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Richardson SJ, Rodriguez-Calvo T, Laiho JE, Kaddis JS, Nyalwidhe JO, Kusmartseva I, Morfopoulou S, Petrosino JF, Plagnol V, Maedler K, Morris MA, Nadler JL, Atkinson MA, von Herrath M, Lloyd RE, Hyoty H, Morgan NG, Pugliese A. Joint analysis of the nPOD-Virus Group data: the association of enterovirus with type 1 diabetes is supported by multiple markers of infection in pancreas tissue. Diabetologia 2025; 68:1226-1241. [PMID: 40090994 PMCID: PMC12069141 DOI: 10.1007/s00125-025-06401-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/03/2024] [Indexed: 03/19/2025]
Abstract
AIMS/HYPOTHESIS Previous pathology studies have associated enterovirus infections with type 1 diabetes by examining the enterovirus capsid protein 1 (VP1) in autopsy pancreases obtained near diabetes diagnosis. The Network for Pancreatic Organ Donors with Diabetes (nPOD) has since obtained pancreases from organ donors with type 1 diabetes (with broad age and disease duration) and donors with disease-associated autoantibodies (AAbs), the latter representing preclinical disease. Two accompanying manuscripts from the nPOD-Virus Group report primary data from a coordinated analysis of multiple enterovirus indices. We aimed to comprehensively assess the association of multiple enterovirus markers with type 1 diabetes. METHODS The nPOD-Virus Group examined pancreases from 197 donors, recovered between 2007 and 2019, classified into five groups: donors with type 1 diabetes, with residual insulin-containing islets (T1D-ICI group, n=41) or with only insulin-deficient islets (T1D-IDI, n=42); donors without diabetes who are AAb-negative (ND, n=83); and rare donors without diabetes expressing a single AAb (AAb+, n=22) or multiple AAbs (AAb++, n=9). We assessed the overall association of multiple indicators of enterovirus infection, case-by-case and between donor groups, as well as assay agreement and reproducibility, using various statistical methods. We examined data from 645 assays performed across 197 nPOD donors. RESULTS Detection of enterovirus indices by independent laboratories had high reproducibility, using both enterovirus-targeted and unbiased methods. T1D-ICI donors had significantly higher (p<0.001) proportions of positive assay outcomes (58.4%) vs T1D-IDI (10.3%), ND (17.8%) and AAb-positive donors (AAb+ 24.6%; AAb++ 35.0%). Head-to-head comparisons revealed increased proportions of donors positive in two independent assays among T1D-ICI vs ND donors (VP1/HLA class I [HLA-I], p<0.0001; VP1/enterovirus-specific RT-PCR (EV-PCR), p=0.076; EV-PCR/HLA-I, p=0.016; proteomics/HLA-I, p<0.0001; VP1/proteomics, p=0.06). Among 110 donors examined for three markers (VP1, EV-PCR and HLA-I), 83.3% of T1D-ICI donors were positive in two or more assays vs 0% of ND (p<0.001), 26.7% of AAb+ (p=0.006), 28.6% of AAb++ (p=0.023) and 0% of T1D-IDI (p<0.001) donors. CONCLUSIONS/INTERPRETATION The nPOD-Virus Group conducted, to date, the largest and most comprehensive analysis of multiple indices of pancreatic enterovirus infections in type 1 diabetes; these were more prevalent in T1D-ICI and AAb++ donors than in other groups. Their preferential detection of these indices in donors with residual beta cells and autoimmunity implicates enterovirus infections across disease progression stages and supports a contribution to beta cell loss, directly or indirectly, even after diagnosis. The relatively small number of infected cells and the low amount of viral RNA support the existence of non-acute, low level, possibly persistent enterovirus infections in the pancreas.
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Affiliation(s)
- Sarah J Richardson
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Jutta E Laiho
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Julius O Nyalwidhe
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Irina Kusmartseva
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Sofia Morfopoulou
- Division of Infection and Immunity, University College London, London, UK
| | | | | | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Margaret A Morris
- Department of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA
- Autoimmunity and Primary Immunodeficiency Disease Section, Autoimmunity and Mucosal Immunology Branch, DAIT NIAD NIH DHHS, Rockville, MD, USA
| | - Jerry L Nadler
- UC Davis School of Medicine, Sacramento, CA, USA
- ACOS-Research Northern California VA Health System, Mather, CA, USA
| | - Mark A Atkinson
- Diabetes Institute, Department of Pathology, University of Florida, Gainesville, FL, USA
| | - Matthias von Herrath
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
| | | | - Heikki Hyoty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
- Department of Paediatrics, Tampere University Hospital, Tampere, Finland
| | - Noel G Morgan
- Islet Biology Exeter (IBEx), Department of Clinical and Biomedical Sciences, University of Exeter Medical School, Exeter, UK
| | - Alberto Pugliese
- Department of Diabetes Immunology, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA.
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2
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Aleti S, Ulrich MT, Ghozy S, Nayak SS. The association of diabetes and the human papillomavirus: a nationwide population‑based cohort study. Minerva Endocrinol (Torino) 2024; 49:366-371. [PMID: 34825553 DOI: 10.23736/s2724-6507.21.03539-9] [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] [Indexed: 11/08/2022]
Abstract
BACKGROUND Previous studies have investigated the correlation between diabetes and HPV vaccination; however, there is little evidence about the association between viral infection and diabetes. This study aims to investigate the association between diabetes and human papillomavirus infection. METHODS Using the USA National Health and Nutrition Examination Survey (2015-2016), records of 571 diabetic and 4170 non‑diabetic patients were extracted. Comparative analyses were used to evaluate differences in the HPV testing results between the two groups. Multivariate logistic regression analyses were used to evaluate independent risk factors for diabetes among all subjects. RESULTS Positive tests were detected in 6.7% of the oral HPV, 19.5% of the Cobas® HPV swab (high-risk group), 40.9% of the Roche® HPV linear array (vaginal swab), and 43.8% of the Roche® HPV linear array (penile swab). The results of multivariate regression analysis, after adjusting for age, gender, race, marital status, and presence of comorbidities, showed no statistically significant association between positive or negative HPV testing and presence of diabetes mellitus, with an exception for the penile swab using Roche® HPV linear array (P=0.020). CONCLUSIONS This retrospective database study of HPV infection and diabetes showed no significant association between patients with HPV and those with diabetes.
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Affiliation(s)
- Soumya Aleti
- Department of Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA
| | - Micheal T Ulrich
- Department of Internal Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA
- Department of Internal Medicine, Riverside University Health System, Riverside, CA, USA
| | - Sherief Ghozy
- Department of Neuroradiology, Mayo Clinic, Rochester, MN, USA
| | - Sandeep S Nayak
- Department of Internal Medicine, NYC Health and Hospitals/Metropolitan, New York, NY, USA -
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Butrym M, Byvald F, Blanter M, Ringqvist EE, Vasylovska S, Marjomäki V, Lau J, Stone VM, Flodström-Tullberg M. Vemurafenib inhibits the replication of diabetogenic enteroviruses in intestinal epithelial and pancreatic beta cells. Antiviral Res 2024; 231:106021. [PMID: 39419452 DOI: 10.1016/j.antiviral.2024.106021] [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: 08/07/2024] [Revised: 09/27/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
Enteroviruses, which infect via the gut, have been implicated in type 1 diabetes (T1D) development. Prolonged faecal shedding of enterovirus has been associated with islet autoimmunity. Additionally, enteroviral proteins and viral RNA have been detected in the pancreatic islets of individuals with recent-onset T1D, implicating their possible role in beta cell destruction. Despite this, no approved antiviral drugs currently exist that specifically target enterovirus infections for utilisation in disease interventions. Drug repurposing allows for the discovery of new clinical uses for existing drugs and can expedite drug discovery. Previously, the cancer drug Vemurafenib demonstrated unprecedented antiviral activity against several enteroviruses. In the present study, we assessed the efficacy of Vemurafenib and an analogue thereof in preventing infection or reducing the replication of enteroviruses associated with T1D. We tested Vemurafenib in intestinal epithelial cells (IECs) and insulin-producing beta cells. Additionally, we established a protocol for infecting human stem cell-derived islets (SC-islets) and used Vemurafenib and its analogue in this model. Our studies revealed that Vemurafenib exhibited strong antiviral properties in IECs and a beta cell line. The antiviral effect was also seen with the Vemurafenib analogue. SC-islets expressed the viral receptors CAR and DAF, with their highest expression in insulin- and glucagon-positive cells, respectively. SC-islets were successfully infected by CVBs and the antiviral activity of Vemurafenib and its analogue was confirmed in most SC-islet batches. In summary, our observations suggest that Vemurafenib and its analogue warrant further exploration as potential antiviral agents for the treatment of enterovirus-induced diseases, including T1D.
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Affiliation(s)
- Marta Butrym
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Fabian Byvald
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Marfa Blanter
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Emma E Ringqvist
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Svitlana Vasylovska
- Department of Medical Cell Biology, Uppsala University, BOX 571, 751 23, Uppsala, Sweden.
| | - Varpu Marjomäki
- Department of Biological and Environmental Science, University of Jyväskylä, P.O. Box 35, FI-40014, Jyväskylä, Finland.
| | - Joey Lau
- Department of Medical Cell Biology, Uppsala University, BOX 571, 751 23, Uppsala, Sweden.
| | - Virginia M Stone
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge / ANA Futura, Karolinska Institutet, Alfred Nobels Allé 8, 141 52, Stockholm, Sweden.
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Friedl N, Sporreiter M, Winkler C, Heublein A, Haupt F, Ziegler AG, Bonifacio E. Progression From Presymptomatic to Clinical Type 1 Diabetes After COVID-19 Infection. JAMA 2024; 332:501-502. [PMID: 39008327 PMCID: PMC11250358 DOI: 10.1001/jama.2024.11174] [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: 03/15/2024] [Accepted: 05/23/2024] [Indexed: 07/16/2024]
Abstract
This study examines whether an association exists between COVID-19 infection and progression to clinical diabetes among youth with presymptomatic type 1 diabetes.
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Affiliation(s)
- Nadine Friedl
- Institute of Diabetes Research, Helmholtz Munich, Munich, Germany
| | | | | | - Anja Heublein
- Institute of Diabetes Research, Helmholtz Munich, Munich, Germany
| | - Florian Haupt
- Institute of Diabetes Research, Helmholtz Munich, Munich, Germany
| | | | - Ezio Bonifacio
- Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
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Breidbart E, Gallagher MP. Type 1 and Covid-19: Diagnosis, Clinical Care, and Health Outcomes during the Pandemic. Endocrinol Metab Clin North Am 2024; 53:135-149. [PMID: 38272592 DOI: 10.1016/j.ecl.2023.11.001] [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] [Indexed: 01/27/2024]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic disrupted health care, creating challenges for people with diabetes and health care systems. Diabetes was recognized as a risk factor for severe disease early in the pandemic. Subsequently, risk factors specific for people with type 1 diabetes were identified, including age, hemoglobin A1c level, and lack of continuous glucose monitoring . Telemedicine, especially when accompanied by diabetes data, allowed effective remote care delivery. However, pre-existing racial disparities in access to diabetes technology persisted and were associated with worse outcomes. Events of the COVID-19 pandemic underscore the importance of continuing to develop flexible and more equitable health care delivery systems.
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Affiliation(s)
- Emily Breidbart
- Department of Pediatrics, Division of Pediatric Endocrinology, NYU Grossman School of Medicine, Hassenfeld Children's Hospital at NYU Langone Health, 135 East 31st Street, Level 2, New York, NY 10016, USA.
| | - Mary Pat Gallagher
- Department of Pediatrics, Division of Pediatric Endocrinology, NYU Grossman School of Medicine, Hassenfeld Children's Hospital at NYU Langone Health, 135 East 31st Street, Level 2, New York, NY 10016, USA
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Blumenfeld O, Rozenshmidt M, Eini I, Laron Z. The COVID-19 Pandemic Increased the Incidence of New-Onset Type One Diabetes in Children. CHILDREN (BASEL, SWITZERLAND) 2024; 11:142. [PMID: 38397254 PMCID: PMC10886898 DOI: 10.3390/children11020142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 02/25/2024]
Abstract
Background: The impact of the COVID-19 pandemic on the incidence rate of childhood type 1 diabetes (T1D) is controversial. Our aim was to analyze the incidence of new-onset T1D among children aged 0-17 before and during the COVID-19 pandemic in Israel. Methods: Data obtained from the national T1D registry for children aged 0-17 were analyzed for the pre-pandemic (1997-2019) and pandemic (2020-2022) periods. In the pre-pandemic period, 7246 children with newly diagnosed T1D were compared with 1490 children diagnosed during the pandemic period. Results: T1D incidence significantly increased in the 0-17 age group from a mean of 12.9/105 (pre-pandemic) to 17.7/105 and 16.7/105 during the first two years of the pandemic (2020 and 2021, respectively) (p = 0.0001). Stratifying by age group (0-4, 5-9, 10-14, and 15-17) revealed a significant increase in the 5-9, 10-14, and 15-17 groups, both in 2020 (p = 0.0001) and in 2021 (p = 0.0001). The incidence rate in the 0-4 age group showed no change in the first year of the pandemic (2020) (p = 0.4). However, in the second year of the pandemic (2021), there was a significant increase from 6.3/105 in the pre-pandemic period to 9.1/105 (p = 0.001). Anti-COVID-19 vaccination in 2022 led to a significant decrease in the incidence rates in the 10-14 and 15-17 age groups (p = 0.03 and p = 0.02, respectively). Conclusion: The COVID-19 pandemic was associated with a significant increase in the incidence of new-onset T1D in prepubertal and pubertal children. Anti-COVID-19 vaccination decreased the incidence rate significantly only in pubertal children.
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Affiliation(s)
- Orit Blumenfeld
- Israel Center for Disease Control, Ministry of Health, Ramat-Gan 5262000, Israel; (M.R.); (I.E.)
| | - Mikhail Rozenshmidt
- Israel Center for Disease Control, Ministry of Health, Ramat-Gan 5262000, Israel; (M.R.); (I.E.)
| | - Idan Eini
- Israel Center for Disease Control, Ministry of Health, Ramat-Gan 5262000, Israel; (M.R.); (I.E.)
| | - Zvi Laron
- Endocrinology and Diabetes Research Unit, Schneider Children’s Medical Center, Petah Tikva 4920235, Israel;
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7
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Dunn SE, Correale J, Gommerman JL, Horwitz MS. Editorial: Environmental factors in autoimmunity. Front Immunol 2024; 14:1361884. [PMID: 38292480 PMCID: PMC10824893 DOI: 10.3389/fimmu.2023.1361884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024] Open
Affiliation(s)
- Shannon E. Dunn
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Jorge Correale
- Institute of Biological Chemistry and Physiocochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | | | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
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Rangert A, Oldin C, Golsäter M, Ludvigsson J, Åkesson K. No association between incidence of type 1 diabetes and rotavirus vaccination in Swedish children. Front Immunol 2023; 14:1175071. [PMID: 37638044 PMCID: PMC10456946 DOI: 10.3389/fimmu.2023.1175071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 07/21/2023] [Indexed: 08/29/2023] Open
Abstract
Background Rotavirus infection is a potential trigger of type 1 diabetes (T1D) and rotavirus vaccination is hypothesized to decrease the incidence of T1D. In Sweden, rotavirus vaccination was introduced in 2014 in two regions and from 2019, nationwide. This study aims to investigate the association between rotavirus vaccination and incidence of T1D in Swedish children and whether rotavirus vaccination is associated with a change in clinical manifestation at diabetes onset. Methods A nationwide register-based study with all Swedish children <15 years of age, diagnosed with T1D 2009-2019 was conducted. 7893 children were retrieved. Nationwide vaccine coverage was collected from Child Health Services. Three vaccine groups were created: I: Vaccination start 2014; II: Gradual vaccination start 2016-2018; III: No vaccination. Incidence rates of T1D before (2009-2014) and after (2014-2019) introduction of rotavirus vaccine were compared. Findings The mean incidence of T1D in children <15 years was 42·61 per 100 000 during the observed period. When comparing the years before and after 2014 the incidence rate ratio (IRR) for children <5 years was 0·86 in group I (p=0·10), 0·85 (p=0·05) in group II and 0·87 (p=0·06) in group III. A similar IRR reduction was also seen among older children who received no vaccine. Children developing or not developing T1D were vaccinated to the same extent. No differences regarding clinical manifestation at onset associated with rotavirus vaccination were seen. Interpretation There is no association between rotavirus vaccination in children and incidence or clinical manifestation of T1D.
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Affiliation(s)
- Amanda Rangert
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Futurum – Academy of Health and Care, Region Jönköping County, Jönköping, Sweden
| | - Carin Oldin
- Child Health Services, Jönköping, Region Jönköping County, Jönköping, Sweden
| | - Marie Golsäter
- Futurum – Academy of Health and Care, Region Jönköping County, Jönköping, Sweden
- Child Health Services, Jönköping, Region Jönköping County, Jönköping, Sweden
- CHILD - Research Group, School of Health and Welfare, Jönköping University, Jönköping, Sweden
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Crown Princess Victoria Children´s Hospital, Linköping, Sweden
| | - Karin Åkesson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
- Department of Pediatrics, Ryhov County Hospital, Jönköping, Sweden
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9
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Kamrath C, Eckert AJ, Holl RW, Rosenbauer J. Impact of the COVID-19 Pandemic on Children and Adolescents with New-Onset Type 1 Diabetes. Pediatr Diabetes 2023; 2023:7660985. [PMID: 40303240 PMCID: PMC12017117 DOI: 10.1155/2023/7660985] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/26/2022] [Accepted: 05/13/2023] [Indexed: 05/02/2025] Open
Abstract
Background The COVID-19 pandemic has an impact on the incidence of type 1 diabetes and frequency of diabetic ketoacidosis. However, the exact relationships are unclear. It is also not known whether this is a short-term phenomenon or whether the effects have long-term relevance. Furthermore, it is not known whether these changes during the pandemic are due to direct effects of SARS-CoV-2 or to changes in the patient's environment during the pandemic. Methods We conducted an extensive literature search on PubMed. For the estimation of relative risks of new-onset type 1 diabetes, we applied a Poisson regression model and for the comparison of incidences and we included the logarithm of person-years. Furthermore, we performed a meta-analysis using the logarithm of the relative risk for new-onset type 1 diabetes as effect size. Results Pooling the relative risk estimates in a random-effects meta-analysis revealed that the type 1 diabetes incidence rate increased by 20% (relative risk 1.200 (95% CI 1.125, 1.281)), and that the risk of new-onset type 1 diabetes after a SARS-CoV-2 infection increased by 62% (relative risk 1.622 (95% CI 1.347, 1.953)) compared with the prepandemic period. Conclusion There is considerable evidence that there is an increase in type 1 diabetes in children during the COVID-19 pandemic. Many studies suggesting a direct effect of SARS-CoV-2 have methodological weaknesses. As no evidence of an increase in presymptomatic cases with isolated islet autoimmunity was found, this could also suggest an accelerated transition from presymptomatic patients to clinically overt type 1 diabetes. Furthermore, there was a marked exacerbation of the preexisting increase in the prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes during the pandemic. Both the increased incidence of paediatric type 1 diabetes and the higher prevalence of diabetic ketoacidosis at diagnosis led to a massive rise in the number of children with diabetic ketoacidosis during the pandemic.
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Affiliation(s)
- Clemens Kamrath
- Centre of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Alexander J. Eckert
- Institute of Epidemiology and Medical Biometry, ZIBMT, Ulm University, Ulm, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Munich, Germany
| | - Reinhard W. Holl
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Munich, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany
| | - Joachim Rosenbauer
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Munich, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Centre, Leibniz Centre for Diabetes Research at Heinrich Heine University Dusseldorf, Dusseldorf, Germany
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10
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Buckner T, Johnson RK, Vanderlinden LA, Carry PM, Romero A, Onengut-Gumuscu S, Chen WM, Fiehn O, Frohnert BI, Crume T, Perng W, Kechris K, Rewers M, Norris JM. An Oxylipin-Related Nutrient Pattern and Risk of Type 1 Diabetes in the Diabetes Autoimmunity Study in the Young (DAISY). Nutrients 2023; 15:945. [PMID: 36839302 PMCID: PMC9962656 DOI: 10.3390/nu15040945] [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: 01/13/2023] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/16/2023] Open
Abstract
Oxylipins, pro-inflammatory and pro-resolving lipid mediators, are associated with the risk of type 1 diabetes (T1D) and may be influenced by diet. This study aimed to develop a nutrient pattern related to oxylipin profiles and test their associations with the risk of T1D among youth. The nutrient patterns were developed with a reduced rank regression in a nested case-control study (n = 335) within the Diabetes Autoimmunity Study in the Young (DAISY), a longitudinal cohort of children at risk of T1D. The oxylipin profiles (adjusted for genetic predictors) were the response variables. The nutrient patterns were tested in the case-control study (n = 69 T1D cases, 69 controls), then validated in the DAISY cohort using a joint Cox proportional hazards model (n = 1933, including 81 T1D cases). The first nutrient pattern (NP1) was characterized by low beta cryptoxanthin, flavanone, vitamin C, total sugars and iron, and high lycopene, anthocyanidins, linoleic acid and sodium. After adjusting for T1D family history, the HLA genotype, sex and race/ethnicity, NP1 was associated with a lower risk of T1D in the nested case-control study (OR: 0.44, p = 0.0126). NP1 was not associated with the risk of T1D (HR: 0.54, p-value = 0.1829) in the full DAISY cohort. Future studies are needed to confirm the nested case-control findings and investigate the modifiable factors for oxylipins.
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Affiliation(s)
- Teresa Buckner
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Kinesiology, Nutrition, and Dietetics, University of Northern Colorado, Greeley, CO 80639, USA
| | - Randi K. Johnson
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Biomedical Informatics, CU School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Lauren A. Vanderlinden
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Patrick M. Carry
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
- Colorado Program for Musculoskeletal Research, Department of Orthopedics, CU School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Alex Romero
- Department of Biomedical Informatics, CU School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Suna Onengut-Gumuscu
- Health Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA
| | - Wei-Min Chen
- Health Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22903, USA
| | - Oliver Fiehn
- NIH-West Coast Metabolomics Center, University of California-Davis, Davis, CA 95616, USA
| | - Brigitte I. Frohnert
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Tessa Crume
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Wei Perng
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Katerina Kechris
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Marian Rewers
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, CU Anschutz, Anschutz Medical Campus, Aurora, CO 80045, USA
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11
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Groele L, Szypowska A. Type 1 diabetes mellitus prevention. Pediatr Endocrinol Diabetes Metab 2023; 29:209-213. [PMID: 38282489 PMCID: PMC10826692 DOI: 10.5114/pedm.2023.134130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 12/21/2023] [Indexed: 01/30/2024]
Affiliation(s)
- Lidia Groele
- Department of Paediatrics, Medical University of Warsaw, Poland
- Department of Paediatric Diabetology and Paediatrics, University Clinical Centre of Warsaw Medical University, Poland
| | - Agnieszka Szypowska
- Department of Paediatrics, Medical University of Warsaw, Poland
- Department of Paediatric Diabetology and Paediatrics, University Clinical Centre of Warsaw Medical University, Poland
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12
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Morse ZJ, Simister RL, Crowe SA, Horwitz MS, Osborne LC. Virus induced dysbiosis promotes type 1 diabetes onset. Front Immunol 2023; 14:1096323. [PMID: 36742327 PMCID: PMC9892191 DOI: 10.3389/fimmu.2023.1096323] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.
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Affiliation(s)
- Zachary J Morse
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Rachel L Simister
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Sean A Crowe
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Marc S Horwitz
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lisa C Osborne
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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13
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Du C, Whiddett RO, Buckle I, Chen C, Forbes JM, Fotheringham AK. Advanced Glycation End Products and Inflammation in Type 1 Diabetes Development. Cells 2022; 11:3503. [PMID: 36359899 PMCID: PMC9657002 DOI: 10.3390/cells11213503] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 08/08/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which the β-cells of the pancreas are attacked by the host's immune system, ultimately resulting in hyperglycemia. It is a complex multifactorial disease postulated to result from a combination of genetic and environmental factors. In parallel with increasing prevalence of T1D in genetically stable populations, highlighting an environmental component, consumption of advanced glycation end products (AGEs) commonly found in in Western diets has increased significantly over the past decades. AGEs can bind to cell surface receptors including the receptor for advanced glycation end products (RAGE). RAGE has proinflammatory roles including in host-pathogen defense, thereby influencing immune cell behavior and can activate and cause proliferation of immune cells such as islet infiltrating CD8+ and CD4+ T cells and suppress the activity of T regulatory cells, contributing to β-cell injury and hyperglycemia. Insights from studies of individuals at risk of T1D have demonstrated that progression to symptomatic onset and diagnosis can vary, ranging from months to years, providing a window of opportunity for prevention strategies. Interaction between AGEs and RAGE is believed to be a major environmental risk factor for T1D and targeting the AGE-RAGE axis may act as a potential therapeutic strategy for T1D prevention.
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Affiliation(s)
- Chenping Du
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Rani O. Whiddett
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
| | - Irina Buckle
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Chen Chen
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
| | - Josephine M. Forbes
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
- Department of Medicine, The University of Melbourne, Austin Health, Heidelberg 3084, Australia
| | - Amelia K. Fotheringham
- Glycation and Diabetes Complications Group, Mater Research Institute-The University of Queensland, Translational Research Institute, Woolloongabba 4102, Australia
- Faculty of Medicine, The University of Queensland, St Lucia 4072, Australia
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14
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Kamrath C, Rosenbauer J, Eckert AJ, Siedler K, Bartelt H, Klose D, Sindichakis M, Herrlinger S, Lahn V, Holl RW. Incidence of Type 1 Diabetes in Children and Adolescents During the COVID-19 Pandemic in Germany: Results From the DPV Registry. Diabetes Care 2022; 45:1762-1771. [PMID: 35043145 DOI: 10.2337/dc21-0969] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 12/16/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The aim of this study was to investigate the incidence of type 1 diabetes in children and adolescents during the coronavirus disease 2019 (COVID-19) pandemic in Germany compared with previous years. RESEARCH DESIGN AND METHODS Based on data from the multicenter German Diabetes Prospective Follow-up Registry, we analyzed the incidence of type 1 diabetes per 100,000 patient-years in children and adolescents from 1 January 2020 through 30 June 2021. Using Poisson regression models, expected incidences for 2020/21 were estimated based on the data from 2011 to 2019 and compared with observed incidences in 2020/21 by estimating incidence rate ratios (IRRs) with 95% CIs. RESULTS From 1 January 2020 to 30 June 2021, 5,162 children and adolescents with new-onset type 1 diabetes in Germany were registered. The observed incidence in 2020/21 was significantly higher than the expected incidence (24.4 [95% CI 23.6-25.2] vs. 21.2 [20.5-21.9]; IRR 1.15 [1.10-1.20]; P < 0.001). IRRs were significantly elevated in June 2020 (IRR 1.43 [1.07-1.90]; P = 0.003), July 2020 (IRR 1.48 [1.12-1.96]; P < 0.001), March 2021 (IRR 1.29 [1.01-1.65]; P = 0.028), and June 2021 (IRR 1.39 [1.04-1.85]; P = 0.010). CONCLUSIONS A significant increase in the incidence of type 1 diabetes in children was observed during the COVID-19 pandemic, with a delay in the peak incidence of type 1 diabetes by ∼3 months after the peak COVID-19 incidence and also after pandemic containment measures. The underlying causes are yet unknown. However, indirect rather than direct effects of the pandemic are more likely to be the cause.
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Affiliation(s)
- Clemens Kamrath
- Center of Child and Adolescent Medicine, Justus Liebig University, Giessen, Germany
| | - Joachim Rosenbauer
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Dusseldorf, Dusseldorf, Germany.,German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Alexander J Eckert
- German Center for Diabetes Research, Munich-Neuherberg, Germany.,Institute of Epidemiology and Medical Biometry, Central Institute of Biomedical Technology, Ulm University, Ulm, Germany
| | - Kai Siedler
- Hospital for Children and Adolescents, Helios Clinics Pforzheim, Pforzheim, Germany
| | - Heike Bartelt
- Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Daniela Klose
- University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Marina Sindichakis
- Hospital for Children and Adolescents, Klinikum Traunstein, Traunstein, Germany
| | - Silke Herrlinger
- Professor Hess Parent-Child Center, Bremen Central Clinic, Bremen, Germany
| | | | - Reinhard W Holl
- German Center for Diabetes Research, Munich-Neuherberg, Germany.,Institute of Epidemiology and Medical Biometry, Central Institute of Biomedical Technology, Ulm University, Ulm, Germany
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15
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Krogvold L, Leete P, Mynarek IM, Russell MA, Gerling IC, Lenchik NI, Mathews C, Richardson SJ, Morgan NG, Dahl-Jørgensen K. Detection of Antiviral Tissue Responses and Increased Cell Stress in the Pancreatic Islets of Newly Diagnosed Type 1 Diabetes Patients: Results From the DiViD Study. Front Endocrinol (Lausanne) 2022; 13:881997. [PMID: 35957810 PMCID: PMC9360491 DOI: 10.3389/fendo.2022.881997] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 05/27/2022] [Indexed: 12/15/2022] Open
Abstract
Aims/hypothesis The Diabetes Virus Detection (DiViD) study has suggested the presence of low-grade enteroviral infection in pancreatic tissue collected from six of six live adult patients newly diagnosed with type 1 diabetes. The present study aimed to compare the gene and protein expression of selected virally induced pathogen recognition receptors and interferon stimulated genes in islets from these newly diagnosed type 1 diabetes (DiViD) subjects vs age-matched non-diabetic (ND) controls. Methods RNA was extracted from laser-captured islets and Affymetrix Human Gene 2.0 ST arrays used to obtain gene expression profiles. Lists of differentially expressed genes were subjected to a data-mining pipeline searching for enrichment of canonical pathways, KEGG pathways, Gene Ontologies, transcription factor binding sites and other upstream regulators. In addition, the presence and localisation of specific viral response proteins (PKR, MxA and MDA5) were examined by combined immunofluorescent labelling in sections of pancreatic tissue. Results The data analysis and data mining process revealed a significant enrichment of gene ontologies covering viral reproduction and infectious cycles; peptide translation, elongation and initiation, as well as oxidoreductase activity. Enrichment was identified in the KEGG pathways for oxidative phosphorylation; ribosomal and metabolic activity; antigen processing and presentation and in canonical pathways for mitochondrial dysfunction, oxidative phosphorylation and EIF2 signaling. Protein Kinase R (PKR) expression did not differ between newly diagnosed type 1 diabetes and ND islets at the level of total RNA, but a small subset of β-cells displayed markedly increased PKR protein levels. These PKR+ β-cells correspond to those previously shown to contain the viral protein, VP1. RNA encoding MDA5 was increased significantly in newly diagnosed type 1 diabetes islets, and immunostaining of MDA5 protein was seen in α- and certain β-cells in both newly diagnosed type 1 diabetes and ND islets, but the expression was increased in β-cells in type 1 diabetes. In addition, an uncharacterised subset of synaptophysin positive, but islet hormone negative, cells expressed intense MDA5 staining and these were more prevalent in DiViD cases. MxA RNA was upregulated in newly diagnosed type 1 diabetes vs ND islets and MxA protein was detected exclusively in newly diagnosed type 1 diabetes β-cells. Conclusion/interpretation The gene expression signatures reveal that pathways associated with cellular stress and increased immunological activity are enhanced in islets from newly diagnosed type 1 diabetes patients compared to controls. The increases in viral response proteins seen in β-cells in newly diagnosed type 1 diabetes provide clear evidence for the activation of IFN signalling pathways. As such, these data strengthen the hypothesis that an enteroviral infection of islet β-cells contributes to the pathogenesis of type 1 diabetes.
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Affiliation(s)
- Lars Krogvold
- Pediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Odontology, University of Oslo, Oslo, Norway
| | - Pia Leete
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Ida M. Mynarek
- Pediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Mark A. Russell
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Ivan C. Gerling
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Nataliya I. Lenchik
- Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Clayton Mathews
- Department of Pathology, University of Florida, Gainesville, FL, United States
| | - Sarah J. Richardson
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Noel G. Morgan
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, United Kingdom
| | - Knut Dahl-Jørgensen
- Pediatric Department, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, University of Oslo, Oslo, Norway
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16
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Qeadan F, Tingey B, Egbert J, Pezzolesi MG, Burge MR, Peterson KA, Honda T. The associations between COVID-19 diagnosis, type 1 diabetes, and the risk of diabetic ketoacidosis: A nationwide cohort from the US using the Cerner Real-World Data. PLoS One 2022; 17:e0266809. [PMID: 35439266 PMCID: PMC9017888 DOI: 10.1371/journal.pone.0266809] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/28/2022] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE To assess the risk of new-onset type 1 diabetes mellitus (T1D) diagnosis following COVID-19 diagnosis and the impact of COVID-19 diagnosis on the risk of diabetic ketoacidosis (DKA) in patients with prior T1D diagnosis. RESEARCH DESIGN AND METHODS Retrospective data consisting of 27,292,879 patients from the Cerner Real-World Data were used. Odds ratios, overall and stratified by demographic predictors, were calculated to assess associations between COVID-19 and T1D. Odds ratios from multivariable logistic regression models, adjusted for demographic and clinical predictors, were calculated to assess adjusted associations between COVID-19 and DKA. Multiple imputation with multivariate imputation by chained equations (MICE) was used to account for missing data. RESULTS The odds of developing new-onset T1D significantly increased in patients with COVID-19 diagnosis (OR: 1.42, 95% CI: 1.38, 1.46) compared to those without COVID-19. Risk varied by demographic groups, with the largest risk among pediatric patients ages 0-1 years (OR: 6.84, 95% CI: 2.75, 17.02) American Indian/Alaskan Natives (OR: 2.30, 95% CI: 1.86, 2.82), Asian or Pacific Islanders (OR: 2.01, 95% CI: 1.61, 2.53), older adult patients ages 51-65 years (OR: 1.77, 95% CI: 1.66, 1.88), those living in the Northeast (OR: 1.71, 95% CI: 1.61, 1.81), those living in the West (OR: 1.65, 95% CI: 1.56, 1.74), and Black patients (OR: 1.59, 95% CI: 1.47, 1.71). Among patients with diagnosed T1D at baseline (n = 55,359), 26.7% (n = 14,759) were diagnosed with COVID-19 over the study period. The odds of developing DKA for those with COVID-19 were significantly higher (OR 2.26, 95% CI: 2.04, 2.50) than those without COVID-19, and the largest risk was among patients with higher Elixhauser Comorbidity Index. CONCLUSIONS COVID-19 diagnosis is associated with significantly increased risk of new-onset T1D, and American Indian/Alaskan Native, Asian/Pacific Islander, and Black populations are disproportionately at risk. In patients with pre-existing T1D, the risk of developing DKA is significantly increased following COVID-19 diagnosis.
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Affiliation(s)
- Fares Qeadan
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
- * E-mail:
| | - Benjamin Tingey
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
| | - Jamie Egbert
- Parkinson School of Health Sciences and Public Health, Loyola Univesity Chicago, Maywood, Illinois, United States of America
| | - Marcus G. Pezzolesi
- Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Mark R. Burge
- Department of Internal Medicine, University of New Mexico Hospital, Albuquerque, New Mexico, United States of America
| | - Kathryn A. Peterson
- Department of Gastroenterology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Trenton Honda
- School of Clinical and Rehabilitation Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, United States of America
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17
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Benner SE, Walter DL, Thuma JR, Courreges M, James CBL, Schwartz FL, McCall KD. Toll-Like Receptor 3 Is Critical to the Pancreatic Islet Milieu That Is Required for Coxsackievirus B4-Induced Type 1 Diabetes in Female Nonobese Diabetic Mice. Pancreas 2022; 51:48-55. [PMID: 35195595 PMCID: PMC8865205 DOI: 10.1097/mpa.0000000000001960] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 12/08/2021] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Genetic and environmental influences play a role as triggers of type 1 diabetes mellitus (T1DM). Female nonobese diabetic (NOD) mice are useful for studying T1DM as they spontaneously develop T1DM, which can be accelerated by some viruses. Toll-like receptor 3 (TLR3) is believed to play a critical role in viral-induced T1DM and β-cell destruction, because female Tlr3 knockout (Tlr3-/-) NOD mice are protected from Coxsackievirus B4 (CVB4)-induced acceleration of T1DM. However, the exact role(s) TLR3 plays in the pathogenesis of CVB4-induced T1DM remain unknown. METHODS This longitudinal study used immunostaining, laser capture microdissection, and reverse transcription real-time polymerase chain reaction of islets from female uninfected and CVB4-infected Tlr3+/+ and Tlr3-/- NOD mice. RESULTS Islets isolated from female Tlr3+/+ NOD mice 4 to 8 weeks of age had higher amounts of insulitis, Cxcl10, Il1b, Tnfa, and Tgfb1 expression compared with Tlr3-/- NOD mice. After CVB4 infection, Tlr3+/+ NOD mice had higher amounts of insulitis and T-cell infiltration at 3 days after infection compared with Tlr3-/- CVB4-infected NOD mice. CONCLUSIONS Toll-like receptor 3 is necessary for establishment of a pancreatic islet inflammatory microenvironment by increasing insulitis and cytokine expression that facilitates CVB4-induced T1DM in female NOD mice.
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Affiliation(s)
- Sarah E. Benner
- From the Molecular and Cellular Biology Program
- Department of Biological Sciences, Ohio University College of Arts & Sciences
| | - Debra L. Walter
- From the Molecular and Cellular Biology Program
- Department of Biological Sciences, Ohio University College of Arts & Sciences
| | | | | | - Calvin B. L. James
- From the Molecular and Cellular Biology Program
- Biomedical Sciences
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH
| | - Frank L. Schwartz
- Departments of Specialty Medicine
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH
| | - Kelly D. McCall
- From the Molecular and Cellular Biology Program
- Department of Biological Sciences, Ohio University College of Arts & Sciences
- Departments of Specialty Medicine
- Biomedical Sciences
- Diabetes Institute, Ohio University Heritage College of Osteopathic Medicine, Athens, OH
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18
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Houeiss P, Luce S, Boitard C. Environmental Triggering of Type 1 Diabetes Autoimmunity. Front Endocrinol (Lausanne) 2022; 13:933965. [PMID: 35937815 PMCID: PMC9353023 DOI: 10.3389/fendo.2022.933965] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic islet β cells are destroyed by immune cells, ultimately leading to overt diabetes. The progressive increase in T1D incidence over the years points to the role of environmental factors in triggering or accelerating the disease process which develops on a highly multigenic susceptibility background. Evidence that environmental factors induce T1D has mostly been obtained in animal models. In the human, associations between viruses, dietary habits or changes in the microbiota and the development of islet cell autoantibodies or overt diabetes have been reported. So far, prediction of T1D development is mostly based on autoantibody detection. Future work should focus on identifying a causality between the different environmental risk factors and T1D development to improve prediction scores. This should allow developing preventive strategies to limit the T1D burden in the future.
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Affiliation(s)
- Pamela Houeiss
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Sandrine Luce
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
| | - Christian Boitard
- Laboratory Immunology of Diabetes, Department EMD, Cochin Institute, INSERMU1016, Paris, France
- Medical Faculty, Paris University, Paris, France
- *Correspondence: Christian Boitard,
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19
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Stone VM, Butrym M, Hankaniemi MM, Sioofy-Khojine AB, Hytönen VP, Hyöty H, Flodström-Tullberg M. Coxsackievirus B Vaccines Prevent Infection-Accelerated Diabetes in NOD Mice and Have No Disease-Inducing Effect. Diabetes 2021; 70:2871-2878. [PMID: 34497136 PMCID: PMC8660981 DOI: 10.2337/db21-0193] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 08/30/2021] [Indexed: 01/11/2023]
Abstract
Enteroviruses, including the Coxsackievirus Bs (CVB), have been implicated as causal agents in human type 1 diabetes. Immunization of at-risk individuals with a CVB vaccine provides an attractive strategy for elucidating the role of CVBs in the disease etiology. Previously, we have shown that an inactivated whole-virus vaccine covering all CVB serotypes (CVB1-6) is safe to administer and highly immunogenic in preclinical models, including nonhuman primates. Before initiating clinical trials with this type of vaccine, it was also important to address 1) whether the vaccine itself induces adverse immune reactions, including accelerating diabetes onset in a diabetes-prone host, and 2) whether the vaccine can prevent CVB-induced diabetes in a well-established disease model. Here, we present results from studies in which female NOD mice were left untreated, mock-vaccinated, or vaccinated with CVB1-6 vaccine and monitored for insulitis occurrence or diabetes development. We demonstrate that vaccination induces virus-neutralizing antibodies without altering insulitis scores or the onset of diabetes. We also show that NOD mice vaccinated with a CVB1 vaccine are protected from CVB-induced accelerated disease onset. Taken together, these studies show that CVB vaccines do not alter islet inflammation or accelerate disease progression in an animal model that spontaneously develops autoimmune type 1 diabetes. However, they can prevent CVB-mediated disease progression in the same model.
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Affiliation(s)
- Virginia M Stone
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marta Butrym
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Minna M Hankaniemi
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | | | - Vesa P Hytönen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Heikki Hyöty
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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20
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Nakayama M, Michels AW. Using the T Cell Receptor as a Biomarker in Type 1 Diabetes. Front Immunol 2021; 12:777788. [PMID: 34868047 PMCID: PMC8635517 DOI: 10.3389/fimmu.2021.777788] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/26/2021] [Indexed: 12/20/2022] Open
Abstract
T cell receptors (TCRs) are unique markers that define antigen specificity for a given T cell. With the evolution of sequencing and computational analysis technologies, TCRs are now prime candidates for the development of next-generation non-cell based T cell biomarkers, which provide a surrogate measure to assess the presence of antigen-specific T cells. Type 1 diabetes (T1D), the immune-mediated form of diabetes, is a prototypical organ specific autoimmune disease in which T cells play a pivotal role in targeting pancreatic insulin-producing beta cells. While the disease is now predictable by measuring autoantibodies in the peripheral blood directed to beta cell proteins, there is an urgent need to develop T cell markers that recapitulate T cell activity in the pancreas and can be a measure of disease activity. This review focuses on the potential and challenges of developing TCR biomarkers for T1D. We summarize current knowledge about TCR repertoires and clonotypes specific for T1D and discuss challenges that are unique for autoimmune diabetes. Ultimately, the integration of large TCR datasets produced from individuals with and without T1D along with computational 'big data' analysis will facilitate the development of TCRs as potentially powerful biomarkers in the development of T1D.
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MESH Headings
- Alleles
- Animals
- Biomarkers
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/etiology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/therapy
- Disease Susceptibility
- Epitopes/chemistry
- Epitopes/immunology
- Epitopes/metabolism
- Genetic Predisposition to Disease
- Genetic Variation
- Histocompatibility Antigens/genetics
- Histocompatibility Antigens/immunology
- Humans
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Peptides/immunology
- Peptides/metabolism
- Protein Binding
- Receptors, Antigen, T-Cell/genetics
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/metabolism
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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Affiliation(s)
- Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Aaron W. Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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21
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Quinn LM, Wong FS, Narendran P. Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality. Front Immunol 2021; 12:737964. [PMID: 34659229 PMCID: PMC8518604 DOI: 10.3389/fimmu.2021.737964] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.
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Affiliation(s)
- Lauren M Quinn
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F Susan Wong
- Department of Diabetes, University Hospitals of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Parth Narendran
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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22
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Morse ZJ, Horwitz MS. Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes. Front Immunol 2021; 12:751337. [PMID: 34721424 PMCID: PMC8554326 DOI: 10.3389/fimmu.2021.751337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
In addition to genetic predisposition, environmental determinants contribute to a complex etiology leading to onset of type 1 diabetes (T1D). Multiple studies have established the gut as an important site for immune modulation that can directly impact development of autoreactive cell populations against pancreatic self-antigens. Significant efforts have been made to unravel how changes in the microbiome function as a contributor to autoimmune responses and can serve as a biomarker for diabetes development. Large-scale longitudinal studies reveal that common environmental exposures precede diabetes pathology. Virus infections, particularly those associated with the gut, have been prominently identified as risk factors for T1D development. Evidence suggests recent-onset T1D patients experience pre-existing subclinical enteropathy and dysbiosis leading up to development of diabetes. The start of these dysbiotic events coincide with detection of virus infections. Thus viral infection may be a contributing driver for microbiome dysbiosis and disruption of intestinal homeostasis prior to T1D onset. Ultimately, understanding the cross-talk between viral infection, the microbiome, and the immune system is key for the development of preventative measures against T1D.
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Affiliation(s)
| | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
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23
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Yin Z, Wu Y, Zhu R, Xu L, Lin Y, Yang H, Fu W, Huang Q, Zhang D, Wang J, Wang W, Wang Y, Cheng T, Xia N. Development of A Neonatal Mouse Model for Coxsackievirus B1 Antiviral Evaluation. Virol Sin 2021; 36:1575-1584. [PMID: 34581960 PMCID: PMC8476979 DOI: 10.1007/s12250-021-00444-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 08/04/2021] [Indexed: 12/22/2022] Open
Abstract
Coxsackievirus B1 (CVB1) is a leading causative agent of severe infectious diseases in humans and has been reported to be associated with outbreaks of aseptic meningitis, myocarditis, and the development of chronic diseases such as type 1 diabetes mellitus (T1DM). There is no approved vaccine or effective antiviral therapy to treat CBV1 infection. And animal models to assess the effects of antiviral agents and vaccine remain limited. In this study, we established a neonatal mouse model of CVB1 using a clinically isolated strain to characterize the pathological manifestations of virus infection and to promote the development of vaccines and antiviral drugs against CVB1. One-day-old BALB/c mice were susceptible to CVB1 infection by intraperitoneal injection. Mice challenged with CVB1 at a low dose [10 median tissue culture infective dose (TCID50)] exhibited a series of clinical symptoms, such as inactivity, emaciation, limb weakness, hair thinning, hunching and even death. Pathological examination and tissue viral load analysis showed that positive signals of CVB1 were detected in the heart, spinal cord, limb muscle and kidney without pathological damage. Particularly, CVB1 had a strong tropism towards the pancreas, causing severe cellular necrosis with inflammatory infiltration, and was spread by viraemia. Notably, the monoclonal antibody (mAb) 6H5 and antisera elicited from CVB1-vaccinated mice effectively protected the mice from CVB1 infection in the mouse model. In summary, the established neonatal mouse model is an effective tool for evaluating the efficacy of CVB1 antiviral reagents and vaccines.
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Affiliation(s)
- Zhichao Yin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Yuanyuan Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Rui Zhu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Longfa Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Yu Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Hongwei Yang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Wenkun Fu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Qiongzi Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Dongqing Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Jue Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Wei Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
| | - Yingbin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China.
| | - Tong Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China.
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, 361102, China
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24
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Geravandi S, Richardson S, Pugliese A, Maedler K. Localization of enteroviral RNA within the pancreas in donors with T1D and T1D-associated autoantibodies. CELL REPORTS MEDICINE 2021; 2:100371. [PMID: 34467248 PMCID: PMC8385321 DOI: 10.1016/j.xcrm.2021.100371] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/07/2021] [Accepted: 07/19/2021] [Indexed: 12/16/2022]
Abstract
Enteroviral infections have been associated with autoimmunity and type 1 diabetes (T1D), but reliable methods to ascertain localization of single infected cells in the pancreas were missing. Using a single-molecule-based fluorescent in situ hybridization (smFISH) method, we detected increased virus infection in pancreases from organ donors with T1D and with disease-associated autoantibodies (AAb+). Although virus-positive β cells are found at higher frequency in T1D pancreases, compared to control donors, but are scarce, most virus-positive cells are scattered in the exocrine pancreas. Augmented CD45+ lymphocytes in T1D pancreases show virus positivity or localization in close proximity to virus-positive cells. Many more infected cells were also found in spleens from T1D donors. The overall increased proportion of virus-positive cells in the pancreas of AAb+ and T1D organ donors suggests that enteroviruses are associated with immune cell infiltration, autoimmunity, and β cell destruction in both preclinical and diagnosed T1D.
Enterovirus-infected cells are significantly increased in AAb+ and T1D pancreases Most of the virus-positive cells are scattered within the exocrine pancreas Virus-positive β cells are rare but more in T1D compared to control donors Also elevated in T1D donors, there is more infection in spleens than in pancreases
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Affiliation(s)
- Shirin Geravandi
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.,JDRF nPOD-Virus Group
| | - Sarah Richardson
- Islet Biology Group (IBEx), Exeter Centre of Excellence in Diabetes (EXCEED), University of Exeter College of Medicine and Health, Exeter, UK.,JDRF nPOD-Virus Group
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology and Metabolism, Miami, FL, USA.,Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL, USA.,JDRF nPOD-Virus Group
| | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.,JDRF nPOD-Virus Group
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25
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Lundstig A, McDonald SL, Maziarz M, Weldon WC, Vaziri-Sani F, Lernmark Å, Nilsson AL. Neutralizing Ljungan virus antibodies in children with newly diagnosed type 1 diabetes. J Gen Virol 2021; 102. [PMID: 34020728 DOI: 10.1099/jgv.0.001602] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Ljungan virus (LV), a Parechovirus of the Picornavirus family, first isolated from a bank vole at the Ljungan river in Sweden, has been implicated in the risk for autoimmune type 1 diabetes. An assay for neutralizing Ljungan virus antibodies (NLVA) was developed using the original 87-012 LV isolate. The goal was to determine NLVA titres in incident 0-18 years old newly diagnosed type 1 diabetes patients (n=67) and school children controls (n=292) from Jämtland county in Sweden. NLVA were found in 41 of 67 (61 %) patients compared to 127 of 292 (44 %) controls (P=0.009). In the type 1 diabetes patients, NLVA titres were associated with autoantibodies to glutamic acid decarboxylase (GADA) (P=0.023), but not to autoantibodies against insulin (IAA) or islet antigen-2 (IA-2A). The NLVA assay should prove useful for further investigations to determine levels of LV antibodies in patients and future studies to determine a possible role of LV in autoimmune type 1 diabetes.
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Affiliation(s)
- Annika Lundstig
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
| | - Sharia L McDonald
- IHRC, Inc, under contract to Polio and Picornavirus Laboratory Branch, Centers for Disease Control and Prevention, Division of Viral Diseases, Atlanta GA, USA
| | - Marlena Maziarz
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
| | - William C Weldon
- Polio and Picornavirus Laboratory Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Fariba Vaziri-Sani
- Kristianstad University, Kristianstad, Sweden.,Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
| | - Anna-Lena Nilsson
- Department of Paediatrics, Östersund Hospital, Östersund, Sweden.,Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Malmö, Sweden
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26
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Shih WL, Tung YC, Chang LY, Fang CT, Tsai WY. Increased Incidence of Pediatric Type 1 Diabetes With Novel Association With Coxsackievirus A Species in Young Children but Declined Incidence in Adolescents in Taiwan. Diabetes Care 2021; 44:1579-1585. [PMID: 34083323 PMCID: PMC8323190 DOI: 10.2337/dc20-1092] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 04/24/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 1 diabetes (T1D) has been linked to enterovirus infection in small population-based epidemiological studies. We investigated the secular relationship of T1D incidence with enterovirus infection and enterovirus species using nationwide population-based analysis. RESEARCH DESIGN AND METHODS We accessed the National Health Insurance Research Database of Taiwan to identify T1D and enterovirus infection cases from 2001 to 2015. Enterovirus serotype isolation rates were obtained from the nationwide laboratory surveillance systems. Negative binomial regression models assessed the incidence trend, and extended Cox proportional hazards models analyzed the association of enterovirus infection with T1D incidence. Spearman correlation coefficients evaluated the correlation between T1D incidence and circulating enterovirus species. RESULTS T1D incidence rates in youth younger than 20 years were 6.30 and 5.02 per 100,000 person-years in 2001 and 2015 (P = 0.287), respectively. T1D incidence increased significantly in children aged 0-6 years (P < 0.001) but decreased in adolescents aged 13-19 years (P = 0.011). The T1D risk in children aged 0-6 years with enterovirus infection was significantly higher than that in noninfected subjects (hazard ratio 1.46; 95% CI 1.35-1.58; P < 0.001). Additionally, TID incidence in children aged 0-6 years was significantly correlated with the isolation rates of coxsackievirus A species (r = 0.60; P = 0.017), but no association was found beyond the age of 7. CONCLUSIONS We demonstrated that T1D incidence increased in children aged 0-6 years but decreased in adolescents aged 13-19 years in Taiwan. Enterovirus-infected subjects younger than 7 years had a higher risk of T1D than noninfected subjects.
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Affiliation(s)
- Wei-Liang Shih
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Infectious Diseases Research and Education Center, Ministry of Health and Welfare and National Taiwan University, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Luan-Yin Chang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan .,Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Tai Fang
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
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27
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Mønsted MØ, Falck ND, Pedersen K, Buschard K, Holm LJ, Haupt-Jorgensen M. Intestinal permeability in type 1 diabetes: An updated comprehensive overview. J Autoimmun 2021; 122:102674. [PMID: 34182210 DOI: 10.1016/j.jaut.2021.102674] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/29/2021] [Accepted: 05/29/2021] [Indexed: 02/06/2023]
Abstract
The etiopathogenesis of the autoimmune disease type 1 diabetes (T1D) is still largely unknown, however, both genetic and environmental factors contribute to the development of the disease. A major contact surface for environmental factors is the gastrointestinal (GI) tract, where barrier defects in T1D likely cause diabetogenic antigens to enter the body tissues, contributing to beta-cell autoimmunity. Human and animal research imply that increased intestinal permeability is an important disease determinant, although the underlying methodologies, interpretations and conclusions are diverse. In this review, an updated comprehensive overview on intestinal permeability in patients with T1D and animal models of T1D is provided in the categories: in vivo permeability, ex vivo permeability, zonulin, molecular permeability and blood markers. Across categories, there is consistency pointing towards increased intestinal permeability in T1D. In animal models of T1D, the intestinal permeability varies with age and strains implying a need for careful selection of method and experimental setup. Furthermore, dietary interventions that affect diabetes incidence in animal models does also impact the intestinal permeability, suggesting an association between increased intestinal permeability and T1D development.
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Affiliation(s)
- Mia Øgaard Mønsted
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Denmark.
| | - Nora Dakini Falck
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Denmark
| | - Kristina Pedersen
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Denmark
| | - Karsten Buschard
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Denmark
| | - Laurits Juulskov Holm
- The Bartholin Institute, Department of Pathology, Rigshospitalet, Copenhagen N, Denmark
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28
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Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden. Sci Rep 2021; 11:8821. [PMID: 33893332 PMCID: PMC8065060 DOI: 10.1038/s41598-021-86229-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 03/04/2021] [Indexed: 11/09/2022] Open
Abstract
HLA-DQ molecules account over 50% genetic risk of type 1 diabetes (T1D), but little is known about associated residues. Through next generation targeted sequencing technology and deep learning of DQ residue sequences, the aim was to uncover critical residues and their motifs associated with T1D. Our analysis uncovered (αa1, α44, α157, α196) and (β9, β30, β57, β70, β135) on the HLA-DQ molecule. Their motifs captured all known susceptibility and resistant T1D associations. Three motifs, “DCAA-YSARD” (OR = 2.10, p = 1.96*10−20), “DQAA-YYARD” (OR = 3.34, 2.69*10−72) and “DQDA-YYARD” (OR = 3.71, 1.53*10−6) corresponding to DQ2.5 and DQ8.1 (the latter two motifs) associated with susceptibility. Ten motifs were significantly associated with resistance to T1D. Collectively, homozygous DQ risk motifs accounted for 43% of DQ-T1D risk, while homozygous DQ resistant motifs accounted for 25% protection to DQ-T1D risk. Of the identified nine residues five were within or near anchoring pockets of the antigenic peptide (α44, β9, β30, β57 and β70), one was the N-terminal of the alpha chain (αa1), one in the CD4-binding region (β135), one in the putative cognate TCR-induced αβ homodimerization process (α157), and one in the intra-membrane domain of the alpha chain (α196). Finding these critical residues should allow investigations of fundamental properties of host immunity that underlie tolerance to self and organ-specific autoimmunity.
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29
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Li G, Chen Z, Lv Z, Li H, Chang D, Lu J. Diabetes Mellitus and COVID-19: Associations and Possible Mechanisms. Int J Endocrinol 2021; 2021:7394378. [PMID: 33859687 PMCID: PMC8025139 DOI: 10.1155/2021/7394378] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 08/02/2020] [Accepted: 03/11/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a recently emerged disease with formidable infectivity and high mortality. Emerging data suggest that diabetes is one of the most prevalent comorbidities in patients with COVID-19. Although their causal relationship has not yet been investigated, preexisting diabetes can be considered as a risk factor for the adverse outcomes of COVID-19. Proinflammatory state, attenuation of the innate immune response, possibly increased level of ACE2, along with vascular dysfunction, and prothrombotic state in people with diabetes probably contribute to higher susceptibility for SARS-CoV-2 infection and worsened prognosis. On the other hand, activated inflammation, islet damage induced by virus infection, and treatment with glucocorticoids could, in turn, result in impaired glucose regulation in people with diabetes, thus working as an amplification loop to aggravate the disease. Therefore, glycemic management in people with COVID-19, especially in those with severe illness, is of considerable importance. The insights may help to reduce the fatality in the effort against COVID-19.
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Affiliation(s)
- Gerui Li
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Ze Chen
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Zhan Lv
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Hang Li
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
| | - Danqi Chang
- Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei, China
| | - Jinping Lu
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei, China
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30
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Type I interferons as key players in pancreatic β-cell dysfunction in type 1 diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:1-80. [PMID: 33832648 DOI: 10.1016/bs.ircmb.2021.02.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet inflammation (insulitis) and specific pancreatic β-cell destruction by an immune attack. Although the precise underlying mechanisms leading to the autoimmune assault remain poorly understood, it is well accepted that insulitis takes place in the context of a conflicting dialogue between pancreatic β-cells and the immune cells. Moreover, both host genetic background (i.e., candidate genes) and environmental factors (e.g., viral infections) contribute to this inadequate dialogue. Accumulating evidence indicates that type I interferons (IFNs), cytokines that are crucial for both innate and adaptive immune responses, act as key links between environmental and genetic risk factors in the development of T1D. This chapter summarizes some relevant pathways involved in β-cell dysfunction and death, and briefly reviews how enteroviral infections and genetic susceptibility can impact insulitis. Moreover, we present the current evidence showing that, in β-cells, type I IFN signaling pathway activation leads to several outcomes, such as long-lasting major histocompatibility complex (MHC) class I hyperexpression, endoplasmic reticulum (ER) stress, epigenetic changes, and induction of posttranscriptional as well as posttranslational modifications. MHC class I overexpression, when combined with ER stress and posttranscriptional/posttranslational modifications, might lead to sustained neoantigen presentation to immune system and β-cell apoptosis. This knowledge supports the concept that type I IFNs are implicated in the early stages of T1D pathogenesis. Finally, we highlight the promising therapeutic avenues for T1D treatment directed at type I IFN signaling pathway.
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31
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Apaolaza PS, Balcacean D, Zapardiel-Gonzalo J, Nelson G, Lenchik N, Akhbari P, Gerling I, Richardson SJ, Rodriguez-Calvo T. Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes. SCIENCE ADVANCES 2021; 7:7/9/eabd6527. [PMID: 33627420 PMCID: PMC7904254 DOI: 10.1126/sciadv.abd6527] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 01/04/2021] [Indexed: 05/04/2023]
Abstract
Previous results indicate the presence of an interferon (IFN) signature in type 1 diabetes (T1D), capable of inducing chronic inflammation and compromising b cell function. Here, we determined the expression of the IFN response markers MxA, PKR, and HLA-I in the islets of autoantibody-positive and T1D donors. We found that these markers can be coexpressed in the same islet, are more abundant in insulin-containing islets, are highly expressed in islets with insulitis, and their expression levels are correlated with the presence of the enteroviral protein VP1. The expression of these markers was associated with down-regulation of multiple genes in the insulin secretion pathway. The coexistence of an IFN response and a microbial stress response is likely to prime islets for immune destruction. This study highlights the importance of therapeutic interventions aimed at eliminating potentially persistent infections and diminishing inflammation in individuals with T1D.
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Affiliation(s)
- Paola S Apaolaza
- Institute of Diabetes Research, Helmholtz Diabetes Center, Helmholtz Zentrum Munich, 80939, Germany
| | - Diana Balcacean
- Institute of Diabetes Research, Helmholtz Diabetes Center, Helmholtz Zentrum Munich, 80939, Germany
| | - Jose Zapardiel-Gonzalo
- Institute of Diabetes Research, Helmholtz Diabetes Center, Helmholtz Zentrum Munich, 80939, Germany
| | - Grace Nelson
- Department of Medicine, University of Tennessee, Memphis, TN 38163, USA
| | - Nataliya Lenchik
- Department of Medicine, University of Tennessee, Memphis, TN 38163, USA
| | - Pouria Akhbari
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter EX2 5DW, UK
| | - Ivan Gerling
- Department of Medicine, University of Tennessee, Memphis, TN 38163, USA
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter EX2 5DW, UK
| | - Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Diabetes Center, Helmholtz Zentrum Munich, 80939, Germany.
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Real-Fernández F, Gallo A, Nuti F, Altamore L, Del Vescovo GG, Traldi P, Ragazzi E, Rovero P, Lapolla A, Papini AM. Cross-reactive peptide epitopes of Enterovirus Coxsackie B4 and human glutamic acid decarboxylase detecting antibodies in latent autoimmune diabetes in adults versus type 1 diabetes. Clin Chim Acta 2021; 515:73-79. [PMID: 33422493 DOI: 10.1016/j.cca.2021.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/31/2020] [Accepted: 01/05/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Diagnosis of latent autoimmune diabetes in adults (LADA) is usually based on the adult age, anti-pancreatic islet cell antibodies detection, and insulin independence. This study investigates the diagnostic value of antibodies against human glutamic acid decarboxylase (hGAD) peptides in LADA and type 1 diabetes mellitus (T1DM) patients, and their cross-reactivity with an Enterovirus Coxsackie B4 (CVB4) shared epitope. METHODS Sera from 27 LADA patients, 23 T1DM patients, and 24 controls were tested in ELISA for antibodies against hGAD peptides and a selected sequence of P2C protein of CVB4 (CVB4P2C). Diagnostic power of peptides was analyzed by ROC-curve analysis and cross-reactivity among peptides evaluated. RESULTS IgM and IgG antibodies showed significant differences between LADA and T1DM versus controls for all peptides. Antibody responses present high agreement among peptides for IgM and IgG-isotypes in T1DM, which is not reproduced in LADA. IgM antibodies showed high predicting diagnostic power particularly in LADA (sensitivity > 85%, specificity 95.8%). CONCLUSIONS Our study highlights the usefulness of peptides as diagnostic antigens in T1DM and LADA, and extends previous findings by comparing IgM and IgG-isotype antibodies in the same population. Additionally, results highlight the role of the entourage in the shared sequon PEVKXK in GAD and CVB4P2C particularly in IgMs identification.
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Affiliation(s)
- Feliciana Real-Fernández
- Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Alessandra Gallo
- Diabetology and Dietetics, Department of Medicine (DIMED), University of Padova, Padova, Italy
| | - Francesca Nuti
- Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | - Lorenzo Altamore
- Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy
| | | | - Pietro Traldi
- Istituto di Ricerca Pediatrica, Città della Speranza, Padova, Italy
| | - Eugenio Ragazzi
- Department of Pharmaceutical and Pharmacological Sciences, School of Medicine and Surgery, University of Padova, Padova, Italy
| | - Paolo Rovero
- Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Neurosciences, Psychology, Drug Research and Child Health, Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Sesto Fiorentino, Italy
| | - Annunziata Lapolla
- Diabetology and Dietetics, Department of Medicine (DIMED), University of Padova, Padova, Italy.
| | - Anna Maria Papini
- Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Italy; PeptLab@UCP, CY Cergy Paris Université, Cergy Pontoise, France.
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Elhag DA, Kumar M, Al Khodor S. Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes. Int J Mol Sci 2020; 22:ijms22010125. [PMID: 33374418 PMCID: PMC7795494 DOI: 10.3390/ijms22010125] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Revised: 12/13/2020] [Accepted: 12/15/2020] [Indexed: 12/11/2022] Open
Abstract
Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.
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Stafford JD, Shaheen ZR, Yeo CT, Corbett JA. Inhibition of mitochondrial oxidative metabolism attenuates EMCV replication and protects β-cells from virally mediated lysis. J Biol Chem 2020; 295:16655-16664. [PMID: 32972972 PMCID: PMC7864063 DOI: 10.1074/jbc.ra120.014851] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 09/06/2020] [Indexed: 12/15/2022] Open
Abstract
Viral infection is one environmental factor that may contribute to the initiation of pancreatic β-cell destruction during the development of autoimmune diabetes. Picornaviruses, such as encephalomyocarditis virus (EMCV), induce a pro-inflammatory response in islets leading to local production of cytokines, such as IL-1, by resident islet leukocytes. Furthermore, IL-1 is known to stimulate β-cell expression of iNOS and production of the free radical nitric oxide. The purpose of this study was to determine whether nitric oxide contributes to the β-cell response to viral infection. We show that nitric oxide protects β-cells against virally mediated lysis by limiting EMCV replication. This protection requires low micromolar, or iNOS-derived, levels of nitric oxide. At these concentrations nitric oxide inhibits the Krebs enzyme aconitase and complex IV of the electron transport chain. Like nitric oxide, pharmacological inhibition of mitochondrial oxidative metabolism attenuates EMCV-mediated β-cell lysis by inhibiting viral replication. These findings provide novel evidence that cytokine signaling in β-cells functions to limit viral replication and subsequent β-cell lysis by attenuating mitochondrial oxidative metabolism in a nitric oxide-dependent manner.
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Affiliation(s)
- Joshua D Stafford
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Zachary R Shaheen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Chay Teng Yeo
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
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Antvorskov JC, Morgen CS, Buschard K, Jess T, Allin KH, Josefsen K. Antibiotic treatment during early childhood and risk of type 1 diabetes in children: A national birth cohort study. Pediatr Diabetes 2020; 21:1457-1464. [PMID: 32902076 PMCID: PMC9291608 DOI: 10.1111/pedi.13111] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 07/06/2020] [Accepted: 08/28/2020] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE/BACKGROUND Antibiotics are widely used during childhood infections and influence the composition of the microbiota, which is established during the first years of life. Evidence from animal models of type 1 diabetes shows that antibiotics might accelerate disease progression, and altered intestinal microbiota has been reported in association with type 1 diabetes in humans. We aimed to test the hypothesis that early exposure to antibiotics (0-24 months of age) was associated with an increased risk of childhood type 1 diabetes development. METHODS We studied 75 615 mother-child dyads from the Danish National Birth Cohort. Information on the use of antibiotics during early childhood and type 1 diabetes development in childhood was available for all children via linkage to the Danish National Prescription Registry and the Danish National Patient Register, respectively. The mean follow-up time was 14.3 years (range 11.5 to 18.4 years, SD 1.4). RESULTS After adjustment for confounders, we found no association between antibiotic exposure and risk of type 1 diabetes (HR 1.26, 95% CI 0.89-1.79). The number of antibiotic courses during early childhood was not associated with type 1 diabetes development when analyzing for one (HR 1.31, 95% CI 0.87-1.99), two (HR 0.99, 95% CI 0.61-1.63), or 3 or more (HR 1.42, 95% CI 0.95-2.11) courses. Furthermore, no specific types of antibiotics (penicillins/beta-lactam antibacterials, sulfonamide/trimethroprim, or macrolides/lincosamides/streptogramins) were associated with increased risk of type 1 diabetes. CONCLUSION Our nationwide cohort study suggests that postnatal exposure to antibiotics does not influence the development of childhood type 1 diabetes.
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Affiliation(s)
| | - Camilla Schmidt Morgen
- National Institute of Public HealthUniversity of Southern DenmarkCopenhagenDenmark,Department of Public Health, Section of Epidemiology, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | | | - Tine Jess
- Center for Clinical Research and PreventionBispebjerg and Frederiksberg Hospital, The Capital RegionCopenhagenDenmark,Department of Epidemiology ResearchStatens Serum InstitutCopenhagenDenmark
| | - Kristine Højgaard Allin
- Center for Clinical Research and PreventionBispebjerg and Frederiksberg Hospital, The Capital RegionCopenhagenDenmark,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Knud Josefsen
- The Bartholin InstituteRigshospitaletCopenhagenDenmark
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Boddu SK, Aurangabadkar G, Kuchay MS. New onset diabetes, type 1 diabetes and COVID-19. Diabetes Metab Syndr 2020; 14:2211-2217. [PMID: 33395782 PMCID: PMC7669477 DOI: 10.1016/j.dsx.2020.11.012] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS New data has emerged regarding higher risk of coronavirus disease 2019 (COVID-19), and its severity and complications in patients with type 2 diabetes mellitus (T2DM). However, there is a dearth of evidence regarding type 1 diabetes mellitus (T1DM). This article explores the possibility of COVID 19 induced diabetes and highlights a potential bidirectional link between COVID 19 and T1DM. METHODS A literature search was performed with Medline (PubMed), Scopus, and Google Scholar electronic databases till October 2020, using relevant keywords (COVID-19 induced diabetes; COVID-19 and type 1 diabetes; COVID-19 induced DKA; new-onset diabetes after SARS-CoV-2 infection) to extract relevant studies describing relationship between COVID-19 and T1DM. RESULTS Past lessons and new data teach us that severe acute respiratory syndrome coronaviruses (SARS-CoV and SARS-CoV-2) can enter islet cells via angiotensin converting enzyme-2 (ACE-2) receptors and cause reversible β-cell damage and transient hyperglycemia. There have been postulations regarding the potential new-onset T1DM triggered by COVID-19. This article reviews the available evidence regarding the impact and interlink between COVID-19 and Τ1DM. We also explore the mechanisms behind the viral etiology of Τ1DM. CONCLUSIONS SARS-CoV-2 can trigger severe diabetic ketoacidosis at presentation in individuals with new-onset diabetes. However, at present, there is no hard evidence that SARS-CoV-2 induces T1DM on it's own accord. Long term follow-up of children and adults presenting with new-onset diabetes during this pandemic is required to fully understand the type of diabetes induced by COVID-19.
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Affiliation(s)
- Sirisha Kusuma Boddu
- Department of Pediatric Endocrinology, Rainbow Children's Hospital, Hyderabad, India
| | - Geeta Aurangabadkar
- Department of Endocrinology, CARE Multispecialty Hospital, Hyderabad, India.
| | - Mohammad Shafi Kuchay
- Division of Endocrinology and Diabetes, Medanta the Medicity Hospital, Haryana, India
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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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Akhbari P, Richardson SJ, Morgan NG. Type 1 Diabetes: Interferons and the Aftermath of Pancreatic Beta-Cell Enteroviral Infection. Microorganisms 2020; 8:microorganisms8091419. [PMID: 32942706 PMCID: PMC7565444 DOI: 10.3390/microorganisms8091419] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/09/2020] [Accepted: 09/11/2020] [Indexed: 02/07/2023] Open
Abstract
Enteroviruses (EVs) have long been implicated in the pathogenesis of type 1 diabetes (T1D), and accumulating evidence has associated virus-induced autoimmunity with the loss of pancreatic beta cells in T1D. Inflammatory cytokines including interferons (IFN) form a primary line of defence against viral infections, and their chronic elevation is a hallmark feature of many autoimmune diseases. IFNs play a key role in activating and regulating innate and adaptive immune responses, and to do so they modulate the expression of networks of genes and transcription factors known generically as IFN stimulated genes (ISGs). ISGs in turn modulate critical cellular processes ranging from cellular metabolism and growth regulation to endoplasmic reticulum (ER) stress and apoptosis. More recent studies have revealed that IFNs also modulate gene expression at an epigenetic as well as post-transcriptional and post-translational levels. As such, IFNs form a key link connecting the various genetic, environmental and immunological factors involved in the initiation and progression of T1D. Therefore, gaining an improved understanding of the mechanisms by which IFNs modulate beta cell function and survival is crucial in explaining the pathogenesis of virally-induced T1D. This should provide the means to prevent, decelerate or even reverse beta cell impairment.
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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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Norris JM, Johnson RK, Stene LC. Type 1 diabetes-early life origins and changing epidemiology. Lancet Diabetes Endocrinol 2020; 8:226-238. [PMID: 31999944 PMCID: PMC7332108 DOI: 10.1016/s2213-8587(19)30412-7] [Citation(s) in RCA: 201] [Impact Index Per Article: 40.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 11/25/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022]
Abstract
Type 1 diabetes is a chronic, immune-mediated disease characterised by the destruction of insulin-producing cells. Standardised registry data show that type 1 diabetes incidence has increased 3-4% over the past three decades, supporting the role of environmental factors. Although several factors have been associated with type 1 diabetes, none of the associations are of a magnitude that could explain the rapid increase in incidence alone. Moreover, evidence of changing prevalence of these exposures over time is insufficient. Multiple factors could simultaneously explain the changing type 1 diabetes incidence, or the magnitude of observed associations could have been underestimated because of exposure measurement error, or the mismodelling of complex exposure-time-response relationships. The identification of environmental factors influencing the risk of type 1 diabetes and increased understanding of the cause at the individual level, regardless of the ability to explain the changing incidence at the population level, is important because of the implications for prevention.
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Affiliation(s)
- Jill M Norris
- Department of Epidemiology, Colorado School of Public Health, Aurora, CO, USA.
| | - Randi K Johnson
- Division of Biomedical Informatics and Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Lars C Stene
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
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Martinov T, Fife BT. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. Ann N Y Acad Sci 2020; 1461:73-103. [PMID: 31025378 PMCID: PMC6994200 DOI: 10.1111/nyas.14106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/25/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non-obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell- and B cell-intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes-prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.
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Affiliation(s)
- Tijana Martinov
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Brian T Fife
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
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Blotsky AL, Rahme E, Dahhou M, Nakhla M, Dasgupta K. Gestational diabetes associated with incident diabetes in childhood and youth: a retrospective cohort study. CMAJ 2020; 191:E410-E417. [PMID: 30988041 DOI: 10.1503/cmaj.181001] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Indicators of childhood- and youth-onset diabetes may be useful for early detection of diabetes; there is a known association between composite exposure of parental type 2 diabetes and gestational diabetes mellitus with childhood- and youth-onset diabetes. We examined associations between gestational diabetes mellitus and incidence of childhood- and youth-onset diabetes in offspring. METHODS Using public health insurance administrative databases from Quebec, Canada, we randomly selected singleton live births with maternal gestational diabetes mellitus (1990-2007) and matched them 1:1 with singleton live births without gestational diabetes mellitus. Follow-up was to Mar. 31, 2012. We examined associations of diabetes in offspring with maternal gestational diabetes mellitus through unadjusted and adjusted Cox proportional hazards models. In secondary analyses, we separately considered age groups ranging from birth to age 12 years, and age 12 to 22 years. RESULTS Incidence of pediatric diabetes (per 10 000 person-years) was higher in offspring born to mothers with gestational diabetes mellitus (4.52, 95% confidence interval [CI] 4.47-4.57) than in mothers without gestational diabetes mellitus (2.4, 95% CI 2.37-2.46). In an adjusted Cox proportional hazards model, maternal gestational diabetes mellitus was associated with development of pediatric diabetes overall (birth to age 22 yr: hazard ratio [HR] 1.77, 95% CI 1.41-2.22), during childhood (birth to age 12 yr: HR 1.43, 95% CI 1.09-1.89), and in youth (age 12 to 22 yr: HR 2.53, 95% CI 1.67-3.85). INTERPRETATION Gestational diabetes mellitus is associated with incident diabetes in offspring during childhood and adolescence. Future studies are needed to examine longer-term outcomes in patients with pediatric diabetes with a maternal history of gestational diabetes mellitus, to ascertain how they compare with other patients with childhood- or youth-onset diabetes, in terms of disease severity and outcomes.
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Affiliation(s)
- Andrea L Blotsky
- Department of Medicine (Blotsky, Rahme, Dasgupta), McGill University; Centre for Outcomes Research and Evaluation (Blotsky, Rahme, Dahhou, Nakhla, Dasgupta), Research Institute of the McGill University Health Centre; Department of Pediatrics (Nakhla), Division of Endocrinology and Metabolism, McGill University, Montréal, Que
| | - Elham Rahme
- Department of Medicine (Blotsky, Rahme, Dasgupta), McGill University; Centre for Outcomes Research and Evaluation (Blotsky, Rahme, Dahhou, Nakhla, Dasgupta), Research Institute of the McGill University Health Centre; Department of Pediatrics (Nakhla), Division of Endocrinology and Metabolism, McGill University, Montréal, Que
| | - Mourad Dahhou
- Department of Medicine (Blotsky, Rahme, Dasgupta), McGill University; Centre for Outcomes Research and Evaluation (Blotsky, Rahme, Dahhou, Nakhla, Dasgupta), Research Institute of the McGill University Health Centre; Department of Pediatrics (Nakhla), Division of Endocrinology and Metabolism, McGill University, Montréal, Que
| | - Meranda Nakhla
- Department of Medicine (Blotsky, Rahme, Dasgupta), McGill University; Centre for Outcomes Research and Evaluation (Blotsky, Rahme, Dahhou, Nakhla, Dasgupta), Research Institute of the McGill University Health Centre; Department of Pediatrics (Nakhla), Division of Endocrinology and Metabolism, McGill University, Montréal, Que
| | - Kaberi Dasgupta
- Department of Medicine (Blotsky, Rahme, Dasgupta), McGill University; Centre for Outcomes Research and Evaluation (Blotsky, Rahme, Dahhou, Nakhla, Dasgupta), Research Institute of the McGill University Health Centre; Department of Pediatrics (Nakhla), Division of Endocrinology and Metabolism, McGill University, Montréal, Que.
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Warshauer JT, Bluestone JA, Anderson MS. New Frontiers in the Treatment of Type 1 Diabetes. Cell Metab 2020; 31:46-61. [PMID: 31839487 PMCID: PMC6986815 DOI: 10.1016/j.cmet.2019.11.017] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/30/2022]
Abstract
Type 1 diabetes is an autoimmune disease caused by the immune-mediated destruction of pancreatic β cells that results in lifelong absolute insulin deficiency. For nearly a century, insulin replacement has been the only therapy for most people living with this disease. Recent advances in technology and our understanding of β cell development, glucose metabolism, and the underlying immune pathogenesis of the disease have led to innovative therapeutic and preventative approaches. A paradigm shift in immunotherapy development toward the targeting of islet-specific immune pathways involved in tolerance has driven the development of therapies that may allow for the prevention or reversal of this disease while avoiding toxicities associated with historical approaches that were broadly immunosuppressive. In this review, we discuss successes, failures, and emerging pharmacological therapies for type 1 diabetes that are changing how we approach this disease, from improving glycemic control to developing the "holy grail" of disease prevention.
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Affiliation(s)
- Jeremy T Warshauer
- Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Jeffrey A Bluestone
- Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
| | - Mark S Anderson
- Endocrine Division, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
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Piganelli JD, Mamula MJ, James EA. The Role of β Cell Stress and Neo-Epitopes in the Immunopathology of Type 1 Diabetes. Front Endocrinol (Lausanne) 2020; 11:624590. [PMID: 33679609 PMCID: PMC7930070 DOI: 10.3389/fendo.2020.624590] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/23/2020] [Indexed: 12/15/2022] Open
Abstract
Due to their secretory function, β cells are predisposed to higher levels of endoplasmic reticulum (ER) stress and greater sensitivity to inflammation than other cell types. These stresses elicit changes in β cells that alter their function and immunogenicity, including defective ribosomal initiation, post-translational modifications (PTMs) of endogenous β cell proteins, and alternative splicing. Multiple published reports confirm the presence of not only CD8+ T cells, but also autoreactive CD4+ T cells within pancreatic islets. Although the specificities of T cells that infiltrate human islets are incompletely characterized, they have been confirmed to include neo-epitopes that are formed through stress-related enzymatic modifications of β cell proteins. This article summarizes emerging knowledge about stress-induced changes in β cells and data supporting a role for neo-antigen formation and cross-talk between immune cells and β cells that provokes autoimmune attack - leading to a breakdown in tissue-specific tolerance in subjects who develop type 1 diabetes.
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Affiliation(s)
- Jon D. Piganelli
- Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Mark J. Mamula
- Section of Rheumatology, Department of Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Eddie A. James
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
- *Correspondence: Eddie A. James,
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Abstract
Virus infections have been linked to the induction of autoimmunity and disease development in human type 1 diabetes. Experimental models have been instrumental in deciphering processes leading to break of immunological tolerance and type 1 diabetes development. Animal models have also been useful for proof-of-concept studies and for preclinical testing of new therapeutic interventions. This chapter describes two robust and clinically relevant mouse models for virus-induced type 1 diabetes; acceleration of disease onset in prediabetic nonobese diabetic (NOD) mice following Coxsackievirus infection and diabetes induction by lymphocytic choriomeningitis virus (LCMV) infection of transgenic mice expressing viral neo-antigens under control of the rat insulin promoter (RIP).
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Affiliation(s)
| | - Malin Flodström-Tullberg
- The Center for Infectious Medicine (CIM), Department of Medicine Huddinge, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Vehik K, Lynch KF, Wong MC, Tian X, Ross MC, Gibbs RA, Ajami NJ, Petrosino JF, Rewers M, Toppari J, Ziegler AG, She JX, Lernmark A, Akolkar B, Hagopian WA, Schatz DA, Krischer JP, Hyöty H, Lloyd RE. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nat Med 2019; 25:1865-1872. [PMID: 31792456 PMCID: PMC6898786 DOI: 10.1038/s41591-019-0667-0] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 10/25/2019] [Indexed: 12/17/2022]
Abstract
Viruses are implicated in autoimmune destruction of pancreatic islet β cells, which results in insulin deficiency and type 1 diabetes (T1D)1-4. Certain enteroviruses can infect β cells in vitro5, have been detected in the pancreatic islets of patients with T1D6 and have shown an association with T1D in meta-analyses4. However, establishing consistency in findings across studies has proven difficult. Obstacles to convincingly linking RNA viruses to islet autoimmunity may be attributed to rapid viral mutation rates, the cyclical periodicity of viruses7 and the selection of variants with altered pathogenicity and ability to spread in populations. β cells strongly express cell-surface coxsackie and adenovirus receptor (CXADR) genes, which can facilitate enterovirus infection8. Studies of human pancreata and cultured islets have shown significant variation in enteroviral virulence to β cells between serotypes and within the same serotype9,10. In this large-scale study of known eukaryotic DNA and RNA viruses in stools from children, we evaluated fecally shed viruses in relation to islet autoimmunity and T1D. This study showed that prolonged enterovirus B rather than independent, short-duration enterovirus B infections may be involved in the development of islet autoimmunity, but not T1D, in some young children. Furthermore, we found that fewer early-life human mastadenovirus C infections, as well as CXADR rs6517774, independently correlated with islet autoimmunity.
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Affiliation(s)
- Kendra Vehik
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
| | - Kristian F Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Matthew C Wong
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Xiangjun Tian
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Matthew C Ross
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Richard A Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Nadim J Ajami
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph F Petrosino
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Marian Rewers
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, USA
| | - 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
| | - 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
| | - Jin-Xiong She
- Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA
| | - Ake Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skane University Hospital, Malmö, Sweden
| | - Beena Akolkar
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | | | - Desmond A Schatz
- Department of Pediatrics, University of Florida Diabetes Institute, Gainesville, FL, USA
| | - Jeffrey P Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Heikki Hyöty
- Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland
| | - Richard E Lloyd
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
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Tanoey J, Gulati A, Patterson C, Becher H. Risk of Type 1 Diabetes in the Offspring Born through Elective or Non-elective Caesarean Section in Comparison to Vaginal Delivery: a Meta-Analysis of Observational Studies. Curr Diab Rep 2019; 19:124. [PMID: 31712908 DOI: 10.1007/s11892-019-1253-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Caesarean section (CS) has been associated with an increased risk of type 1 diabetes (T1D). The lack of exposure to maternal vaginal and anal microbiome and bypassing the labor process often observed in elective CS may affect neonatal immune system development. This study aims to summarize the effects of elective and non-elective CS on T1D risk in the offspring. METHODS A systematic literature search was conducted online for publications providing data on elective and non-elective CS with T1D diagnosis in children and young adults, followed by a meta-analysis from selected studies. Newcastle-Ottawa Scale and GRADEpro tool were applied for quality analysis. RESULTS Nine observational studies comprising over 5 million individuals fulfilled the inclusion criteria. Crude OR estimates showed a 12% increased T1D risk from elective CS compared to vaginal delivery with significant heterogeneity. Adjusted ORs from seven studies did not show T1D risk differences from either CS category, and heterogeneity was detected between studies. Separate analysis of cohort and case-control studies reduced the heterogeneity and revealed a slight increase in T1D risk associated with elective CS in cohort studies (adjusted OR = 1.12 (1.01-1.24)), and a higher increased risk associated with non-elective CS in case-control studies (adjusted OR = 1.19 (1.06-1.34)). CONCLUSION Summarized crude risk estimates showed a small increased T1D risk in children and young adults born through elective CS compared to vaginal delivery, but with significant heterogeneity. Adjusted risk estimates by study design indicated a slightly increased T1D risks associated with elective or non-elective CS.
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Affiliation(s)
- Justine Tanoey
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
| | - Amit Gulati
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Chris Patterson
- Centre for Public Health, University of Belfast, Grosvenor Road, Belfast, BT12 6BJ, UK
| | - Heiko Becher
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
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Ilonen J, Lempainen J, Veijola R. The heterogeneous pathogenesis of type 1 diabetes mellitus. Nat Rev Endocrinol 2019; 15:635-650. [PMID: 31534209 DOI: 10.1038/s41574-019-0254-y] [Citation(s) in RCA: 279] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/13/2019] [Indexed: 12/14/2022]
Abstract
Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments.
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Affiliation(s)
- Jorma Ilonen
- Institue of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland.
| | - Johanna Lempainen
- Institue of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland
- Department of Paediatrics, University of Turku and Turku University Hospital, Turku, Finland
| | - Riitta Veijola
- Department of Paediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland
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49
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Siljander H, Honkanen J, Knip M. Microbiome and type 1 diabetes. EBioMedicine 2019; 46:512-521. [PMID: 31257149 PMCID: PMC6710855 DOI: 10.1016/j.ebiom.2019.06.031] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 12/15/2022] Open
Abstract
The steep increase in the incidence of type 1 diabetes (T1D), in the Western world after World War II, cannot be explained solely by genetic factors but implies that this rise must be due to crucial interactions between predisposing genes and environmental changes. Three parallel phenomena in early childhood – the dynamic development of the immune system, maturation of the gut microbiome, and the appearance of the first T1D-associated autoantibodies – raise the question whether these phenomena might reflect causative relationships. Plenty of novel data on the role of the microbiome in the development of T1D has been published over recent years and this review summarizes recent findings regarding the associations between islet autoimmunity, T1D, and the intestinal microbiota.
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Affiliation(s)
- Heli Siljander
- Children's Hospital, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
| | - Jarno Honkanen
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
| | - Mikael Knip
- Children's Hospital, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland; Tampere Center for Child Health Research, Tampere University Hospital, 33520 Tampere, Finland; Folkhälsan Research Center, 00290 Helsinki, Finland.
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50
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Dunne JL, Richardson SJ, Atkinson MA, Craig ME, Dahl-Jørgensen K, Flodström-Tullberg M, Hyöty H, Insel RA, Lernmark Å, Lloyd RE, Morgan NG, Pugliese A. Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia 2019; 62:744-753. [PMID: 30675626 PMCID: PMC6450860 DOI: 10.1007/s00125-019-4811-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.
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Affiliation(s)
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK.
| | - Mark A Atkinson
- Departments of Pathology and Pediatrics, University of Florida, College of Medicine, Gainesville, FL, USA
| | - Maria E Craig
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Knut Dahl-Jørgensen
- Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Malin Flodström-Tullberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - 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, Skåne University Hospital, Malmö, Sweden
| | - Richard E Lloyd
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Noel G Morgan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK
| | - Alberto Pugliese
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
- Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA
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