 years of follow-up we performed the present cross-sectional analysis. HLA-DRB345, -DRB1, -DQA1, -DQB1, -DPA1 and -DPB1 genotypes were determined using next generation sequencing. Lipidomic profiles were determined using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Lipidomics data were analyzed according to genotype. RESULTS Variation in levels of several specific phospholipid species were related to level of autoimmunity but not development of T1D. Five glycosylated ceramides were increased in insulin autoantibody (IAA) positive adolescent subjects compared to adolescent subjects without this autoantibody. Additionally, HLA genotypes seemed to influence levels of long chain triacylglycerol (TG). CONCLUSION Lipidomic profiling of adolescent subjects in high risk of T1D may improve sub-phenotyping in this high risk population.
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Affiliation(s)
- Agnes Andersson Svärd
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden.
| | - Simranjeet Kaur
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Kajetan Trôst
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Tommi Suvitaival
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
| | - Åke Lernmark
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden
| | - Marlena Maziarz
- Department of Clinical Sciences, Skåne University Hospital, Lund University/CRC, Malmö, Sweden
| | - Flemming Pociot
- Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Ferrat LA, Vehik K, Sharp SA, Lernmark Å, Rewers MJ, She JX, Ziegler AG, Toppari J, Akolkar B, Krischer JP, Weedon MN, Oram RA, Hagopian WA. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nat Med 2020; 26:1247-1255. [PMID: 32770166 PMCID: PMC7556983 DOI: 10.1038/s41591-020-0930-4] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 05/08/2020] [Indexed: 11/08/2022]
Abstract
Type 1 diabetes (T1D)-an autoimmune disease that destroys the pancreatic islets, resulting in insulin deficiency-often begins early in life when islet autoantibody appearance signals high risk1. However, clinical diabetes can follow in weeks or only after decades, and is very difficult to predict. Ketoacidosis at onset remains common2,3 and is most severe in the very young4,5, in whom it can be life threatening and difficult to treat6-9. Autoantibody surveillance programs effectively prevent most ketoacidosis10-12 but require frequent evaluations whose expense limits public health adoption13. Prevention therapies applied before onset, when greater islet mass remains, have rarely been feasible14 because individuals at greatest risk of impending T1D are difficult to identify. To remedy this, we sought accurate, cost-effective estimation of future T1D risk by developing a combined risk score incorporating both fixed and variable factors (genetic, clinical and immunological) in 7,798 high-risk children followed closely from birth for 9.3 years. Compared with autoantibodies alone, the combined model dramatically improves T1D prediction at ≥2 years of age over horizons up to 8 years of age (area under the receiver operating characteristic curve ≥ 0.9), doubles the estimated efficiency of population-based newborn screening to prevent ketoacidosis, and enables individualized risk estimates for better prevention trial selection.
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Affiliation(s)
- Lauric A Ferrat
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Seth A Sharp
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University and Skåne University Hospital, Malmö, Sweden
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany
- Forschergruppe Diabetes, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- Forschergruppe Diabetes e.V., Munich, Germany
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Beena Akolkar
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey P Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Michael N Weedon
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
- Academic Renal Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
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Andersson Svärd A, Maziarz M, Ramelius A, Lundgren M, Lernmark Å, Elding Larsson H. Decreased HLA-DQ expression on peripheral blood cells in children with varying number of beta cell autoantibodies. J Transl Autoimmun 2020; 3:100052. [PMID: 32743532 PMCID: PMC7388396 DOI: 10.1016/j.jtauto.2020.100052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/02/2020] [Indexed: 12/18/2022] Open
Abstract
The risk for type 1 diabetes is strongly associated with HLA-DQ and the appearance of beta cell autoantibodies against either insulin, glutamate decarboxylase (GAD65), insulinoma-associated protein-2 (IA-2), or zinc transporter 8 (ZnT8). Prolonged exposure to autoantibodies may be related to T cell exhaustion known to occur in chronic infections or autoimmune disorders. It was hypothesized that autoantibody exposure may affect HLA-DQ expression on peripheral blood cells and thereby contribute to T cell exhaustion thought to be associated with the pathogenesis of type 1 diabetes. The aim of this study was to determine whether autoantibody exposure as an expression of autoimmunity burden was related to peripheral blood cell HLA-DQ cell surface expression in either 1) a cross-sectional analysis or 2) cumulative as area under the trajectory of autoantibodies during long term follow-up in the Diabetes Prediction in Skåne (DiPiS) study. Children (n = 67), aged 10–15 years were analyzed for complete blood count, HLA-DQ cell surface median fluorescence intensity (MFI), autoantibody frequency, and HLA genotypes by Next Generation Sequencing. Decreased HLA-DQ cell surface MFI with an increasing number of autoantibodies was observed in CD16+, CD14+CD16−, CD4+ and CD8+ cells but not in CD19+ cells and neutrophils. HLA-DQ cell surface MFI was associated with HLA-DQ2/8 in CD4+ T cells, marginally in CD14+CD16− monocytes and CD8+ T cells. These associations appeared to be related to autoimmunity burden. The results suggest that HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
PBMC HLA-DQ surface expression in beta cell autoimmunity is poorly understood. Children, 10–15 years of age without or with beta cell autoantibodies were analyzed. HLA-DQ cell surface expression decreased with increasing number of autoantibodies. HLA-DQ cell surface expression was related to HLA and autoimmunity burden.
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Affiliation(s)
- Agnes Andersson Svärd
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Marlena Maziarz
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Anita Ramelius
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Markus Lundgren
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, 205 02, Malmö, Sweden
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Alonso GT, Coakley A, Pyle L, Manseau K, Thomas S, Rewers A. Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Colorado Children, 2010-2017. Diabetes Care 2020; 43:117-121. [PMID: 31601639 PMCID: PMC6925579 DOI: 10.2337/dc19-0428] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 09/24/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We examined trends in diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes at a large pediatric diabetes center between 2010 and 2017, overlapping with the Affordable Care Act's overhaul of U.S. health care. RESEARCH DESIGN AND METHODS Colorado residents <18 years old who were diagnosed with type 1 diabetes from 2010 to 2017 and subsequently followed at the Barbara Davis Center for Diabetes were included. Logistic regression models were used to test associations among age, sex, race/ethnicity, insurance, language, year of diagnosis, and rural/nonrural residence and DKA at diagnosis. Linear regression models were used to test the association of each predictor with HbA1c at diagnosis. RESULTS There were 2,429 subjects who met the inclusion criteria. From 2010 to 2017, the rate of DKA increased from 41 to 58%. It increased from 35.3 to 59.6% among patients with private insurance (odds ratio 1.10 [95% CI 1.05-1.15]; P < 0.0001) but remained unchanged (52.2-58.8%) among children with public insurance (1.03 [0.97-1.09]; P = 0.36). In the multivariable model, public insurance (1.33 [1.08-1.64]; P = 0.007), rural address (1.42 [1.08-1.86]; P = 0.013), and HbA1c (1.32 [1.26-1.38]; P < 0.0001) were positively associated with DKA, whereas age, race/ethnicity, sex, and primary language were not. CONCLUSIONS The increase in the rate of DKA in patients with newly diagnosed type 1 diabetes was driven by patients with private insurance. This paradoxically occurred during a time of increasing health insurance coverage. More study is needed to understand the factors driving these changes.
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Affiliation(s)
- G Todd Alonso
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Alex Coakley
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Laura Pyle
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO.,Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO
| | | | - Sarah Thomas
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Arleta Rewers
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
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de Souza LCVF, Kraemer GDC, Koliski A, Carreiro JE, Cat MNL, Lacerda LD, França SN. DIABETIC KETOACIDOSIS AS THE INITIAL PRESENTATION OF TYPE 1 DIABETES IN CHILDREN AND ADOLESCENTS: EPIDEMIOLOGICAL STUDY IN SOUTHERN BRAZIL. REVISTA PAULISTA DE PEDIATRIA : ORGAO OFICIAL DA SOCIEDADE DE PEDIATRIA DE SAO PAULO 2019; 38:e2018204. [PMID: 31778415 PMCID: PMC6909258 DOI: 10.1590/1984-0462/2020/38/2018204] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 10/27/2018] [Indexed: 12/01/2022]
Abstract
OBJECTIVE To analyze the variables associated with the presence of diabetic ketoacidosis in type 1 diabetes mellitus (T1DM) diagnosis and its impact on the progression of the disease. METHODS We reviewed the records of 274 children and adolescents under 15 years, followed in a Pediatric Endocrinology clinic of a university hospital in Curitiba-PR. They had their first appointment between January 2005 and April 2015. RESULTS Most patients received their T1DM diagnosis during a diabetic ketoacidosis episode. The associated factors were: lower age and greater number of visits to a physician's office prior to diagnosis; diabetic ketoacidosis was less frequent in patients who had siblings with T1DM and those diagnosed at the first appointment. Nausea and vomiting, abdominal pain, tachydyspnea, and altered level of consciousness were more common in the diabetic ketoacidosis group. There was no association with socioeconomic status, duration of symptoms before diagnosis, and length of the honeymoon period. CONCLUSIONS Prospective studies are necessary to better define the impact of these factors on diagnosis and disease control. Campaigns to raise awareness among health professionals and the general population are essential to promote early diagnosis and proper treatment of diabetes mellitus in children and adolescents.
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Ziegler AG, Achenbach P, Berner R, Casteels K, Danne T, Gündert M, Hasford J, Hoffmann VS, Kordonouri O, Lange K, Elding Larsson H, Lundgren M, Snape MD, Szypowska A, Todd JA, Bonifacio E. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol. BMJ Open 2019; 9:e028578. [PMID: 31256036 PMCID: PMC6609035 DOI: 10.1136/bmjopen-2018-028578] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes. METHODS AND ANALYSIS Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes. ETHICS AND DISSEMINATION The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. TRIAL REGISTRATION NUMBER NCT03364868.
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Affiliation(s)
- Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Medical faculty, Munich, Germany
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Medical faculty, Munich, Germany
| | - Reinhard Berner
- Department of Paediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kristina Casteels
- Department of Paediatrics, University Hospitals Leuven, Leuven, Belgium
- Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Thomas Danne
- Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany
| | - Melanie Gündert
- Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany
| | - Joerg Hasford
- Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany
| | | | - Olga Kordonouri
- Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany
| | - Karin Lange
- Department of Medical Psychology, Hannover Medical School, Hannover, Germany
| | - Helena Elding Larsson
- Unit for Paediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Sweden
- Department of Paediatrics, Skåne University Hospital, Malmö, Sweden
| | - Markus Lundgren
- Unit for Paediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Sweden
| | - Matthew D Snape
- Department of Paediatrics, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
| | | | - John A Todd
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Ezio Bonifacio
- Centre for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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Duca LM, Reboussin BA, Pihoker C, Imperatore G, Saydah S, Mayer-Davis E, Rewers A, Dabelea D. Diabetic ketoacidosis at diagnosis of type 1 diabetes and glycemic control over time: The SEARCH for diabetes in youth study. Pediatr Diabetes 2019; 20:172-179. [PMID: 30556249 PMCID: PMC6361710 DOI: 10.1111/pedi.12809] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/05/2018] [Accepted: 12/10/2018] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The diagnosis of type 1 diabetes (T1D) in youth is often associated with diabetic ketoacidosis (DKA). We aimed to evaluate if the presence of DKA at diagnosis of T1D is associated with less favorable hemoglobin A1c (HbA1c) trajectories over time. METHODS The SEARCH for Diabetes in Youth study of 1396 youth aged <20 years with newly diagnosed T1D were followed for up to 13 (median 8 [interquartile range or IQR 6-9]) years after diagnosis. Of these, 397 (28%) had DKA (bicarbonate level < 15 mmol/L and/or pH < 7.25 (venous) or < 7.30 (arterial or capillary) or mention of DKA in medical records) at diabetes onset. Longitudinal HbA1c levels were measured at each follow-up visit (average number of HbA1c measures 3.4). A linear piecewise mixed effects model was used to analyze the effect of DKA status at diagnosis of T1D on long-term glycemic control, adjusting for age at diagnosis, diabetes duration at baseline, sex, race/ethnicity, household income, health insurance status, time-varying insulin regimen and glucose self-monitoring, study site, and baseline fasting C-peptide level. RESULTS At baseline, HbA1c levels were significantly higher in youth with T1D diagnosed in DKA vs those who were not (9.9% ± 1.5% vs 8.5% ± 1.4%, respectively). After the first year with diabetes, there was a significant difference in the rate of change in HbA1c levels by DKA status: HbA1c was 0.16% higher each year in youth with DKA compared to those without (interaction P-value<0.0001), after adjusting for aforementioned covariates. CONCLUSIONS DKA at T1D diagnosis is associated with worsening glycemic control over time, independent of demographic, socioeconomic, and treatment-related factors and baseline fasting C-peptide.
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Affiliation(s)
- Lindsey M Duca
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Beth A Reboussin
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Catherine Pihoker
- Department of Pediatrics, University of Washington, Seattle, Washington
| | - Giuseppina Imperatore
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Sharon Saydah
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Elizabeth Mayer-Davis
- Departments of Nutrition and Medicine, Gillings School of Global Public Health and School of Medicine, University of North Carolina, Chapel Hill, North Carolina
| | - Arleta Rewers
- Department of Pediatrics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Dana Dabelea
- Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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Lundgren M, Jonsdottir B, Elding Larsson H. Effect of screening for type 1 diabetes on early metabolic control: the DiPiS study. Diabetologia 2019; 62:53-57. [PMID: 30109365 PMCID: PMC6290658 DOI: 10.1007/s00125-018-4706-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/03/2018] [Indexed: 12/25/2022]
Abstract
AIMS/HYPOTHESIS It has been shown that children previously enrolled in follow-up studies have better glycaemic control during the early period after diabetes diagnosis. The aim of this study was to analyse glycaemic control over a longer period, past the period of partial remission, after diagnosis in children followed before diagnosis in the Swedish Diabetes Prediction in Skåne (DiPiS) study compared with children of equal age not enrolled in pre-diabetes follow-up, receiving equivalent diabetes care. METHODS HbA1c from diagnosis and for the following 5 years, as well as differences in insulin dosage, BMI, pump use, partial remission according to insulin dose-adjusted HbA1c and baseline demographics were compared between children who were enrolled in follow-up and had received information on diabetes risk (n = 51) and children not enrolled in follow-up (n = 78). RESULTS The group followed before diagnosis had a higher proportion of first-degree relatives (FDRs) with diabetes (28% vs 5.6%; p = 0.001) and a higher proportion of participants with mothers born in Sweden (100% vs 89%; p = 0.02). No significant differences in total daily insulin dose, pump use or other baseline sociodemographic factors were detected between the groups. Median HbA1c at diagnosis and at 1, 2, 3, 4 and 5 years after diabetes diagnosis was significantly lower in children followed before diagnosis (all p < 0.05), and was not related to FDR status. CONCLUSIONS/INTERPRETATION Compared with controls not previously enrolled in follow-up, our study shows that children enrolled in longitudinal follow-up before the diagnosis of diabetes have better glycaemic control, measured by HbA1c, up to 5 years after diagnosis and during the initial period of partial remission. Improved glycaemic control in the initial years of living with type 1 diabetes could affect long-term outcome and complications and might also improve study enrolment in future longitudinal studies.
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Affiliation(s)
- Markus Lundgren
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, S-205 02, Malmö, Sweden.
- Department of Pediatrics, Kristianstad Central Hospital, Kristianstad, Sweden.
| | - Berglind Jonsdottir
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, S-205 02, Malmö, Sweden
- Pediatric Endocrinology and Gastroenterology, Skåne University hospital, Malmö, Sweden
| | - Helena Elding Larsson
- Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Jan Waldenströms gata 35, S-205 02, Malmö, Sweden
- Pediatric Endocrinology and Gastroenterology, Skåne University hospital, Malmö, Sweden
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Salami F, Lee HS, Freyhult E, Elding Larsson H, Lernmark Å, Törn C. Reduction in White Blood Cell, Neutrophil, and Red Blood Cell Counts Related to Sex, HLA, and Islet Autoantibodies in Swedish TEDDY Children at Increased Risk for Type 1 Diabetes. Diabetes 2018; 67:2329-2336. [PMID: 30104249 PMCID: PMC6198343 DOI: 10.2337/db18-0355] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/29/2018] [Indexed: 12/19/2022]
Abstract
Islet autoantibodies (IAs) precede the clinical onset of type 1 diabetes (T1D); however, the knowledge is limited about whether the prodrome affects complete blood counts (CBCs) in 4- to 12-year-old children with increased genetic risk for T1D. This study tested whether CBCs were altered in 4- to 12-year-old children without (n = 376) or with one or several IAs against insulin, GAD65, or IA-2 (n = 72). CBC was analyzed during longitudinal follow-up in 448 Swedish children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A linear mixed-effects model was used to assess potential association between IA and CBC measurements over time. The white blood cell and neutrophil counts were reduced in children with IAs, primarily in boys. In contrast, girls had lower levels of hemoglobin and hematocrit. Positivity for multiple IAs showed the lowest counts in white blood cells and neutrophils in boys and red blood cells, hemoglobin, and hematocrit in girls. These associations were primarily observed in children with the HLA-DR3-DQ2/DR4-DQ8 genotype. We conclude that the reduction in neutrophils and red blood cells in children with multiple IAs and HLA-DR3-DQ2/DR4-DQ8 genotype may signal a sex-dependent islet autoimmunity detected in longitudinal CBCs.
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Affiliation(s)
- Falastin Salami
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Hye-Seung Lee
- Health Informatics Institute, Department of Pediatrics, University of South Florida, Tampa, FL
| | - Eva Freyhult
- Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | - Carina Törn
- Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
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Rewers M, Hyöty H, Lernmark Å, Hagopian W, She JX, Schatz D, Ziegler AG, Toppari J, Akolkar B, Krischer J. The Environmental Determinants of Diabetes in the Young (TEDDY) Study: 2018 Update. Curr Diab Rep 2018; 18:136. [PMID: 30353256 PMCID: PMC6415767 DOI: 10.1007/s11892-018-1113-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE OF REVIEW The environmental triggers of islet autoimmunity leading to type 1 diabetes (T1D) need to be elucidated to inform primary prevention. The Environmental Determinants of Diabetes in the Young (TEDDY) Study follows from birth 8676 children with T1D risk HLA-DR-DQ genotypes in the USA, Finland, Germany, and Sweden. Most study participants (89%) have no first-degree relative with T1D. The primary outcomes include the appearance of one or more persistent islet autoantibodies (islet autoimmunity, IA) and clinical T1D. RECENT FINDINGS As of February 28, 2018, 769 children had developed IA and 310 have progressed to T1D. Secondary outcomes include celiac disease and autoimmune thyroid disease. While the follow-up continues, TEDDY has already evaluated a number of candidate environmental triggers, including infections, probiotics, micronutrient, and microbiome. TEDDY results suggest that there are multiple pathways leading to the destruction of pancreatic beta-cells. Ongoing measurements of further specific exposures, gene variants, and gene-environment interactions and detailed "omics" studies will provide novel information on the pathogenesis of T1D.
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Affiliation(s)
- Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct, Aurora, CO, 80045, USA.
| | - Heikki Hyöty
- Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University, Malmö, Sweden
| | | | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | | | - Anette-G Ziegler
- Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum, Munich, Germany
| | - Jorma Toppari
- Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, University of Turku, Turku, Finland
| | - Beena Akolkar
- Department of Pediatrics, Turku University Hospital, Turku, Finland
- National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
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Smith LB, Liu X, Johnson SB, Tamura R, Larsson HE, Ahmed S, Veijola R, Haller MJ, Akolkar B, Hagopian WA, Rewers MJ, Krischer J, Steck AK. Family adjustment to diabetes diagnosis in children: Can participation in a study on type 1 diabetes genetic risk be helpful? Pediatr Diabetes 2018; 19:1025-1033. [PMID: 29577538 PMCID: PMC6030424 DOI: 10.1111/pedi.12674] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 01/15/2018] [Accepted: 02/26/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diagnosis of type 1 diabetes often causes a negative psychological impact on families. We examined whether parents and children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study differ in their psychological adjustment to diabetes diagnosis compared to children diagnosed with diabetes in the community. METHODS TEDDY follows 8676 children at genetic risk for type 1 diabetes from birth. Fifty-four TEDDY children diagnosed with diabetes and 54 age-matched community control children diagnosed with diabetes were enrolled. Participants were aged 3 to 10 years and study visits occurred at 3, 6, and 12 months postdiagnosis. Psychological measures included an adapted diabetes-specific State Anxiety Inventory, the Pediatric Quality of Life Inventory-Diabetes Module, and the Pediatric Inventory for Parents, which measures frequency and difficulty of parenting stress. RESULTS A generalized estimating equation analysis based on a difference score between TEDDY children and community controls found no significant differences between TEDDY parents and community controls on parent diabetes-specific anxiety (P = .30). However, TEDDY children exhibited better diabetes-specific quality of life (P = .03) and TEDDY parents reported lower frequency (P = .004) and difficulty (P = .008) of parenting stress compared to community controls. CONCLUSIONS Children diagnosed with at-risk for type 1 diabetes who have previously enrolled in research monitoring have improved diabetes quality of life and lower parenting stress postdiagnosis compared to children diagnosed in the community. Families in follow-up studies may be more prepared if their child is diagnosed with diabetes.
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Affiliation(s)
- Laura B. Smith
- Diabetes Center, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Xiang Liu
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Suzanne Bennett Johnson
- Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, Florida, USA
| | - Roy Tamura
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Simi Ahmed
- Immunology of T1D, JDRF International, New York, New York, USA
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Michael J. Haller
- Department of Pediatrics, University of Florida, Gainesville, Florida, USA
| | - Beena Akolkar
- Division of Diabetes, Endocrinology, & Metabolism, National Institute of Diabetes, Digestive, & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Marian J. Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA
| | - Andrea K. Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
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Lee JJ, Thompson MJ, Usher-Smith JA, Koshiaris C, Van den Bruel A. Opportunities for earlier diagnosis of type 1 diabetes in children: A case-control study using routinely collected primary care records. Prim Care Diabetes 2018; 12:254-264. [PMID: 29548694 DOI: 10.1016/j.pcd.2018.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Revised: 01/18/2018] [Accepted: 02/03/2018] [Indexed: 11/15/2022]
Abstract
BACKGROUND The epidemiology of type 1 diabetes mellitus (T1DM) suggests diagnostic delays may contribute to children developing diabetic ketoacidosis at diagnosis. We sought to quantify opportunities for earlier diagnosis of T1DM in primary care. METHODS A matched case-control study of children (0-16 years) presenting to UK primary care, examining routinely collected primary care consultation types and National Institute for Health and Care Excellence (NICE) warning signs in the 13 weeks before diagnosis. RESULTS Our primary analysis included 1920 new T1DM cases and 7680 controls. In the week prior to diagnosis more cases than controls had medical record entries (663, 34.5% vs 1014, 13.6%, odds ratio 3.46, 95% CI 3.07-3.89; p<0.0001) and the incidence rate of face-to-face consultations was higher in cases (mean 0.32 vs 0.11, incidence rate ratio 2.90, 2.61-3.21; p<0.0001). The preceding week entries were found in 330 cases and 943 controls (17.2% vs 12.3%, OR 1.49, 1.3-1.7, p<0.0001), but face-to-face consultations were no different (IRR 1.08 (0.9-1.29, p=0.42)). INTERPRETATION There may be opportunities to reduce time to diagnosis for up to one third of cases, by up to two weeks. Diagnostic opportunities might be maximised by measures that improve access to primary care, and public awareness of T1DM.
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Affiliation(s)
- Joseph Jonathan Lee
- Nuffield Department of Primary Care Health Sciences, Radcliffe Primary Care, Radcliffe Observatory Quarter, Woodstock Rd, Oxford OX2 6GG, UK.
| | - Matthew James Thompson
- Department of Family Medicine, University of Washington, Box 354696, Seattle, WA 89195-4596, USA.
| | - Juliet Alexandra Usher-Smith
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Box 113 Cambridge Biomedical Campus, Cambridge CB2 0SR, UK.
| | - Constantinos Koshiaris
- Nuffield Department of Primary Care Health Sciences, Radcliffe Primary Care, Radcliffe Observatory Quarter, Woodstock Rd, Oxford OX2 6GG, UK.
| | - Ann Van den Bruel
- Nuffield Department of Primary Care Health Sciences, Radcliffe Primary Care, Radcliffe Observatory Quarter, Woodstock Rd, Oxford OX2 6GG, UK.
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Hekkala AM, Ilonen J, Toppari J, Knip M, Veijola R. Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children. Pediatr Diabetes 2018; 19:314-319. [PMID: 28544185 DOI: 10.1111/pedi.12541] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Revised: 04/05/2017] [Accepted: 04/24/2017] [Indexed: 01/10/2023] Open
Abstract
We studied the frequency of diabetic ketoacidosis (DKA) in children at diagnosis of type 1 diabetes (T1D) in a region where newborn infants have since 1995 been recruited for genetic screening for human leukocyte antigen (HLA)-conferred disease susceptibility and prospective follow up. The aim was to study whether participation in newborn screening and follow up affected the frequency of DKA, and to follow the time trends in DKA frequency. We first included children born in Oulu University Hospital since 1995 when the prospective studies have been ongoing and diagnosed with T1D <15 years by 2015 (study cohort 1, n = 517). Secondly, we included all children diagnosed with T1D <15 years in this center during 2002-2014 (study cohort 2, n = 579). Children who had an increased genetic risk for T1D and participated in prospective follow up had low frequency of DKA at diagnosis (5.0%). DKA was present in 22.7% of patients not screened for genetic risk, 26.7% of those who were screened but had not an increased risk and 23.4% of children with increased genetic risk but who were not followed up. In study cohort 2 the overall frequency of DKA was 18.5% (13.0% in children <5 years, 14.0% in children 5-10 years and 28.6% in children ≥10 years at diagnosis; P<.001). In children <2 years the frequency of DKA was 17.1%. Participation in prospective follow-up studies reduces the frequency of DKA in children at diagnosis of T1D, but genetic screening alone does not decrease DKA risk.
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Affiliation(s)
- Anne M Hekkala
- Department of Pediatrics, MRC Oulu, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, University of Turku, and Turku University Hospital, Turku, Finland
| | - Jorma Toppari
- Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.,Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Mikael Knip
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland.,Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.,Folkhälsan Research Center, Helsinki, Finland
| | - Riitta Veijola
- Department of Pediatrics, MRC Oulu, PEDEGO Research Unit, University of Oulu and Oulu University Hospital, Oulu, Finland
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Jayaraman S, Jayaraman A. Long-Term Provision of Acidified Drinking Water Fails to Influence Autoimmune Diabetes and Encephalomyelitis. J Diabetes Res 2018; 2018:3424691. [PMID: 30035128 PMCID: PMC6032981 DOI: 10.1155/2018/3424691] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023] Open
Abstract
Induction of autoimmune diseases is predisposed by background genetics and influenced by environmental factors including diet and infections. Since consumption of acidified drinking water leads to eradication of gastrointestinal pathogens in animals, we tested whether it may also influence the development of autoimmune diseases. The frequency of spontaneously occurring type 1 diabetes in female NOD mice that were maintained on acidified drinking water by the vendor did not alter after switching to neutral water in our facility. In addition, experimentally induced autoimmune encephalomyelitis was also unaffected by the pH of the drinking water. Interestingly, administration of complete Freund's adjuvant alone or emulsified with a neuronal peptide to induce neurodegenerative disease during the prediabetic stage completely prevented the onset of diabetes regardless of the pH of the drinking water. However, exposure to microbial products later in life had only a partial blocking effect on diabetes induction, which was also not influenced by the ionic content of the drinking water. Taken together, these data indicate that the onset of autoimmune diseases is not influenced by the gastrointestinal pathogen-depleting treatment, acidified drinking water. Thus, administration of acidic drinking water does not appear to be an option for treating autoimmune diseases.
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Affiliation(s)
- Sundararajan Jayaraman
- Department of Microbiology and Immunology, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA
- Department of Surgery, University of Illinois College of Medicine at Peoria, 624 NE Glen Oak Ave, Suite 2675, Peoria, IL 61603, USA
| | - Arathi Jayaraman
- Department of Microbiology and Immunology, University of Illinois at Chicago, 909 South Wolcott Avenue, Chicago, IL 60612, USA
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49
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Gu Y, Zhao Z, High H, Yang T, Yu L. Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay. ACTA ACUST UNITED AC 2017; 8. [PMID: 29487479 PMCID: PMC5796772 DOI: 10.4172/2155-9899.1000531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Yong Gu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA.,Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhiyuan Zhao
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Hilary High
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
| | - Tao Yang
- Department of Endocrinology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA
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50
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Steck AK, Larsson HE, Liu X, Veijola R, Toppari J, Hagopian WA, Haller MJ, Ahmed S, Akolkar B, Lernmark Å, Rewers MJ, Krischer JP. Residual beta-cell function in diabetes children followed and diagnosed in the TEDDY study compared to community controls. Pediatr Diabetes 2017; 18:794-802. [PMID: 28127835 PMCID: PMC5529265 DOI: 10.1111/pedi.12485] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 11/14/2016] [Accepted: 11/17/2016] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE To explore whether children diagnosed with type 1 diabetes during islet autoantibody surveillance through The Environmental Determinants of Diabetes in the Young (TEDDY) study retain greater islet function than children diagnosed through the community. METHODS TEDDY children identified at birth with high-risk human leukocyte antigen and followed every 3 months until diabetes diagnosis were compared to age-matched children diagnosed with diabetes in the community. Both participated in long-term follow up after diagnosis. Hemoglobin A1c (HbA1c) and mixed meal tolerance test were performed within 1 month of diabetes onset, then at 3, 6, and 12 months, and biannually thereafter. RESULTS Comparison of 43 TEDDY and 43 paired control children showed that TEDDY children often had no symptoms (58%) at diagnosis and none had diabetic ketoacidosis (DKA) compared with 98% with diabetes symptoms and 14% DKA in the controls (P < 0.001 and P = 0.03, respectively). At diagnosis, mean HbA1c was lower in TEDDY (6.8%, 51 mmol/mol) than control (10.5%, 91 mmol/mol) children (P < 0.0001). TEDDY children had significantly higher area under the curve and peak C-peptide values than the community controls throughout the first year postdiagnosis. Total insulin dose and insulin dose-adjusted A1c were lower throughout the first year postdiagnosis for TEDDY compared with control children. CONCLUSIONS Higher C-peptide levels in TEDDY vs community-diagnosed children persist for at least 12 months following diabetes onset and appear to represent a shift in the disease process of about 6 months. Symptom-free diagnosis, reduction of DKA, and the potential for immune intervention with increased baseline C-peptide may portend additional long-term benefits of early diagnosis.
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Affiliation(s)
- Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Helena Elding Larsson
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Xiang Liu
- Health Informatics Institute, University of South Florida, Tampa, Florida
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Toppari
- Turku Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland
- Department of Pediatrics, Turku University Hospital, Turku, Finland
| | - William A Hagopian
- Pacific Northwest Diabetes Research Institute, University of Washington, Seattle, WA
| | - Michael J Haller
- Department of Pediatrics, University of Florida, Gainesville, Florida
| | - Simi Ahmed
- Immunology of T1D, JDRF International, New York, New York
| | - Beena Akolkar
- Division of Diabetes, Endocrinology & Metabolism, National Institute of Diabetes, Digestive, & Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
| | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado
| | - Jeffrey P Krischer
- Health Informatics Institute, University of South Florida, Tampa, Florida
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