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Hani NS, Thomas IH. Changes in Pediatric Type 2 Diabetes During the COVID-19 Pandemic. Pediatr Ann 2024; 53:e249-e253. [PMID: 38949870 DOI: 10.3928/19382359-20240502-03] [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: 07/03/2024]
Abstract
Type 2 diabetes (T2D) is a growing concern among the pediatric population. During the coronavirus disease 2019 (COVID-19) pandemic, the incidence of pediatric T2D increased. This was more notable among males and Black people. Increased rates of T2D may be due to rising obesity rates observed during the pandemic, behavioral and nutritional changes due to the lockdown, and decreased structure typically provided by in-person schooling. New-onset T2D presentations are more severe than in years prior to the pandemic, with higher initial hemoglobin A1C levels and increased rates of diabetic ketoacidosis. Increased severity in presentation may be due to hesitation in seeking care, increased virtual care, and limited access to health care resources. The pathophysiology of the relationship between T2D and COVID-19 in youth is not clear at this time. More studies are needed to understand the true long-term impact of the COVID-19 pandemic on T2D in youth. [Pediatr Ann. 2024;53(7):e249-e253.].
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Karavanaki K, Rodolaki K, Soldatou A, Karanasios S, Kakleas K. Covid-19 infection in children and adolescents and its association with type 1 diabetes mellitus (T1d) presentation and management. Endocrine 2023; 80:237-252. [PMID: 36462147 PMCID: PMC9734866 DOI: 10.1007/s12020-022-03266-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/17/2022] [Indexed: 12/04/2022]
Abstract
Children seem to be affected by the new SARS-CoV-2 virus less severely than adults, with better prognosis and low mortality. Serious complications of COVID-19 infection in children include multisystem inflammatory response syndrome in COVID-19 infection (MIS-C), myo-or pericarditis and, less frequently, long COVID syndrome. On the other hand, adults with type 1 (T1D) or type 2 diabetes (T2D) are among the most vulnerable groups affected by COVID-19, with increased morbidity and mortality. Moreover, an association of SARS-CoV-2 with diabetes has been observed, possibly affecting the frequency and severity of the first clinical presentation of T1D or T2D, as well as the development of acute diabetes after COVID-19 infection. The present review summarizes the current data on the incidence of T1D among children and adolescents during the COVID-19 pandemic, as well as its severity. Moreover, it reports on the types of newly diagnosed diabetes after COVID infection and the possible pathogenetic mechanisms. Additionally, this study presents current data on the effect of SARS-CoV-2 on diabetes control in patients with known T1D and on the severity of clinical presentation of COVID infection in these patients. Finally, this review discusses the necessity of immunization against COVID 19 in children and adolescents with T1D.
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Affiliation(s)
- Kyriaki Karavanaki
- Diabetes and Metabolism Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens,"P&A Kyriakou" Children's Hospital, Athens, Greece
| | - Kalliopi Rodolaki
- First Department of Pediatrics, National and Kapodistrian University of Athens,"Aghia Sophia" Children's Hospital, Athens, Greece
| | - Alexandra Soldatou
- Diabetes and Metabolism Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens,"P&A Kyriakou" Children's Hospital, Athens, Greece
| | - Spyridon Karanasios
- Diabetes and Metabolism Unit, 2nd Department of Pediatrics, National and Kapodistrian University of Athens,"P&A Kyriakou" Children's Hospital, Athens, Greece
| | - Kostas Kakleas
- First Department of Pediatrics, National and Kapodistrian University of Athens,"Aghia Sophia" Children's Hospital, Athens, Greece.
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3
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Wu R, Mumtaz M, Maxwell AJ, Isaacs SR, Laiho JE, Rawlinson WD, Hyöty H, Craig ME, Kim KW. Respiratory infections and type 1 diabetes: Potential roles in pathogenesis. Rev Med Virol 2023; 33:e2429. [PMID: 36790804 PMCID: PMC10909571 DOI: 10.1002/rmv.2429] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/13/2023] [Accepted: 01/29/2023] [Indexed: 02/16/2023]
Abstract
Among the environmental factors associated with type 1 diabetes (T1D), viral infections of the gut and pancreas has been investigated most intensely, identifying enterovirus infections as the prime candidate trigger of islet autoimmunity (IA) and T1D development. However, the association between respiratory tract infections (RTI) and IA/T1D is comparatively less known. While there are significant amounts of epidemiological evidence supporting the role of respiratory infections in T1D, there remains a paucity of data characterising infectious agents at the molecular level. This gap in the literature precludes the identification of the specific infectious agents driving the association between RTI and T1D. Furthermore, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections on the development of IA/T1D remains undeciphered. Here, we provide a comprehensive overview of the evidence to date, implicating RTIs (viral and non-viral) as potential risk factors for IA/T1D.
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Affiliation(s)
- Roy Wu
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Mohsin Mumtaz
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Anna J. Maxwell
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Sonia R. Isaacs
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
| | - Jutta E. Laiho
- Department of VirologyFaculty of Medicine and Health TechnologyTampere UniversityTampereFinland
| | - William D. Rawlinson
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
- School of Biomedical SciencesFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- School of Biotechnology and Biomolecular SciencesFaculty of ScienceUniversity of New South WalesRandwickNew South WalesAustralia
| | - Heikki Hyöty
- Department of VirologyFaculty of Medicine and Health TechnologyTampere UniversityTampereFinland
- Fimlab LaboratoriesTampereFinland
| | - Maria E. Craig
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
- Institute of Endocrinology and DiabetesChildren's Hospital at WestmeadSydneyNew South WalesAustralia
- Faculty of Medicine and HealthDiscipline of Child and Adolescent HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Ki Wook Kim
- Discipline of Paediatrics and Child HealthSchool of Clinical MedicineFaculty of Medicine and HealthUniversity of New South WalesRandwickNew South WalesAustralia
- Virology and Serology DivisionNew South Wales Health PathologyPrince of Wales HospitalRandwickNew South WalesAustralia
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Nagy G, Szekely TE, Somogyi A, Herold M, Herold Z. New therapeutic approaches for type 1 diabetes: Disease-modifying therapies. World J Diabetes 2022; 13:835-850. [PMID: 36312000 PMCID: PMC9606789 DOI: 10.4239/wjd.v13.i10.835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 08/08/2022] [Accepted: 09/15/2022] [Indexed: 02/05/2023] Open
Abstract
It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.
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Affiliation(s)
- Geza Nagy
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Tekla Evelin Szekely
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Aniko Somogyi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Magdolna Herold
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest H-1088, Hungary
| | - Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7603062. [PMID: 35958821 PMCID: PMC9357813 DOI: 10.1155/2022/7603062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 07/15/2022] [Indexed: 11/18/2022]
Abstract
Enteroviruses (EV) are among the leading environmental triggers of childhood-onset type 1 diabetes (T1D). Our aim was to determine the prevalence of antibodies against EV and their association with T1D in different age groups (n = 62), including young adults, and to compare these data with results from HLA-matched control participants (n = 62). IgA, IgG, and IgM antibodies against EV were detected. IgA EV antibodies were present in 46.8% of participants with T1D (median level 10.9 EIU) and in 11.3% of controls (median level 3.4 EIU). IgA EV positivity and higher level of IgA EV antibodies were both significant risk factors for T1D (odds ratio (OR) 8.33; 95% confidence interval (CI) 2.52–27.6; p = 0.0005 and OR 1.04; 95% CI 1.01–1.06; p = 0.0105, respectively). Importantly, the prevalence of IgA EV antibodies in the subgroups of both children and young adults was also significantly different between participants with T1D and their matched controls (p = 0.0089 and p = 0.0055, respectively). Such differences were not seen for IgG and IgM EV antibodies. However, IgG EV antibodies were associated with 65 kDa glutamic acid decarboxylase antibodies, but not with zinc transporter 8 and protein tyrosine phosphatase IA2 antibodies. The genotype frequency of PTPN22 (rs2476601) and IFIH1 (rs1990760) was not associated with EV positivity. This study showed that EV infections may be an important disease-promoting factor of T1D not only in childhood-onset but also in adult-onset T1D. However, to further confirm this association, direct virological studies are needed in the latter T1D group.
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Liu C, Yuan YC, Guo MN, Xin Z, Chen GJ, Bentley AR, Hua L, Zheng JP, Ekoru K, Yang JK. Incidence of Type 1 Diabetes May Be Underestimated in the Chinese Population: Evidence From 21.7 Million People Between 2007 and 2017. Diabetes Care 2021; 44:2503-2509. [PMID: 34413068 PMCID: PMC8546282 DOI: 10.2337/dc21-0342] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 07/25/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Previous reports of the annual incidence of type 1 diabetes (T1D) in China were conducted using retrospective hospital cases, which may not reflect the reality. This longitudinal study estimated T1D incidence in a Chinese population of 21.7 million from 2007 to 2017. RESEARCH DESIGN AND METHODS A population-based registry of T1D was performed by the Beijing Municipal Health Commission Information Center. Annual incidence and 95% CIs were calculated by age group and sex. The association of sex with T1D incidence and predicted new cases of T1D were assessed using Poisson regression models. Annual percentage change and average annual percentage of change were assessed using Joinpoint regression. RESULTS Overall, there were 6,875 individuals who developed T1D from 2007 to 2017 in this population. T1D incidence (/100,000 persons) (95% CI) significantly increased from 2.72 (2.51, 2.93) in 2007 to 3.60 (3.38, 3.78) in 2017 (P < 0.001). The T1D onset peak was in the 10-14-year-old age group. While no significant trend was found in the 0-14- and 15-29-year-old age groups, T1D incidence markedly increased from 1.87 to 3.52 in the ≥30-year-old age group (P < 0.05). The prevalence of diabetic ketoacidosis at diagnosis was highest in the 0-4-year-old age group. We predicted new cases of T1D will increase 1.57-fold over the next decade. CONCLUSIONS T1D incidence in this large Chinese population is higher than has been reported previously. From 2007 to 2017, although the incidence peak was in the 10-14-year age group, the T1D incidence increased sharply in adults but not in youth.
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Affiliation(s)
- Chang Liu
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Beijing Diabetes Institute, Beijing, China
| | - Ying-Chao Yuan
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Beijing Diabetes Institute, Beijing, China
| | - Mo-Ning Guo
- Beijing Municipal Health Commission Information Center, Beijing, China
| | - Zhong Xin
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.,Beijing Diabetes Institute, Beijing, China
| | - Guan-Jie Chen
- The Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
| | - Amy R Bentley
- The Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
| | - Lin Hua
- School of Biomedical Engineering, Capital Medical University, Beijing, China
| | - Jian-Peng Zheng
- Beijing Municipal Health Commission Information Center, Beijing, China
| | - Kenneth Ekoru
- The Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
| | - Jin-Kui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China .,Beijing Diabetes Institute, Beijing, China
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Abstract
This article summarizes clinical observations and management strategies in pediatric type 1 diabetes (T1D) during the coronavirus disease 2019 (COVID-19) pandemic. Despite initial fears that children with diabetes would, similar to adults with diabetes, be at risk for severe COVID-19, most pediatric patients with a history of T1D who developed COVID-19 had mild disease or were asymptomatic similar to their peers without diabetes. The article also summarizes the use of telemedicine to provide ongoing care for pediatric patients with T1D during the COVID-19 pandemic. Finally, the article highlights important lessons learned about management of pediatric diabetes during the COVID-19 pandemic.
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Faulkner CL, Luo YX, Isaacs S, Rawlinson WD, Craig ME, Kim KW. The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies. Rev Med Virol 2021; 31:1-14. [PMID: 33378601 PMCID: PMC8518965 DOI: 10.1002/rmv.2209] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/15/2022]
Abstract
Viruses are postulated as primary candidate triggers of islet autoimmunity (IA) and type 1 diabetes (T1D), based on considerable epidemiological and experimental evidence. Recent studies have investigated the association between all viruses (the 'virome') and IA/T1D using metagenomic next-generation sequencing (mNGS). Current associations between the early life virome and the development of IA/T1D were analysed in a systematic review and meta-analysis of human observational studies from Medline and EMBASE (published 2000-June 2020), without language restriction. Inclusion criteria were as follows: cohort and case-control studies examining the virome using mNGS in clinical specimens of children ≤18 years who developed IA/T1D. The National Health and Medical Research Council level of evidence scale and Newcastle-Ottawa scale were used for study appraisal. Meta-analysis for exposure to specific viruses was performed using random-effects models, and the strength of association was measured using odds ratios (ORs) and 95% confidence intervals (CIs). Eligible studies (one case-control, nine nested case-control) included 1,425 participants (695 cases, 730 controls) and examined IA (n = 1,023) or T1D (n = 402). Meta-analysis identified small but significant associations between IA and number of stool samples positive for all enteroviruses (OR 1.14, 95% CI 1.00-1.29, p = 0.05; heterogeneity χ2 = 1.51, p = 0.68, I2 = 0%), consecutive positivity for enteroviruses (1.55, 1.09-2.20, p = 0.01; χ2 = 0.19, p = 0.91, I2 = 0%) and number of stool samples positive specifically for enterovirus B (1.20, 1.01-1.42, p = 0.04; χ2 = 0.03, p = 0.86, I2 = 0%). Virome analyses to date have demonstrated associations between enteroviruses and IA that may be clinically significant. However, larger prospective mNGS studies with more frequent sampling and follow-up from pregnancy are required to further elucidate associations between early virus exposure and IA/T1D.
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Affiliation(s)
- Clare L. Faulkner
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Yi Xuan Luo
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - Sonia Isaacs
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
| | - William D. Rawlinson
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- School of Medical SciencesUniversity of New South WalesSydneyNew South WalesAustralia
- Faculty of ScienceSchool of Biotechnology and Biomolecular SciencesUniversity of New South WalesSydneyNew South WalesAustralia
| | - Maria E. Craig
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
- Institute of Endocrinology and DiabetesChildren's Hospital at WestmeadSydneyNew South WalesAustralia
- Discipline of Child and Adolescent HealthUniversity of SydneySydneyNew South WalesAustralia
| | - Ki Wook Kim
- School of Women's and Children's HealthUniversity of New South Wales Faculty of MedicineSydneyNew South WalesAustralia
- Serology and Virology DivisionNSW Health PathologyVirology Research LaboratoryPrince of Wales HospitalSydneyNew South WalesAustralia
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Isaacs SR, Foskett DB, Maxwell AJ, Ward EJ, Faulkner CL, Luo JYX, Rawlinson WD, Craig ME, Kim KW. Viruses and Type 1 Diabetes: From Enteroviruses to the Virome. Microorganisms 2021; 9:microorganisms9071519. [PMID: 34361954 PMCID: PMC8306446 DOI: 10.3390/microorganisms9071519] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/12/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022] Open
Abstract
For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.
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Affiliation(s)
- Sonia R. Isaacs
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Dylan B. Foskett
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Anna J. Maxwell
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Emily J. Ward
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Clare L. Faulkner
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - Jessica Y. X. Luo
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
| | - William D. Rawlinson
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Faculty of Medicine and Health, School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
- Faculty of Science, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia
| | - Maria E. Craig
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Institute of Endocrinology and Diabetes, Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
- Faculty of Medicine and Health, Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Ki Wook Kim
- Faculty of Medicine and Health, School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW 2031, Australia; (S.R.I.); (D.B.F.); (A.J.M.); (E.J.W.); (C.L.F.); (J.Y.X.L.); (W.D.R.); (M.E.C.)
- Virology Research Laboratory, Serology and Virology Division, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW 2031, Australia
- Correspondence: ; Tel.: +61-2-9382-9096
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10
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Dehghani Firouzabadi F, Dehghani Firouzabadi M, Moosaie F, Rafiee S, Esteghamati A. Type 1 diabetic manifestations in a young man triggered by COVID-19. Clin Case Rep 2021; 9:e04211. [PMID: 34178332 PMCID: PMC8212012 DOI: 10.1002/ccr3.4211] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/22/2021] [Accepted: 04/11/2021] [Indexed: 12/20/2022] Open
Abstract
COVID-19 could potentially lead to the progression of the course of undiagnosed type 1 diabetes in an infected individuals.
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Affiliation(s)
- Fatemeh Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC)Vali‐Asr HospitalSchool of MedicineTehran University of Medical SciencesTehranIran
- ENT and Head and Neck Research Center and DepartmentFive Senses Health Research InstituteIran University of Medical SciencesTehranIran
| | - Mohammad Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC)Vali‐Asr HospitalSchool of MedicineTehran University of Medical SciencesTehranIran
- ENT and Head and Neck Research Center and DepartmentFive Senses Health Research InstituteIran University of Medical SciencesTehranIran
| | - Fatemeh Moosaie
- Endocrinology and Metabolism Research Center (EMRC)Vali‐Asr HospitalSchool of MedicineTehran University of Medical SciencesTehranIran
| | - Saeedeh Rafiee
- ENT and Head and Neck Research Center and DepartmentFive Senses Health Research InstituteIran University of Medical SciencesTehranIran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC)Vali‐Asr HospitalSchool of MedicineTehran University of Medical SciencesTehranIran
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11
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Cinek O, Kramna L, Odeh R, Alassaf A, Ibekwe MAU, Ahmadov G, Elmahi BME, Mekki H, Lebl J, Abdullah MA. Eukaryotic viruses in the fecal virome at the onset of type 1 diabetes: A study from four geographically distant African and Asian countries. Pediatr Diabetes 2021; 22:558-566. [PMID: 33786936 DOI: 10.1111/pedi.13207] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/21/2020] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Studies of the fecal virome in type 1 diabetes (T1D) have been limited to populations of Europe and the United States. We therefore sought to characterize the stool virome in children after onset of T1D and in matched control subjects from four geographically distant African and Asian countries. METHODS Samples of stool were collected from 73 children and adolescents shortly after T1D onset (Azerbaijan 19, Jordan 20, Nigeria 14, Sudan 20) and 105 matched control subjects of similar age and locale. Metagenomic sequencing of the DNA and RNA virome was performed, and virus positivity was defined as more than 0.001% of reads of the sample. Selected viruses were also quantified using real-time PCR. Conditional logistic regression was used to model associations with eukaryotic virus positivity. RESULTS Signals of 387 different viral species were detected; at least one eukaryotic virus was detected in 71% case and 65% control samples. Neither of observed eukaryotic virus species or genera differed in frequency between children with T1D and controls. There was a suggestive association of the total count of different viral genera per sample between cases (1.45 genera) and controls (1.10 genera, OR 1.24, 95%CI 0.98-1.57), and an unplanned subanalysis suggested marginally more frequent endogenous retrovirus signal in cases (in 28.8% vs. in 8.6% controls, OR = 4.55, 95%CI 1.72-12). CONCLUSIONS No clear and consistent association with T1D was observed in the fecal viromes from four distant non-European populations. The finding of borderline associations of human endogenous retroviruses merits further exploration.
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Affiliation(s)
- Ondrej Cinek
- Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Lenka Kramna
- Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Rasha Odeh
- Department of Pediatrics, School of Medicine, University of Jordan, Amman, Jordan
| | - Abeer Alassaf
- Department of Pediatrics, School of Medicine, University of Jordan, Amman, Jordan
| | - Mary Ann Ugochi Ibekwe
- Department of Pediatrics, Federal Teaching Hospital Abakaliki, Ebonyi State University, Abakaliki, Nigeria
| | | | - Bashir Mukhtar Elwasila Elmahi
- Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.,Sudan Childhood Diabetes Center, Khartoum, Sudan
| | - Hanan Mekki
- Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Jan Lebl
- Department of Pediatrics, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Mohammed Ahmed Abdullah
- Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan.,Sudan Childhood Diabetes Center, Khartoum, Sudan
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12
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Khater S, Aouar A, Bensmain N, Bendedouche S, Chabni N, Hamdaoui H, Moussouni A, Moqaddem Z. Very High Incidence of Type 1 Diabetes Among Children Aged Under 15 Years in Tlemcen, Northwest Algeria (2015-2018). J Clin Res Pediatr Endocrinol 2021; 13:44-51. [PMID: 32938578 PMCID: PMC7947720 DOI: 10.4274/jcrpe.galenos.2020.2020.0073] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/07/2020] [Indexed: 02/02/2023] Open
Abstract
Objective In Algeria, there is a lack of epidemiological data concerning childhood type 1 diabetes (T1D). The International Diabetes Federation estimated in 2019 that Algeria ranked 7th among countries with the highest prevalence of T1D. This study aimed to determine the incidence of T1D in children <15 years, living in Tlemcen in Northwest Algeria. Methods A retrospective study using data from children (<15 years) who have been diagnosed with T1D in Tlemcen between 2015 and 2018, using the two-source capture–recapture method to estimate the completeness of ascertainment (%). Total average incidences, by sex, by onset age group, and by season of onset were calculated per 100,000 and per year. Results During the study period, 437 new cases of T1D were registered, among them, 233 boys and 204 girls, with a sex ratio of 1.14. The average annual incidence rate of childhood T1D was 38.5/100,000 with a 95% confidence interval (CI): 35.20-41.79; boys: 40.51, 95% CI: 38.16-42.85; girls: 36.49, 95% CI: 34.17-38.80. Overall incidence rates in 2015, 2016, 2017 and 2018 were respectively 36.6 (95% CI: 33.72-39.48), 38.7 (95% CI: 35.43-41.97), 39.3 (95% CI: 35.97-42.62) and 39.5 (95% CI: 36.12-42.87)/100,000. Newly diagnosed children were more likely to present in winter and autumn. Ketoacidosis at diagnosis was diagnosed in 29.2%. Conclusion The mean incidence of childhood T1D in Tlemcen was 38.5/100,000, this incidence is in the “extremely high” category of the World Health Organization DiaMond project classification of diabetes giving this region a very high risk.
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Affiliation(s)
- Sarra Khater
- Abou Beker Belkaid University, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, Tlemcen, Algeria
| | - Ammaria Aouar
- Abou Beker Belkaid University, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, Tlemcen, Algeria
| | - Nawel Bensmain
- Abou Beker Belkaid University, Statistics and Random Models Laboratory, Tlemcen, Algeria
| | - Salih Bendedouche
- Abou Beker Belkaid University, Tlemcen University Hospital, Department of Pediatrics, Tlemcen, Algeria
| | - Nafissa Chabni
- Abou Beker Belkaid University, Tlemcen University Hospital, Department of Epidemiology, Tlemcen, Algeria
| | - Houari Hamdaoui
- Abou Beker Belkaid University, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, Tlemcen, Algeria
| | | | - Zakarya Moqaddem
- Abou Beker Belkaid University, Valorisation of Human Actions for the Protection of the Environment and Application in Public Health Laboratory, Tlemcen, Algeria
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13
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Battaglia M, Buckner JH, Levings MK, Richardson SJ, Wong FS, Tree TI. Identifying the 'Achilles heel' of type 1 diabetes. Clin Exp Immunol 2021; 204:167-178. [PMID: 33368173 DOI: 10.1111/cei.13570] [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: 10/28/2020] [Revised: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/22/2022] Open
Abstract
When Thetis dipped her son Achilles into the River Styx to make him immortal, she held him by the heel, which was not submerged, and thus created a weak spot that proved deadly for Achilles. Millennia later, Achilles heel is part of today's lexicon meaning an area of weakness or a vulnerable spot that causes failure. Also implied is that an Achilles heel is often missed, forgotten or under-appreciated until it is under attack, and then failure is fatal. Paris killed Achilles with an arrow 'guided by the Gods'. Understanding the pathogenesis of type 1 diabetes (T1D) in order to direct therapy for prevention and treatment is a major goal of research into T1D. At the International Congress of the Immunology of Diabetes Society, 2018, five leading experts were asked to present the case for a particular cell/element that could represent 'the Achilles heel of T1D'. These included neutrophils, B cells, CD8+ T cells, regulatory CD4+ T cells, and enteroviruses, all of which have been proposed to play an important role in the pathogenesis of type 1 diabetes. Did a single entity emerge as 'the' Achilles heel of T1D? The arguments are summarized here, to make this case.
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Affiliation(s)
- M Battaglia
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy
| | - J H Buckner
- Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - M K Levings
- BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - S J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - F S Wong
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - T I Tree
- Department of Immunobiology, School of Immunology and Microbial Sciences (SIMS), King's College London, London, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London, UK
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14
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Wang K, Ye F, Chen Y, Xu J, Zhao Y, Wang Y, Lan T. Association Between Enterovirus Infection and Type 1 Diabetes Risk: A Meta-Analysis of 38 Case-Control Studies. Front Endocrinol (Lausanne) 2021; 12:706964. [PMID: 34557158 PMCID: PMC8453141 DOI: 10.3389/fendo.2021.706964] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/09/2021] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The association between enterovirus infection and type 1 diabetes (T1D) is controversial, and this meta-analysis aimed to explore the correlation. METHODS PubMed, Embase, Web of Science, and Cochrane Database were searched from inception to April 2020. Studies were included if they could provide sufficient information to calculate odds ratios and 95% confidence intervals. All analyses were performed using STATA 15.1. RESULTS Thirty-eight studies, encompassing 5921 subjects (2841 T1D patients and 3080 controls), were included. The pooled analysis showed that enterovirus infection was associated with T1D (P < 0.001). Enterovirus infection was correlated with T1D in the European (P < 0.001), African (P = 0.002), Asian (P = 0.001), Australian (P = 0.011), and Latin American (P = 0.002) populations, but no conclusion could be reached for North America. The association between enterovirus infection and T1D was detected in blood and tissue samples (both P < 0.001); no association was found in stool samples. CONCLUSION Our findings suggest that enterovirus infection is associated with T1D.
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Affiliation(s)
- Kan Wang
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
- *Correspondence: Kan Wang, ; Fei Ye,
| | - Fei Ye
- First Department of Neurology, Affiliated Jinhua Hospital, Jinhua Municipal Central Hospital, Zhejiang University School of Medicine, Jinhua, China
- *Correspondence: Kan Wang, ; Fei Ye,
| | - Yong Chen
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Jianxin Xu
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Yufang Zhao
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Yeping Wang
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
| | - Tian Lan
- Jinhua Maternity and Child Health Care Hospital, Jinhua, China
- Jinhua Women and Children’s Hospital, Jinhua, China
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15
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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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16
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Nyalwidhe JO, Jurczyk A, Satish B, Redick S, Qaisar N, Trombly MI, Vangala P, Racicot R, Bortell R, Harlan DM, Greiner DL, Brehm MA, Nadler JL, Wang JP. Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge. Microorganisms 2020; 8:microorganisms8020295. [PMID: 32093375 PMCID: PMC7074978 DOI: 10.3390/microorganisms8020295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 02/14/2020] [Accepted: 02/18/2020] [Indexed: 01/04/2023] Open
Abstract
Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant β-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived β (SC-β) cells are insulin-producing cell clusters that closely resemble native β cells. To better understand the events precipitated by enteroviral infection of β cells, we investigated transcriptional and proteomic changes in SC-β cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-β cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following infection, and combined transcriptional and proteomic analysis revealed activation of innate immune pathways, including type I interferon (IFN), IFN-stimulated genes, nuclear factor-kappa B (NF-κB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-β cells was impaired. These transcriptional, proteomic, and functional findings are in agreement with responses in primary human islets infected with CVB ex vivo. Human SC-β cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-β cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.
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Affiliation(s)
- Julius O. Nyalwidhe
- Department of Microbiology and Molecular Cell Biology and Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (J.O.N.); (J.L.N.)
| | - Agata Jurczyk
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Basanthi Satish
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Sambra Redick
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Natasha Qaisar
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Melanie I. Trombly
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Pranitha Vangala
- Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA;
| | - Riccardo Racicot
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - David M. Harlan
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
| | - Dale L. Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Michael A. Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (A.J.); (S.R.); (R.B.); (D.L.G.); (M.A.B.)
| | - Jerry L. Nadler
- Department of Microbiology and Molecular Cell Biology and Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23501, USA; (J.O.N.); (J.L.N.)
- Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA
| | - Jennifer P. Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA; (B.S.); (N.Q.); (M.I.T.); (R.R.); (D.M.H.)
- Correspondence: ; Tel.: +01-508-856-8414
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17
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Bergamin CS, Pérez-Hurtado E, Oliveira L, Gabbay M, Piveta V, Bittencourt C, Russo D, Carmona RDC, Sato M, Dib SA. Enterovirus Neutralizing Antibodies, Monocyte Toll Like Receptors Expression and Interleukin Profiles Are Similar Between Non-affected and Affected Siblings From Long-Term Discordant Type 1 Diabetes Multiplex-Sib Families: The Importance of HLA Background. Front Endocrinol (Lausanne) 2020; 11:555685. [PMID: 33071971 PMCID: PMC7538605 DOI: 10.3389/fendo.2020.555685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 08/14/2020] [Indexed: 12/15/2022] Open
Abstract
Enteroviruses are main candidates among environmental agents in the development of type 1 diabetes (T1D). However, the relationship between virus and the immune system response during T1D pathogenesis is heterogeneous. This is an interesting paradigm and the search for answers would help to highlight the role of viral infection in the etiology of T1D. The current data is a cross-sectional study of affected and non-affected siblings from T1D multiplex-sib families to analyze associations among T1D, genetic, islet autoantibodies and markers of innate immunity. We evaluated the prevalence of anti-virus antibodies (Coxsackie B and Echo) and its relationships with human leukocyte antigen (HLA) class II alleles, TLR expression (monocytes), serum cytokine profile and islet β cell autoantibodies in 51 individuals (40 T1D and 11 non-affected siblings) from 20 T1D multiplex-sib families and 54 healthy control subjects. The viral antibody profiles were similar among all groups, except for antibodies against CVB2, which were more prevalent in the non-affected siblings. TLR4 expression was higher in the T1D multiplex-sib family's members than in the control subjects. TLR4 expression showed a positive correlation with CBV2 antibody prevalence (rS: 0.45; P = 0.03), CXCL8 (rS: 0.65, P = 0.002) and TNF-α (rS: 0.5, P = 0.01) serum levels in both groups of T1D multiplex-sib family. Furthermore, within these families, there was a positive correlation between HLA class II alleles associated with high risk for T1D and insulinoma-associated protein 2 autoantibody (IA-2A) positivity (odds ratio: 38.8; P = 0.021). However, the HLA protective haplotypes against T1D prevalence was higher in the non-affected than the affected siblings. This study shows that although the prevalence of viral infection is similar among healthy individuals and members from the T1D multiplex-sib families, the innate immune response is higher in the affected and in the non-affected siblings from these families than in the healthy controls. However, autoimmunity against β-islet cells and an absence of protective HLA alleles were only observed in the T1D multiplex-sib members with clinical disease, supporting the importance of the genetic background in the development of T1D and heterogeneity of the interaction between environmental factors and disease pathogenesis despite the high genetic diversity of the Brazilian population.
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Affiliation(s)
- Carla Sanchez Bergamin
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
- *Correspondence: Carla Sanchez Bergamin
| | - Elizabeth Pérez-Hurtado
- Immunology Division, Microbiology, Immunology and Parasitological Department, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Luanda Oliveira
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Monica Gabbay
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Valdecira Piveta
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Célia Bittencourt
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
| | - Denise Russo
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Rita de Cássia Carmona
- Enteric Diseases Laboratory, Virology Center From Instituto Adolfo Lutz, São Paulo, Brazil
| | - Maria Sato
- Laboratory of Dermatology and Immunodeficiencies, LIM-56, Department of Dermatology and Tropical Medicine Institute of São Paulo, Faculdade de Medicina - Universidade de São Paulo, São Paulo, Brazil
| | - Sergio A. Dib
- Endocrinology Division, Department of Medicine, Diabetes Center, Escola Paulista de Medicina - Universidade Federal de São Paulo, São Paulo, Brazil
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18
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Lalwani A, Warren J, Liuwantara D, Hawthorne WJ, O'Connell PJ, Gonzalez FJ, Stokes RA, Chen J, Laybutt DR, Craig ME, Swarbrick MM, King C, Gunton JE. β Cell Hypoxia-Inducible Factor-1α Is Required for the Prevention of Type 1 Diabetes. Cell Rep 2019; 27:2370-2384.e6. [PMID: 31116982 PMCID: PMC6661122 DOI: 10.1016/j.celrep.2019.04.086] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 01/31/2019] [Accepted: 04/18/2019] [Indexed: 12/28/2022] Open
Abstract
The development of autoimmune disease type 1 diabetes (T1D) is determined by both genetic background and environmental factors. Environmental triggers include RNA viruses, particularly coxsackievirus (CV), but how they induce T1D is not understood. Here, we demonstrate that deletion of the transcription factor hypoxia-inducible factor-1α (HIF-1α) from β cells increases the susceptibility of non-obese diabetic (NOD) mice to environmentally triggered T1D from coxsackieviruses and the β cell toxin streptozotocin. Similarly, knockdown of HIF-1α in human islets leads to a poorer response to coxsackievirus infection. Studies in coxsackievirus-infected islets demonstrate that lack of HIF-1α leads to impaired viral clearance, increased viral load, inflammation, pancreatitis, and loss of β cell mass. These findings show an important role for β cells and, specifically, lack of β cell HIF-1α in the development of T1D. These data suggest new strategies for the prevention of T1D.
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Affiliation(s)
- Amit Lalwani
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Joanna Warren
- Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - David Liuwantara
- National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Wayne J Hawthorne
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Philip J O'Connell
- National Pancreas Transplant Unit (NPTU), Westmead Hospital, Sydney, NSW, Australia
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, Bethesda, MD, USA
| | - Rebecca A Stokes
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
| | - Jennifer Chen
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia
| | - D Ross Laybutt
- Islet Biology, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Maria E Craig
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; The Children's Hospital at Westmead, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Kensington, NSW, Australia
| | - Michael M Swarbrick
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Kensington, NSW, Australia
| | - Cecile King
- Mucosal Autoimmunity, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Jenny E Gunton
- Center for Diabetes, Obesity, and Endocrinology (CDOE), The Westmead Institute for Medical Research (WIMR), The University of Sydney, Sydney, NSW, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia.
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19
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Patterson CC, Harjutsalo V, Rosenbauer J, Neu A, Cinek O, Skrivarhaug T, Rami-Merhar B, Soltesz G, Svensson J, Parslow RC, Castell C, Schoenle EJ, Bingley PJ, Dahlquist G, Jarosz-Chobot PK, Marčiulionytė D, Roche EF, Rothe U, Bratina N, Ionescu-Tirgoviste C, Weets I, Kocova M, Cherubini V, Rojnic Putarek N, deBeaufort CE, Samardzic M, Green A. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia 2019; 62:408-417. [PMID: 30483858 DOI: 10.1007/s00125-018-4763-3] [Citation(s) in RCA: 299] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 09/28/2018] [Indexed: 12/17/2022]
Abstract
AIMS/HYPOTHESIS Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. METHODS Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. RESULTS Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. CONCLUSIONS/INTERPRETATION Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.
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Affiliation(s)
- Christopher C Patterson
- Centre for Public Health and UKCRC Centre of Excellence for Public Health Northern Ireland, Queen's University Belfast, Grosvenor Road, Belfast, BT12 6BJ, UK.
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
| | - Joachim Rosenbauer
- German Diabetes Center, Institute of Biometrics and Epidemiology, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Andreas Neu
- University Children's Hospital, Tübingen, Germany
| | - Ondrej Cinek
- Department of Pediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czechia
| | - Torild Skrivarhaug
- Division of Adolescent and Paediatric Medicine, Institute of Clinical Medicine, University of Oslo, Oslo University Hospital, Oslo, Norway
| | - Birgit Rami-Merhar
- Department of Pediatric and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Gyula Soltesz
- Department of Paediatrics, Medical School, University of Pécs, Pécs, Hungary
| | - Jannet Svensson
- Department of Paediatrics and Adolescent Medicine, Copenhagen University Hospital, Herlev and Gentofte, Denmark
| | - Roger C Parslow
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK
| | - Conxa Castell
- Department of Health, Government of Catalonia, Barcelona, Spain
| | - Eugen J Schoenle
- Department of Endocrinology and Diabetology, University Children's Hospital, Zurich, Switzerland
| | - Polly J Bingley
- Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, UK
| | - Gisela Dahlquist
- Department of Clinical Sciences, Paediatrics, University of Umeå, Umeå, Sweden
| | | | - Dalė Marčiulionytė
- Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania
- Institute of Microbiology and Virology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Edna F Roche
- Department of Paediatrics, Tallaght University Hospital, Trinity College Dublin, The University of Dublin, Dublin, Ireland
| | - Ulrike Rothe
- Health Sciences/Public Health, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Natasa Bratina
- Diabetes and Metabolic Diseases, University Children's Hospital, Department of Endocrinology, Ljubljana, Slovenia
| | | | - Ilse Weets
- Diabetes Research Center and Laboratory of Clinical Biology, Brussels Free University-Vrije Universiteit Brussel, University Hospital Brussels-Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Mirjana Kocova
- Department of Endocrinology and Genetics, University Children's Hospital, Skopje, Republic of Macedonia
| | | | - Natasa Rojnic Putarek
- Department of Pediatric Endocrinology and Diabetes, University Hospital Zagreb, Zagreb, Croatia
| | - Carine E deBeaufort
- Department of Paediatric Diabetes and Endocrinology, University of Luxembourg, Luxembourg, Luxembourg
| | - Mira Samardzic
- Department of Endocrinology, Institute for Sick Children, Podgorica, Montenegro
| | - Anders Green
- Odense Patient data Exploratory Network (OPEN), Odense University Hospital/Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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20
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Alper CA, Larsen CE, Trautwein MR, Alford DR. A stochastic epigenetic Mendelian oligogenic disease model for type 1 diabetes. J Autoimmun 2018; 96:123-133. [PMID: 30309752 DOI: 10.1016/j.jaut.2018.09.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 09/12/2018] [Indexed: 01/14/2023]
Abstract
The incidence of type 1 diabetes (T1D) and some other complex diseases is increasing. The cause has been attributed to an undefined changing environment. We examine the role of the environment (or any changing non-genetic mechanism) in causing the rising incidence, and find much evidence against it: 1) Dizygotic twin T1D concordance is the same as siblings of patients in general; 2) If the environment is responsible for both the discordance among identical twins of patients with T1D and its rising incidence, the twin concordance rate should be rising, but it is not; 3) Migrants from high-to low-incidence countries continue to have high-incidence children; 4) TID incidence among the offspring of two T1D parents is identical to the monozygotic twin rate. On the other hand, genetic association studies of T1D have revealed strong susceptibility in the major histocompatibility complex and many optional additive genes of small effect throughout the human genome increasing T1D risk. We have, from an analysis of previously published family studies, developed a stochastic epigenetic Mendelian oligogenic (SEMO) model consistent with published observations. The model posits a few required recessive causal genes with incomplete penetrance explaining virtually all of the puzzling features of T1D, including its rising incidence and the specific low T1D incidence rates among first-degree relatives of patients. Since historic selection against any causal gene could prevent T1D, we postulate that the rising incidence is because of increasing population mixing of parents from some previously isolated populations that had selected against different causal genes.
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Affiliation(s)
- Chester A Alper
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
| | - Charles E Larsen
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA; Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA
| | - Michael R Trautwein
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
| | - Dennis R Alford
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, USA
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21
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Abstract
PURPOSE OF REVIEW To provide an overview of studies that have detected enteroviruses (EV) in samples from people with type 1 diabetes (T1D), the techniques they have used, and which challenges they have encountered. RECENT FINDINGS Recent studies have detected EVs in serum, blood, stools, nasal swabs, and pancreas of people with T1D before or around clinical onset of disease, indicating that an association between EV infections and T1D exists. However, definitive evidence for its role as disease triggers is lacking. Recent access to human samples is starting to provide the necessary tools to define their role in disease pathogenesis. Emerging evidence suggests that chronic infections take place in the pancreas of diabetic donors. However, the development of sensitive techniques able to detect low amounts of viral protein and RNA still constitute a major challenge for the field. New evidence at the protein, RNA, and host immune response level suggests a role for EV infections in the development of autoimmunity. In the upcoming years, new technologies, collaborative efforts, and therapeutic interventions are likely to find a definitive answer for their role in disease pathogenesis.
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Affiliation(s)
- Teresa Rodriguez-Calvo
- Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Institute of Diabetes Research, Ingolstaedter Landstrasse 1, 85764, Munich-Neuherberg, Germany.
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22
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Weng J, Zhou Z, Guo L, Zhu D, Ji L, Luo X, Mu Y, Jia W. Incidence of type 1 diabetes in China, 2010-13: population based study. BMJ 2018; 360:j5295. [PMID: 29298776 PMCID: PMC5750780 DOI: 10.1136/bmj.j5295] [Citation(s) in RCA: 202] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To estimate the incidence of type 1 diabetes in all age groups in China during 2010-13. DESIGN Population based, registry study using data from multiple independent sources. SETTING National registration system in all 505 hospitals providing diabetes care, and communities of patients with diabetes in 13 areas across China, covering more than 133 million person years at risk, approximately 10% of the whole population. PARTICIPANTS 5018 people of all ages with newly diagnosed type 1 diabetes and resident in the study areas from 1 January 2010 to 31 December 2013. MAIN OUTCOME MEASURES Incidence of type 1 diabetes per 100 000 person years by age, sex, and study area. Type 1 diabetes was doctor diagnosed and further validated by onsite follow-up. Completeness of case ascertainment was assessed using the capture mark recapture method. RESULTS 5018 cases of newly diagnosed type 1 diabetes were ascertained: 1239 participants were aged <15 years, 1799 were aged 15-29 years, and 1980 were aged ≥30 years. The proportion of new onset cases in participants aged ≥20 years was 65.3%. The estimated incidence of type 1 diabetes per 100 000 persons years for all ages in China was 1.01 (95% confidence interval 0.18 to 1.84). Incidence per 100 000 persons years by age group was 1.93 (0.83 to 3.03) for 0-14 years, 1.28 (0.45 to 2.11) for 15-29 years, and 0.69 (0.00 to 1.51) for ≥30 years, with a peak in age group 10-14 years. The incidence in under 15s was positively correlated with latitude (r=0.88, P<0.001), although this association was not observed in age groups 15-29 years or ≥30 years. CONCLUSION Most cases of new onset type 1 diabetes in China occurred among adults. The incidence of type 1 diabetes in Chinese children was among the lowest reported in the study.
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Awadalla NJ, Hegazy AA, Abd El-Salam M, Elhady M. Environmental Factors Associated with Type 1 Diabetes Development: A Case Control Study in Egypt. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2017; 14:E615. [PMID: 28590451 PMCID: PMC5486301 DOI: 10.3390/ijerph14060615] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 06/01/2017] [Accepted: 06/03/2017] [Indexed: 01/14/2023]
Abstract
Uncertainty still exists regarding the role of some environmental risk in the development of type 1 diabetes mellitus (T1DM) both globally and in Egypt. The objective here was to explore the potential environmental risk factors associated with the development of T1DM among children in Egypt. A case-controlled study of 204 T1DM children and an equal number of age and sex-matched controls was conducted in Assiut, Egypt. Data regarding the parental, gestational, neonatal, and childhood possible risk factors for T1DM were evaluated. The final sex adjusted multivariable logistic regression model revealed that the risk for T1DM was significantly higher among rural residents (aOR = 2.03, 95% CI: 1.30-4.25), those with parental history of T1DM (aOR = 9.03, 95% CI: 1.02-83.32), birth through cesarean section (aOR = 2.13, 95% CI: 1.09-5.03), and having history of early introduction of cow milk in the first year of life (aOR = 19.49, 95% CI: 8.73-45.53). On the other hand, a protective effect was observed between at least six months' breastfeeding, vitamin D supplementation in the first year of life, high physical activity, and the development of T1DM. Educational programs should be adopted to improve awareness and knowledge of the parents to avoid the increased risk factors and encourage protective practices.
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Affiliation(s)
- Nabil J Awadalla
- Department of Family and Community Medicine, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia.
- Department of Community Medicine, Faculty of Medicine, Mansoura University, Mansoura 3551, Egypt.
| | - Amal A Hegazy
- Department of Family and Community Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
- Department of Community and Occupational Medicine, Faculty of Medicine (for girls), Al-Azhar University, Cairo 11651, Egypt.
| | - Manal Abd El-Salam
- Department of Pediatrics, Faculty of Medicine (for girls), Al-Azhar University, Cairo 11651, Egypt.
| | - Marwa Elhady
- Department of Pediatrics, Faculty of Medicine (for girls), Al-Azhar University, Cairo 11651, Egypt.
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24
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Rehni AK, Liu A, Perez-Pinzon MA, Dave KR. Diabetic aggravation of stroke and animal models. Exp Neurol 2017; 292:63-79. [PMID: 28274862 PMCID: PMC5400679 DOI: 10.1016/j.expneurol.2017.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 02/03/2017] [Accepted: 03/03/2017] [Indexed: 12/16/2022]
Abstract
Cerebral ischemia in diabetics results in severe brain damage. Different animal models of cerebral ischemia have been used to study the aggravation of ischemic brain damage in the diabetic condition. Since different disease conditions such as diabetes differently affect outcome following cerebral ischemia, the Stroke Therapy Academic Industry Roundtable (STAIR) guidelines recommends use of diseased animals for evaluating neuroprotective therapies targeted to reduce cerebral ischemic damage. The goal of this review is to discuss the technicalities and pros/cons of various animal models of cerebral ischemia currently being employed to study diabetes-related ischemic brain damage. The rational use of such animal systems in studying the disease condition may better help evaluate novel therapeutic approaches for diabetes related exacerbation of ischemic brain damage.
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Affiliation(s)
- Ashish K Rehni
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Allen Liu
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Kunjan R Dave
- Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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25
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Newby BN, Mathews CE. Type I Interferon Is a Catastrophic Feature of the Diabetic Islet Microenvironment. Front Endocrinol (Lausanne) 2017; 8:232. [PMID: 28959234 PMCID: PMC5604085 DOI: 10.3389/fendo.2017.00232] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/25/2017] [Indexed: 01/01/2023] Open
Abstract
A detailed understanding of the molecular pathways and cellular interactions that result in islet beta cell (β cell) destruction is essential for the development and implementation of effective therapies for prevention or reversal of type 1 diabetes (T1D). However, events that define the pathogenesis of human T1D have remained elusive. This gap in our knowledge results from the complex interaction between genetics, the immune system, and environmental factors that precipitate T1D in humans. A link between genetics, the immune system, and environmental factors are type 1 interferons (T1-IFNs). These cytokines are well known for inducing antiviral factors that limit infection by regulating innate and adaptive immune responses. Further, several T1D genetic risk loci are within genes that link innate and adaptive immune cell responses to T1-IFN. An additional clue that links T1-IFN to T1D is that these cytokines are a known constituent of the autoinflammatory milieu within the pancreas of patients with T1D. The presence of IFNα/β is correlated with characteristic MHC class I (MHC-I) hyperexpression found in the islets of patients with T1D, suggesting that T1-IFNs modulate the cross-talk between autoreactive cytotoxic CD8+ T lymphocytes and insulin-producing pancreatic β cells. Here, we review the evidence supporting the diabetogenic potential of T1-IFN in the islet microenvironment.
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Affiliation(s)
- Brittney N. Newby
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, United States
- *Correspondence: Clayton E. Mathews,
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26
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Isaacs SR, Wang J, Kim KW, Yin C, Zhou L, Mi QS, Craig ME. MicroRNAs in Type 1 Diabetes: Complex Interregulation of the Immune System, β Cell Function and Viral Infections. Curr Diab Rep 2016; 16:133. [PMID: 27844276 DOI: 10.1007/s11892-016-0819-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Since the discovery of the first mammalian microRNA (miRNA) more than two decades ago, a plethora of miRNAs has been identified in humans, now amounting to more than 2500. Essential for post-transcriptional regulation of gene networks integral for developmental pathways and immune response, it is not surprising that dysregulation of miRNAs is often associated with the aetiology of complex diseases including cancer, diabetes and autoimmune disorders. Despite massive expansion of small RNA studies and extensive investigation in diverse disease contexts, the role of miRNAs in type 1 diabetes has only recently been explored. Key studies using human islets have recently implicated virus-induced miRNA dysregulation as a pivotal mechanism of β cell destruction, while the interplay between miRNAs, the immune system and β cell survival has been illustrated in studies using animal and cellular models of disease. The role of specific miRNAs as major players in immune system homeostasis highlights their exciting potential as therapeutics and prognostic biomarkers of type 1 diabetes.
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Affiliation(s)
- Sonia R Isaacs
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
- UNSW and POWH Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, 2031, Australia
| | - Jie Wang
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Dermatology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Ki Wook Kim
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia
- UNSW and POWH Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, 2031, Australia
| | - Congcong Yin
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Dermatology, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Li Zhou
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Dermatology, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Qing Sheng Mi
- Henry Ford Immunology Program, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Dermatology, Henry Ford Health System, Detroit, MI, 48202, USA
- Department of Internal Medicine, Henry Ford Health System, Detroit, MI, 48202, USA
| | - Maria E Craig
- School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia.
- UNSW and POWH Virology Research Laboratory, Prince of Wales Hospital, Sydney, NSW, 2031, Australia.
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, 2145, Australia.
- Discipline of Child and Adolescent Health, University of Sydney, Sydney, NSW, 2006, Australia.
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27
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Abstract
Type 1 diabetes is a multifactorial disease in which genetic and environmental factors play a key role. The triggering event is still obscure, and so are many of the immune events that follow. In this brief review, we discuss the possible role of potential environmental factors and which triggers are believed to have a role in the disease. In addition, as the disease evolves, beta cells are lost and this occurs in a very heterogeneous fashion. Our knowledge of how beta cell mass declines and our view of the disease’s pathogenesis are also debated. We highlight the major hallmarks of disease, among which are MHC-I (major histocompatibility complex class I) expression and insulitis. The dependence versus independence of antigen for the immune infiltrate is also discussed, as both the influence from bystander T cells and the formation of neo-epitopes through post-translational modifications are thought to influence the course of the disease. As human studies are proliferating, our understanding of the disease’s pathogenesis will increase exponentially. This article aims to shed light on some of the burning questions in type 1 diabetes research.
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Affiliation(s)
- Gustaf Christoffersson
- Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, 92037, USA
| | - Teresa Rodriguez-Calvo
- Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, 92037, USA
| | - Matthias von Herrath
- Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, 92037, USA; Novo Nordisk Diabetes Research & Development Center, Seattle, Washington, 98109, USA
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28
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Sánchez-Zamora YI, Juarez-Avelar I, Vazquez-Mendoza A, Hiriart M, Rodriguez-Sosa M. Altered Macrophage and Dendritic Cell Response in Mif-/- Mice Reveals a Role of Mif for Inflammatory-Th1 Response in Type 1 Diabetes. J Diabetes Res 2016; 2016:7053963. [PMID: 27699180 PMCID: PMC5028830 DOI: 10.1155/2016/7053963] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 07/10/2016] [Indexed: 12/13/2022] Open
Abstract
Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif-/- or wild-type (Wt) BALB/c mice. We found that Mif-/- mice treated with STZ (Mif-/-STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif-/-STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif-/-STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif-/-STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM.
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Affiliation(s)
- Yuriko Itzel Sánchez-Zamora
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Imelda Juarez-Avelar
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | | | - Marcia Hiriart
- Departamento de Neurodesarrollo y Fisiología, Instituto de Fisiología Celular, UNAM, 04510 Coyoacán, MEX, Mexico
| | - Miriam Rodriguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores (FES) Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
- *Miriam Rodriguez-Sosa:
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29
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Bian X, Wallstrom G, Davis A, Wang J, Park J, Throop A, Steel J, Yu X, Wasserfall C, Schatz D, Atkinson M, Qiu J, LaBaer J. Immunoproteomic Profiling of Antiviral Antibodies in New-Onset Type 1 Diabetes Using Protein Arrays. Diabetes 2016; 65:285-96. [PMID: 26450993 PMCID: PMC4686945 DOI: 10.2337/db15-0179] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 10/01/2015] [Indexed: 12/25/2022]
Abstract
The rapid rise in the incidence of type 1 diabetes (T1D) suggests the involvement of environmental factors including viral infections. We evaluated the association between viral infections and T1D by profiling antiviral antibodies using a high-throughput immunoproteomics approach in patients with new-onset T1D. We constructed a viral protein array comprising the complete proteomes of seven viruses associated with T1D and open reading frames from other common viruses. Antibody responses to 646 viral antigens were assessed in 42 patients with T1D and 42 age- and sex-matched healthy control subjects (mean age 12.7 years, 50% males). Prevalence of antiviral antibodies agreed with known infection rates for the corresponding virus based on epidemiological studies. Antibody responses to Epstein-Barr virus (EBV) were significantly higher in case than control subjects (odds ratio 6.6; 95% CI 2.0-25.7), whereas the other viruses showed no differences. The EBV and T1D association was significant in both sex and age subgroups (≤12 and >12 years), and there was a trend toward early EBV infections among the case subjects. These results suggest a potential role for EBV in T1D development. We believe our innovative immunoproteomics platform is useful for understanding the role of viral infections in T1D and other disorders where associations between viral infection and disease are unclear.
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Affiliation(s)
- Xiaofang Bian
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Garrick Wallstrom
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Amy Davis
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Jie Wang
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Jin Park
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Andrea Throop
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Jason Steel
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Xiaobo Yu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Clive Wasserfall
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Desmond Schatz
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL
| | - Mark Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Ji Qiu
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
| | - Joshua LaBaer
- Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ
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Abstract
Type 1 diabetes (T1D) results from genetic predisposition and environmental factors leading to the autoimmune destruction of pancreatic beta cells. Recently, a rapid increase in the incidence of childhood T1D has been observed worldwide; this is too fast to be explained by genetic factors alone, pointing to the spreading of environmental factors linked to the disease. Enteroviruses (EVs) are perhaps the most investigated environmental agents in relationship to the pathogenesis of T1D. While several studies point to the likelihood of such correlation, epidemiological evidence in its support is inconclusive or in some instances even against it. Hence, it is still unknown if and how EVs are involved in the development of T1D. Here we review recent findings concerning the biology of EV in beta cells and the potential implications of this knowledge for the understanding of beta cell dysfunction and autoimmune destruction in T1D.
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Affiliation(s)
- Antje Petzold
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Michele Solimena
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- />Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Klaus-Peter Knoch
- />Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Fetscherstr.74, 01307 Dresden, Germany
- />German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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31
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Insel RA, Dunne JL, Atkinson MA, Chiang JL, Dabelea D, Gottlieb PA, Greenbaum CJ, Herold KC, Krischer JP, Lernmark Å, Ratner RE, Rewers MJ, Schatz DA, Skyler JS, Sosenko JM, Ziegler AG. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 2015; 38:1964-74. [PMID: 26404926 PMCID: PMC5321245 DOI: 10.2337/dc15-1419] [Citation(s) in RCA: 673] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Insights from prospective, longitudinal studies of individuals at risk for developing type 1 diabetes have demonstrated that the disease is a continuum that progresses sequentially at variable but predictable rates through distinct identifiable stages prior to the onset of symptoms. Stage 1 is defined as the presence of β-cell autoimmunity as evidenced by the presence of two or more islet autoantibodies with normoglycemia and is presymptomatic, stage 2 as the presence of β-cell autoimmunity with dysglycemia and is presymptomatic, and stage 3 as onset of symptomatic disease. Adoption of this staging classification provides a standardized taxonomy for type 1 diabetes and will aid the development of therapies and the design of clinical trials to prevent symptomatic disease, promote precision medicine, and provide a framework for an optimized benefit/risk ratio that will impact regulatory approval, reimbursement, and adoption of interventions in the early stages of type 1 diabetes to prevent symptomatic disease.
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Affiliation(s)
| | | | - Mark A Atkinson
- UF Diabetes Institute, University of Florida, Gainesville, FL
| | | | - Dana Dabelea
- Colorado School of Public Health, University of Colorado, Denver, CO
| | - Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO
| | | | - Kevan C Herold
- Department of Immunobiology, Yale School of Medicine, New Haven, CT
| | - Jeffrey P Krischer
- Department of Pediatrics, Pediatric Epidemiology Center, Morsani College of Medicine, University of South Florida, Tampa, FL
| | - Åke Lernmark
- Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden
| | | | - Marian J Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO
| | | | - Jay S Skyler
- Diabetes Research Institute, University of Miami, Miami, FL
| | - Jay M Sosenko
- Diabetes Research Institute, University of Miami, Miami, FL
| | - Anette-G Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany
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Bian X, Wiktor P, Kahn P, Brunner A, Khela A, Karthikeyan K, Barker K, Yu X, Magee M, Wasserfall CH, Gibson D, Rooney ME, Qiu J, LaBaer J. Antiviral antibody profiling by high-density protein arrays. Proteomics 2015; 15:2136-45. [PMID: 25758251 PMCID: PMC4545592 DOI: 10.1002/pmic.201400612] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Revised: 02/12/2015] [Accepted: 03/07/2015] [Indexed: 12/14/2022]
Abstract
Viral infections elicit antiviral antibodies and have been associated with various chronic diseases. Detection of these antibodies can facilitate diagnosis, treatment of infection, and understanding of the mechanisms of virus-associated diseases. In this work, we assayed antiviral antibodies using a novel high-density nucleic acid programmable protein array (HD-NAPPA) platform. Individual viral proteins were expressed in situ directly from plasmids encoding proteins in an array of microscopic reaction chambers. Quality of protein display and serum response was assured by comparing intra- and inter-array correlation within or between printing batches with average correlation coefficients of 0.91 and 0.96, respectively. HD-NAPPA showed higher signal-to-background ratio compared with standard NAPPA on planar glass slides and ELISA. Antibody responses to 761 antigens from 25 different viruses were profiled among patients with juvenile idiopathic arthritis and type 1 diabetes. Common and unique antibody reactivity patterns were detected between patients and healthy controls. We believe HD-viral-NAPPA will enable the study of host-pathogen interactions at unprecedented dimensions and elucidate the role of pathogen infections in disease development.
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Affiliation(s)
- Xiaofang Bian
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Peter Wiktor
- Center for Bioelectronics and Biosensors, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Peter Kahn
- Engineering Arts LLC, Tempe, AZ, 85281, USA
| | - Al Brunner
- Engineering Arts LLC, Tempe, AZ, 85281, USA
| | - Amritpal Khela
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Kailash Karthikeyan
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Kristi Barker
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Xiaobo Yu
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Mitch Magee
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Clive H. Wasserfall
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32603, USA
| | - David Gibson
- Northern Ireland Centre for Stratified Medicine, Ulster University, C-TRIC, Glenshane Road, Londonderry, BT47 6SB, UK
| | - Madeleine E Rooney
- Arthritis Research Group, Centre for Infection and Immunity, Health Science Building, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK
| | - Ji Qiu
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
| | - Joshua LaBaer
- The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA
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Gallagher GR, Brehm MA, Finberg RW, Barton BA, Shultz LD, Greiner DL, Bortell R, Wang JP. Viral infection of engrafted human islets leads to diabetes. Diabetes 2015; 64:1358-69. [PMID: 25392246 PMCID: PMC4375078 DOI: 10.2337/db14-1020] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes.
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Affiliation(s)
- Glen R Gallagher
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Michael A Brehm
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Robert W Finberg
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Bruce A Barton
- Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA
| | | | - Dale L Greiner
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Rita Bortell
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA
| | - Jennifer P Wang
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA
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Schulte BM, Gielen PR, Kers-Rebel ED, Schreibelt G, van Kuppeveld FJM, Adema GJ. Enterovirus-infected β-cells induce distinct response patterns in BDCA1+ and BDCA3+ human dendritic cells. PLoS One 2015; 10:e0121670. [PMID: 25806537 PMCID: PMC4373773 DOI: 10.1371/journal.pone.0121670] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/03/2015] [Indexed: 12/16/2022] Open
Abstract
Enteroviruses often cause mild disease, yet are also linked to development of autoimmune diabetes. Dendritic cells (DCs) shape both innate and adaptive immune responses, including anti-viral responses. How different human DC subsets shape anti-viral responses, whether they have complementary or overlapping functions and how this relates to autoimmune responses is largely unknown. We used enterovirus-infected β-cells and freshly isolated human myeloid DC (mDC) subsets as a model for autoimmune type 1 diabetes. Our data show that both the BDCA1+ and BDCA3+ mDC subsets engulf mock- as well as virus-infected β-cells, albeit BDCA1+ mDCs are more efficient. Uptake of enterovirus-infected, but not mock-infected cells, activated both DC subsets as indicated by the induction of co-stimulatory molecules and secretion of type I and type III interferons. Both subsets produced similar amounts of interferon-α, yet the BDCA3+ DC were superior in IFN-λ production. The BDCA1+ mDCs more strongly upregulated PD-L1, and were superior in IL-12 and IL-10 production as compared to the BDCA3+ DC. Despite lack of IL-12 production by the BDCA3+ DC, both BDCA1+ and BDCA3+ DCs activated T cells in allogeneic mixed lymphocyte reaction towards a Th1-type reactivity while suppressing Th2-associated cytokines.
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Affiliation(s)
- Barbara M. Schulte
- Department of Tumor Immunology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Paul R. Gielen
- Department of Tumor Immunology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Esther D. Kers-Rebel
- Department of Tumor Immunology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Gerty Schreibelt
- Department of Tumor Immunology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | - Frank J. M. van Kuppeveld
- Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Gosse J. Adema
- Department of Tumor Immunology, Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
- * E-mail:
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35
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Harris KG, Coyne CB. Death waits for no man--does it wait for a virus? How enteroviruses induce and control cell death. Cytokine Growth Factor Rev 2014; 25:587-96. [PMID: 25172372 DOI: 10.1016/j.cytogfr.2014.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 08/05/2014] [Indexed: 12/29/2022]
Abstract
Enteroviruses (EVs) are the most common human viral pathogens. They cause a variety of pathologies, including myocarditis and meningoencephalopathies, and have been linked to the onset of type I diabetes. These pathologies result from the death of cells in the myocardium, central nervous system, and pancreas, respectively. Understanding the role of EVs in inducing cell death is crucial to understanding the etiologies of these diverse pathologies. EVs both induce and delay host cell death, and their exquisite control of this balance is crucial for their success as human viral pathogens. Thus, EVs are tightly involved with cell death signaling pathways and interact with host cell signaling at multiple points. Here, we review the literature detailing the mechanisms of EV-induced cell death. We discuss the mechanisms by which EVs induce cell death, the signaling pathways involved in these pathways, and the strategies by which EVs antagonize cell death pathways. We also discuss the role of cell death in both the resulting pathology in the host and in the facilitation of viral spread.
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Affiliation(s)
- Katharine G Harris
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, United States
| | - Carolyn B Coyne
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15219, United States.
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36
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Abstract
Type 1 diabetes is a multifactorial disease resulting from a complex interplay between host genetics, the immune system and the environment, that culminates in the destruction of insulin-producing beta cells. The incidence of type 1 diabetes is increasing at an alarming rate, especially in children under the age of 5 (Gepts in Diabetes 14(10):619-613, 1965; Foulis et al. in Lancet 29(5):267-274, 1986; Gamble, Taylor and Cumming in British Medical Journal 4(5887):260-262 1973). Genetic predisposition, although clearly important, cannot explain this rise, and so, it has been proposed that changes in the 'environment' and/or changes in 'how we respond to our environment' must contribute to this rising incidence. In order to gain an improved understanding of the factors influencing the disease process, it is important, firstly, to focus on the organ at the centre of the illness-the pancreas. This review summarises our knowledge of the pathology of the endocrine pancreas in human type 1 diabetes and, in particular, explores the progression of this understanding over the past 25 years.
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Affiliation(s)
- Sarah J Richardson
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building Barrack Road, Exeter, EX2 5DW, Devon, UK,
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Richardson SJ, Leete P, Dhayal S, Russell MA, Oikarinen M, Laiho JE, Svedin E, Lind K, Rosenling T, Chapman N, Bone AJ, Foulis AK, Frisk G, Flodstrom-Tullberg M, Hober D, Hyoty H, Morgan NG. Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas. Diabetologia 2014; 57:392-401. [PMID: 24190581 DOI: 10.1007/s00125-013-3094-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 10/02/2013] [Indexed: 01/14/2023]
Abstract
AIMS/HYPOTHESIS Enteroviral infection has been implicated in the development of islet autoimmunity in type 1 diabetes and enteroviral antigen expression has been detected by immunohistochemistry in the pancreatic beta cells of patients with recent-onset type 1 diabetes. However, the immunohistochemical evidence relies heavily on the use of a monoclonal antibody, clone 5D8/1, raised against an enteroviral capsid protein, VP1. Recent data suggest that the clone 5D8/1 may also recognise non-viral antigens; in particular, a component of the mitochondrial ATP synthase (ATP5B) and an isoform of creatine kinase (CKB). Therefore, we evaluated the fidelity of immunolabelling by clone 5D8/1 in the islets of patients with type 1 diabetes. METHODS Enteroviral VP1, CKB and ATP5B expression were analysed by western blotting, RT-PCR and immunocytochemistry in a range of cultured cell lines, isolated human islets and human tissue. RESULTS Clone 5D8/1 labelled CKB, but not ATP5B, on western blots performed under denaturing conditions. In cultured human cell lines, isolated human islets and pancreas sections from patients with type 1 diabetes, the immunolabelling of ATP5B, CKB and VP1 by 5D8/1 was readily distinguishable. Moreover, in a human tissue microarray displaying more than 80 different cells and tissues, only two (stomach and colon; both of which are potential sites of enterovirus infection) were immunopositive when stained with clone 5D8/1. CONCLUSIONS/INTERPRETATION When used under carefully optimised conditions, the immunolabelling pattern detected in sections of human pancreas with clone 5D8/1 did not reflect cross-reactivity with either ATP5B or CKB. Rather, 5D8/1 is likely to be representative of enteroviral antigen expression.
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Affiliation(s)
- Sarah J Richardson
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW, UK,
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