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Zhao LP, Papadopoulos GK, Skyler JS, Pugliese A, Parikh HM, Kwok WW, Lybrand TP, Bondinas GP, Moustakas AK, Wang R, Pyo CW, Nelson WC, Geraghty DE, Lernmark Å. Progression to type 1 diabetes in the DPT-1 and TN07 clinical trials is critically associated with specific residues in HLA-DQA1-B1 heterodimers. Diabetologia 2024; 67:2481-2493. [PMID: 39354095 PMCID: PMC11519105 DOI: 10.1007/s00125-024-06274-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/24/2024] [Indexed: 10/03/2024]
Abstract
AIMS/HYPOTHESIS The aim of this work was to explore molecular amino acids (AAs) and related structures of HLA-DQA1-DQB1 that underlie its contribution to the progression from stages 1 or 2 to stage 3 type 1 diabetes. METHODS Using high-resolution DQA1 and DQB1 genotypes from 1216 participants in the Diabetes Prevention Trial-Type 1 and the Diabetes Prevention Trial, we applied hierarchically organised haplotype association analysis (HOH) to decipher which AAs contributed to the associations of DQ with disease and their structural properties. HOH relied on the Cox regression to quantify the association of DQ with time-to-onset of type 1 diabetes. RESULTS By numerating all possible DQ heterodimers of α- and β-chains, we showed that the heterodimerisation increases genetic diversity at the cellular level from 43 empirically observed haplotypes to 186 possible heterodimers. Heterodimerisation turned several neutral haplotypes (DQ2.2, DQ2.3 and DQ4.4) to risk haplotypes (DQ2.2/2.3-DQ4.4 and DQ4.4-DQ2.2). HOH uncovered eight AAs on the α-chain (-16α, -13α, -6α, α22, α23, α44, α72, α157) and six AAs on the β-chain (-18β, β9, β13, β26, β57, β135) that contributed to the association of DQ with progression of type 1 diabetes. The specific AAs concerned the signal peptide (minus sign, possible linkage to expression levels), pockets 1, 4 and 9 in the antigen-binding groove of the α1β1 domain, and the putative homodimerisation of the αβ heterodimers. CONCLUSIONS/INTERPRETATION These results unveil the contribution made by DQ to type 1 diabetes progression at individual residues and related protein structures, shedding light on its immunological mechanisms and providing new leads for developing treatment strategies. DATA AVAILABILITY Clinical trial data and biospecimen samples are available through the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository portal ( https://repository.niddk.nih.gov/studies ).
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Affiliation(s)
- Lue Ping Zhao
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - George K Papadopoulos
- Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute (TEI) of Epirus, Arta, Greece
| | - Jay S Skyler
- Diabetes Research Institute and Division of Endocrinology, Diabetes & Metabolism, University of Miami Miler School of Medicine, Miami, FL, USA
| | - Alberto Pugliese
- Department of Diabetes Immunology, City of Hope, South Pasadena, CA, USA
| | - Hemang M Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | - Terry P Lybrand
- Department of Chemistry, Vanderbilt University, Nashville, TN, USA
| | - George P Bondinas
- Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Cephalonia, Greece
| | - Antonis K Moustakas
- Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Cephalonia, Greece
| | - Ruihan Wang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Chul-Woo Pyo
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Wyatt C Nelson
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Daniel E Geraghty
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.
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Xue C, Chen K, Gao Z, Bao T, Dong L, Zhao L, Tong X, Li X. Common mechanisms underlying diabetic vascular complications: focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction. Cell Commun Signal 2023; 21:298. [PMID: 37904236 PMCID: PMC10614351 DOI: 10.1186/s12964-022-01016-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/11/2022] [Indexed: 11/01/2023] Open
Abstract
Diabetic vascular complications (DVCs), including macro- and micro- angiopathy, account for a high percentage of mortality in patients with diabetes mellitus (DM). Endothelial dysfunction is the initial and role step for the pathogenesis of DVCs. Hyperglycemia and lipid metabolism disorders contribute to endothelial dysfunction via direct injury of metabolism products, crosstalk between immunity and inflammation, as well as related interaction network. Although physiological and phenotypic differences support their specified changes in different targeted organs, there are still several common mechanisms underlying DVCs. Also, inhibitors of these common mechanisms may decrease the incidence of DVCs effectively. Thus, this review may provide new insights into the possible measures for the secondary prevention of DM. And we discussed the current limitations of those present preventive measures in DVCs research. Video Abstract.
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Affiliation(s)
- Chongxiang Xue
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Keyu Chen
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zezheng Gao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Tingting Bao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China
- Beijing University of Chinese Medicine, Beijing, 100029, China
| | - LiShuo Dong
- Changchun University of Traditional Chinese Medicine, Changchun, 130117, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
| | - Xiaolin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
| | - Xiuyang Li
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing, 100053, China.
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
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Voeltz D, Brinks R, Tönnies T, Hoyer A. Future number of people with diagnosed type 1 diabetes in Germany until 2040: an analysis based on claims data. BMJ Open Diabetes Res Care 2023; 11:11/2/e003156. [PMID: 37024151 PMCID: PMC10083786 DOI: 10.1136/bmjdrc-2022-003156] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 03/24/2023] [Indexed: 04/08/2023] Open
Abstract
INTRODUCTION We aim to project the number of people with diagnosed type 1 diabetes in Germany between 2010 and 2040. RESEARCH DESIGN AND METHODS We first estimate the age-specific and sex-specific incidence and prevalence of type 1 diabetes in Germany in 2010 using data from 65 million insurees of the German statutory health insurance. Then, we use the illness-death model to project the prevalence of type 1 diabetes until 2040. We alter the incidence and mortality underlying the illness-death model in several scenarios to explore the impact of possible temporal trends on the number of people with type 1 diabetes. RESULTS Applying the prevalence from 2010 to the official population projections of Germany's Federal Statistical Office yields a total number of 252 000 people with type 1 diabetes in Germany in 2040 (+1% compared with 2010). Incorporating different annual trends of the incidence and mortality in the projection model results in a future number of people with type 1 diabetes between 292 000 (+18%) and 327 000 (+32%). CONCLUSIONS For the first time in Germany, we provide estimates for the incidence, prevalence, and number of people with diagnosed type 1 diabetes for the whole German population between 2010 and 2040. The relative increase of the people with type 1 diabetes ranges from 1% to 32% in 2040 compared with 2010. The projected results are mainly influenced by temporal trends in the incidence. Ignoring these trends, that is, applying a constant prevalence to population projections, probably underestimates future chronic disease numbers.
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Affiliation(s)
- Dina Voeltz
- Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, Germany
- Department of Statistics, Ludwig Maximilians University Munich, Munchen, Germany
| | - Ralph Brinks
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
- Chair for Medical Biometry and Epidemiology, Witten/Herdecke University, Faculty of Health/School of Medicine, Witten, Germany
| | - Thaddäus Tönnies
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-University Duesseldorf, Duesseldorf, Germany
| | - Annika Hoyer
- Biostatistics and Medical Biometry, Medical School OWL, Bielefeld University, Bielefeld, Germany
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Min T, Bain SC. Emerging drugs for the treatment of type 1 diabetes mellitus: a review of phase 2 clinical trials. Expert Opin Emerg Drugs 2023; 28:1-15. [PMID: 36896700 DOI: 10.1080/14728214.2023.2188191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
INTRODUCTION Despite therapeutic advances in the field of diabetes management since the discovery of insulin 100 years ago, there are still unmet clinical needs for people with type 1 diabetes mellitus (T1DM). AREAS COVERED Genetic testing and islet autoantibodies testing allow researchers to design prevention studies. This review discusses the emerging therapy for prevention of T1DM, disease modification therapy in early course of T1DM, and therapies and technologies for established T1DM. We focus on phase 2 clinical trials with promising results, thus avoiding the exhausted list of every new therapy for T1DM. EXPERT OPINION Teplizumab has demonstrated potential as a preventative agent for individuals at risk prior to the onset of overt dysglycemia. However, these agents are not without side effects, and there are uncertainties on long-term safety. Technological advances have led a substantial influence on quality of life of people suffering from T1DM. There remains variation in uptake of new technologies across the globe. Novel insulins (ultra-long acting), oral insulin, and inhaled insulin attempt to narrow the gap of unmet needs. Islet cell transplant is another exciting field, and stem cell therapy might have potential to provide unlimited supply of islet cells.
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Affiliation(s)
- Thinzar Min
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
- Department of Diabetes and Endocrinology, Neath Port Talbot Hospital, Swansea Bay University Health Board, Swansea, UK
| | - Stephen C Bain
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
- Department of Diabetes and Endocrinology, Singleton Hospital, Swansea Bay University Health Board, Swansea, UK
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Li Z, Shi J, Li N, Wang M, Jin Y, Zheng ZJ. Temporal trends in the burden of non-communicable diseases in countries with the highest malaria burden, 1990–2019: Evaluating the double burden of non-communicable and communicable diseases in epidemiological transition. Global Health 2022; 18:90. [PMID: 36274138 PMCID: PMC9589679 DOI: 10.1186/s12992-022-00882-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 09/30/2022] [Indexed: 11/25/2022] Open
Abstract
Background
Non-communicable diseases (NCDs) are rapidly increasing in sub-Saharan African countries, where 96% of global malaria deaths occur. This study aimed to investigate the disease burden of NCDs in countries with the current highest malaria mortality. Methods
Data for this study were obtained from the Global Burden of Disease 2019 study (1990–2019). We selected the ten countries with malaria’s highest age-standardised mortality rate (ASMR) and identified and ranked the five NCDs with the highest ASMR in each country. Measures of the NCDs disease burden included ASMR, age-standardised disability-adjusted life-years (DALY), years of life lost (YLL) and years lost due to a disability (YLD). The Estimated annual percentage change (EAPC) was used to examine the trends of the NCDs disease burden from 1990 to 2019. Results
As of 2019, the ASMR of chronic liver disease, kidney disease, diabetes mellitus, Alzheimer’s disease and other dementias, hypertensive heart disease and stroke were higher than the global average. From 1990 to 2019, the ASMR for Alzheimer’s disease and other dementias, type II diabetes mellitus, and chronic kidney disease increased by 3.0%, 10.8%, 13.3%, and the age-standardised DALY rate increased by 3.7%, 27.6%, 6.3%, and the increases tended to be in younger populations. Conclusion
The double burden of non-communicable and communicable diseases is crippling the health systems of many sub-Saharan African countries and is often neglected. The prevention, surveillance, and control of diseases require an integrated strategy, with governments and non-government organisations aligned and supported by the global initiative. Supplementary Information The online version contains supplementary material available at 10.1186/s12992-022-00882-w.
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Smigoc Schweiger D. Recent Advances in Immune-Based Therapies for Type 1 Diabetes. Horm Res Paediatr 2022; 96:631-645. [PMID: 35533645 DOI: 10.1159/000524866] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 04/18/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive destruction of the pancreatic beta cells, leading to a lifelong dependence on insulin. It is associated with an increased morbidity and mortality from diabetes-related complications and a significant treatment burden. However, there has been substantial progress in therapeutic strategies that can affect the course of the disease. SUMMARY This review addresses advances in immunotherapy aimed at preserving residual beta-cell function in individuals with a recent onset of T1D and arresting the disease in pre-symptomatic stages. Recent and ongoing clinical trials have investigated the efficacy and safety of various immunotherapeutic strategies aimed at targeting several mechanisms of autoimmunity, which are thought to be important in disease pathogenesis, and therapies that also address beta-cell health. So far, T-cell-directed therapies that led to a favourable balance between T-effector cell depletion or modulation and preservation or expansion of regulatory T cells have shown the most success. Furthermore, regarding the timing of intervention, teplizumab was the first immunomodulatory agent to demonstrate a significant delay in disease progression in high-risk individuals before clinical onset. KEY MESSAGES As more targeted immune interventions with potentially fewer side effects are closer to the translation into clinical practice, some new challenges may need to be addressed. The use of combination approaches that include immunotherapeutic strategies targeting different aspects of the immune system and interventions that improve beta-cell health may be required, along with the use of individualized patient-tailored approaches, a move towards early intervention, and a focus on patient-reported outcome measures.
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Affiliation(s)
- Darja Smigoc Schweiger
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
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Tatovic D, McAteer MA, Barry J, Barrientos A, Rodríguez Terradillos K, Perera I, Kochba E, Levin Y, Dul M, Coulman SA, Birchall JC, von Ruhland C, Howell A, Stenson R, Alhadj Ali M, Luzio SD, Dunseath G, Cheung WY, Holland G, May K, Ingram JR, Chowdhury MMU, Wong FS, Casas R, Dayan C, Ludvigsson J. Safety of the use of Gold Nanoparticles conjugated with proinsulin peptide and administered by hollow microneedles as an immunotherapy in Type 1 diabetes. IMMUNOTHERAPY ADVANCES 2022; 2:ltac002. [PMID: 35919496 PMCID: PMC9327128 DOI: 10.1093/immadv/ltac002] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/24/2022] [Indexed: 11/17/2022] Open
Abstract
Antigen-specific immunotherapy is an immunomodulatory strategy for autoimmune diseases, such as type 1 diabetes, in which patients are treated with autoantigens to promote immune tolerance, stop autoimmune β-cell destruction and prevent permanent dependence on exogenous insulin. In this study, human proinsulin peptide C19-A3 (known for its positive safety profile) was conjugated to ultrasmall gold nanoparticles (GNPs), an attractive drug delivery platform due to the potential anti-inflammatory properties of gold. We hypothesised that microneedle intradermal delivery of C19-A3 GNP may improve peptide pharmacokinetics and induce tolerogenic immunomodulation and proceeded to evaluate its safety and feasibility in a first-in-human trial. Allowing for the limitation of the small number of participants, intradermal administration of C19-A3 GNP appears safe and well tolerated in participants with type 1 diabetes. The associated prolonged skin retention of C19-A3 GNP after intradermal administration offers a number of possibilities to enhance its tolerogenic potential, which should be explored in future studies
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Affiliation(s)
- D Tatovic
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | | | - J Barry
- Midatech Pharma PLC, Cardiff, UK
| | | | | | - I Perera
- Midatech Pharma PLC, Cardiff, UK
| | - E Kochba
- NanoPass Technologies Ltd., Nes Ziona, Israel
| | - Y Levin
- NanoPass Technologies Ltd., Nes Ziona, Israel
| | - M Dul
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, UK
| | - S A Coulman
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, UK
| | - J C Birchall
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, UK
| | - C von Ruhland
- Central Biotechnology Services, Cardiff University, Cardiff, UK
| | - A Howell
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | - R Stenson
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | - M Alhadj Ali
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | - S D Luzio
- Swansea Trials Unit, Swansea University Medical School, UK
| | - G Dunseath
- Swansea Trials Unit, Swansea University Medical School, UK
| | - W Y Cheung
- Diabetes Research Unit Cymru, Institute for Life Sciences, Swansea University, Swansea, UK
| | - G Holland
- Swansea Trials Unit, Swansea University Medical School, UK
| | - K May
- Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
| | - J R Ingram
- Division of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - M M U Chowdhury
- Welsh Institute of Dermatology, University Hospital of Wales, Cardiff, UK
| | - F S Wong
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | - R Casas
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - C Dayan
- Diabetes Research Group, Cardiff University School of Medicine, Cardiff, UK
| | - J Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences and Crown Princess Victoria Children´s Hospital, Linköping University, Linköping, Sweden
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Purdel C, Ungurianu A, Margina D. Metabolic and Metabolomic Insights Regarding the Omega-3 PUFAs Intake in Type 1 Diabetes Mellitus. Front Mol Biosci 2021; 8:783065. [PMID: 34926582 PMCID: PMC8678113 DOI: 10.3389/fmolb.2021.783065] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 11/22/2021] [Indexed: 12/16/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is currently considered an autoimmune disease characterized by the destruction of pancreatic β-cells, insulin deficiency, and dysglycemia. Dietary factors, including omega-3 polyunsaturated fatty acids (ω-3 PUFAs), were reported to influence T1DM. Therefore, a better understanding of the potential role of ω-3 PUFAs in the development and progression of T1DM will help to improve the clinical management of the disease. In this review, we explored the current understanding of molecular mechanisms and signaling pathways induced by ω-3 PUFAs and the beneficial effects of ω-3 PUFAs intake in the prevention and treatment of T1DM, as well as the underlying possible metabolomic (lipidomics) changes.
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Affiliation(s)
- Carmen Purdel
- Department of Toxicology, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Ungurianu
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Denisa Margina
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Quinn LM, Wong FS, Narendran P. Environmental Determinants of Type 1 Diabetes: From Association to Proving Causality. Front Immunol 2021; 12:737964. [PMID: 34659229 PMCID: PMC8518604 DOI: 10.3389/fimmu.2021.737964] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
The rising incidence of type 1 diabetes (T1D) cannot be ascribed to genetics alone, and causative environmental triggers and drivers must also be contributing. The prospective TEDDY study has provided the greatest contributions in modern time, by addressing misconceptions and refining the search strategy for the future. This review outlines the evidence to date to support the pathways from association to causality, across all stages of T1D (seroconversion to beta cell failure). We focus on infections and vaccinations; infant growth and childhood obesity; the gut microbiome and the lifestyle factors which cultivate it. Of these, the environmental determinants which have the most supporting evidence are enterovirus infection, rapid weight gain in early life, and the microbiome. We provide an infographic illustrating the key environmental determinants in T1D and their likelihood of effect. The next steps are to investigate these environmental triggers, ideally though gold-standard randomised controlled trials and further prospective studies, to help explore public health prevention strategies.
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Affiliation(s)
- Lauren M Quinn
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - F Susan Wong
- Department of Diabetes, University Hospitals of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Parth Narendran
- Institute of Immunology and Immunotherapy, Research College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.,Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
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De Silva K, Lim S, Mousa A, Teede H, Forbes A, Demmer RT, Jönsson D, Enticott J. Nutritional markers of undiagnosed type 2 diabetes in adults: Findings of a machine learning analysis with external validation and benchmarking. PLoS One 2021; 16:e0250832. [PMID: 33951067 PMCID: PMC8099133 DOI: 10.1371/journal.pone.0250832] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 04/14/2021] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Using a nationally-representative, cross-sectional cohort, we examined nutritional markers of undiagnosed type 2 diabetes in adults via machine learning. METHODS A total of 16429 men and non-pregnant women ≥ 20 years of age were analysed from five consecutive cycles of the National Health and Nutrition Examination Survey. Cohorts from years 2013-2016 (n = 6673) was used for external validation. Undiagnosed type 2 diabetes was determined by a negative response to the question "Have you ever been told by a doctor that you have diabetes?" and a positive glycaemic response to one or more of the three diagnostic tests (HbA1c > 6.4% or FPG >125 mg/dl or 2-hr post-OGTT glucose > 200mg/dl). Following comprehensive literature search, 114 potential nutritional markers were modelled with 13 behavioural and 12 socio-economic variables. We tested three machine learning algorithms on original and resampled training datasets built using three resampling methods. From this, the derived 12 predictive models were validated on internal- and external validation cohorts. Magnitudes of associations were gauged through odds ratios in logistic models and variable importance in others. Models were benchmarked against the ADA diabetes risk test. RESULTS The prevalence of undiagnosed type 2 diabetes was 5.26%. Four best-performing models (AUROC range: 74.9%-75.7%) classified 39 markers of undiagnosed type 2 diabetes; 28 via one or more of the three best-performing non-linear/ensemble models and 11 uniquely by the logistic model. They comprised 14 nutrient-based, 12 anthropometry-based, 9 socio-behavioural, and 4 diet-associated markers. AUROC of all models were on a par with ADA diabetes risk test on both internal and external validation cohorts (p>0.05). CONCLUSIONS Models performed comparably to the chosen benchmark. Novel behavioural markers such as the number of meals not prepared from home were revealed. This approach may be useful in nutritional epidemiology to unravel new associations with type 2 diabetes.
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Affiliation(s)
- Kushan De Silva
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
| | - Siew Lim
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
| | - Aya Mousa
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
| | - Helena Teede
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
| | - Andrew Forbes
- Biostatistics Unit, Division of Research Methodology, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Melbourne, Australia
| | - Ryan T Demmer
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America.,Mailman School of Public Health, Columbia University, New York, New York, United States of America
| | - Daniel Jönsson
- Department of Periodontology, Faculty of Odontology, Malmö University, Malmö, Sweden.,Swedish Dental Service of Skane, Lund, Sweden
| | - Joanne Enticott
- Monash Centre for Health Research and Implementation, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing, and Health Sciences, Monash University, Clayton, Australia
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Papachrisanthou MM, Fuller KM. Pediatric Screenings: Helpful or Hinderance? J Nurse Pract 2021. [DOI: 10.1016/j.nurpra.2020.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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12
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Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev 2020; 40:1200-1219. [PMID: 32112452 DOI: 10.1002/med.21654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
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Affiliation(s)
- Selena Le Bagge
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Amelia K Fotheringham
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sherman S Leung
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Josephine M Forbes
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Mater Clinical School, The University of Queensland, Brisbane, Queensland, Australia
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13
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Leger T, He B, Azarnoush K, Jouve C, Rigaudiere JP, Joffre F, Bouvier D, Sapin V, Pereira B, Demaison L. Dietary EPA Increases Rat Mortality in Diabetes Mellitus, A Phenomenon Which Is Compensated by Green Tea Extract. Antioxidants (Basel) 2019; 8:antiox8110526. [PMID: 31690052 PMCID: PMC6912216 DOI: 10.3390/antiox8110526] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 10/25/2019] [Accepted: 10/31/2019] [Indexed: 01/11/2023] Open
Abstract
Diabetes is characterized by a high mortality rate which is often associated with heart failure. Green tea and eicosapentaenoic acid (EPA) are known to lessen some of the harmful impacts of diabetes and to exert cardio-protection. The aim of the study was to determine the effects of EPA, green tea extract (GTE), and a combination of both on the cardiac consequences of diabetes mellitus, induced in Wistar rats by injection of a low dose of streptozotocin (33 mg/kg) combined with a high fat diet. Cardiac mechanical function, coronary reactivity, and parameters of oxidative stress, inflammation, and energy metabolism were evaluated. In the context of diabetes, GTE alone limited several diabetes-related symptoms such as inflammation. It also slightly improved coronary reactivity and considerably enhanced lipid metabolism. EPA alone caused the rapid death of the animals, but this effect was negated by the addition of GTE in the diet. EPA and GTE combined enhanced coronary reactivity considerably more than GTE alone. In a context of significant oxidative stress such as during diabetes mellitus, EPA enrichment constitutes a risk factor for animal survival. It is essential to associate it with the antioxidants contained in GTE in order to decrease mortality rate and preserve cardiac function.
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Affiliation(s)
- Thibault Leger
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
| | - Beibei He
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
| | - Kasra Azarnoush
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
- Heart Surgery Department, Gabriel Montpied Hospital, Clermont-Ferrand University Hospital, 63000 Clermont-Ferrand, France.
- Hôpital Nord, Saint-Etienne University Hospital, Saint-Priest-en-Jarez, France.
| | - Chrystèle Jouve
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
| | - Jean-Paul Rigaudiere
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
| | - Florent Joffre
- ITERG, 11 rue Gaspard Monge, - ZA Pessac Canéjan, F-33610 Canéjan, France.
| | - Damien Bouvier
- Department of Medical Biochemistry and Molecular Biology, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
| | - Vincent Sapin
- Department of Medical Biochemistry and Molecular Biology, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
| | - Bruno Pereira
- Department of Clinical Research and Innovation, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France.
| | - Luc Demaison
- Unité de Nutrition Humaine (UNH), INRA/Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
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Carlsson S. Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes. Front Physiol 2019; 10:320. [PMID: 30971952 PMCID: PMC6444059 DOI: 10.3389/fphys.2019.00320] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022] Open
Abstract
As the heterogeneity of diabetes is becoming increasingly clear, opportunities arise for more accurate assessment of factors influencing disease onset, which may lead to more efficient primary prevention. LADA - latent autoimmune diabetes in adults - is a common, hybrid form of diabetes with features of both type 1 and type 2 diabetes. This review aims to summarize current knowledge on the pathophysiological and etiological overlap and differences between LADA and type 2 diabetes, discuss similarities between LADA and type 1 diabetes and point at future research needs. Studies conducted to date show a clear genetic overlap between LADA and type 1 diabetes with a high risk conferred by variants in the human leukocyte antigen (HLA) region. In contrast, data from the limited number of studies on lifestyle factors available indicate that LADA may share several environmental risk factors with type 2 diabetes including overweight, physical inactivity, alcohol consumption (protective) and smoking. These factors are known to influence insulin sensitivity, suggesting that insulin resistance, in addition to insulin deficiency due to autoimmune destruction of the beta cells, may play a key role in the pathogenesis of LADA. Moreover, this implies that onset of LADA, similar to type 2 diabetes, to some extent could be prevented or postponed by lifestyle modification such as weight reduction and increased physical activity. The preventive potential of LADA is an important topic to elucidate in future studies, preferably intervention studies.
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Affiliation(s)
- Sofia Carlsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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15
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Wentworth JM, Bediaga NG, Giles LC, Ehlers M, Gitelman SE, Geyer S, Evans-Molina C, Harrison LC. Beta cell function in type 1 diabetes determined from clinical and fasting biochemical variables. Diabetologia 2019; 62:33-40. [PMID: 30167735 PMCID: PMC6518395 DOI: 10.1007/s00125-018-4722-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 08/01/2018] [Indexed: 02/07/2023]
Abstract
AIMS/HYPOTHESIS Beta cell function in type 1 diabetes is commonly assessed as the average plasma C-peptide concentration over 2 h following a mixed-meal test (CPAVE). Monitoring of disease progression and response to disease-modifying therapy would benefit from a simpler, more convenient and less costly measure. Therefore, we determined whether CPAVE could be reliably estimated from routine clinical variables. METHODS Clinical and fasting biochemical data from eight randomised therapy trials involving participants with recently diagnosed type 1 diabetes were used to develop and validate linear models to estimate CPAVE and to test their accuracy in estimating loss of beta cell function and response to immune therapy. RESULTS A model based on disease duration, BMI, insulin dose, HbA1c, fasting plasma C-peptide and fasting plasma glucose most accurately estimated loss of beta cell function (area under the receiver operating characteristic curve [AUROC] 0.89 [95% CI 0.87, 0.92]) and was superior to the commonly used insulin-dose-adjusted HbA1c (IDAA1c) measure (AUROC 0.72 [95% CI 0.68, 0.76]). Model-estimated CPAVE (CPEST) reliably identified treatment effects in randomised trials. CPEST, compared with CPAVE, required only a modest (up to 17%) increase in sample size for equivalent statistical power. CONCLUSIONS/INTERPRETATION CPEST, approximated from six variables at a single time point, accurately identifies loss of beta cell function in type 1 diabetes and is comparable to CPAVE for identifying treatment effects. CPEST could serve as a convenient and economical measure of beta cell function in the clinic and as a primary outcome measure in trials of disease-modifying therapy in type 1 diabetes.
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Affiliation(s)
- John M Wentworth
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia.
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
- Department of Diabetes and Endocrinology, Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
| | - Naiara G Bediaga
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Lynne C Giles
- School of Public Health, The University of Adelaide, Adelaide, SA, Australia
| | - Mario Ehlers
- Clinical Trials Group, Immune Tolerance Network, San Francisco, CA, USA
- Eli Lilly and Company, San Diego, CA, USA
| | | | | | | | - Leonard C Harrison
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC, 3052, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia
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16
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Redondo MJ, Steck AK, Pugliese A. Genetics of type 1 diabetes. Pediatr Diabetes 2018; 19:346-353. [PMID: 29094512 PMCID: PMC5918237 DOI: 10.1111/pedi.12597] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 09/18/2017] [Accepted: 09/20/2017] [Indexed: 12/23/2022] Open
Abstract
Type 1 diabetes (T1D) results from immune-mediated loss of pancreatic beta cells leading to insulin deficiency. It is the most common form of diabetes in children, and its incidence is on the rise. This article reviews the current knowledge on the genetics of T1D. In particular, we discuss the influence of HLA and non-HLA genes on T1D risk and disease progression through the preclinical stages of the disease, and the development of genetic scores that can be applied to disease prediction. Racial/ethnic differences, challenges and future directions in the genetics of T1D are also discussed.
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Affiliation(s)
- Maria J. Redondo
- Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030
| | - Andrea K. Steck
- University of Colorado School of Medicine, Barbara Davis Center for Childhood Diabetes, Aurora, CO, 80045
| | - Alberto Pugliese
- Diabetes Research Institute, Department of Medicine, Division of Endocrinology and Metabolism, Department of Microbiology and Immunology, Leonard Miller School of Medicine, University of Miami, Miami, FL 33136
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17
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Abstract
Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.
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Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue - Suite 3054, Miami, FL, 33136, USA.
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18
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Chen J, Song Y, Bojadzic D, Tamayo-Garcia A, Landin AM, Blomberg BB, Buchwald P. Small-Molecule Inhibitors of the CD40-CD40L Costimulatory Protein-Protein Interaction. J Med Chem 2017; 60:8906-8922. [PMID: 29024591 PMCID: PMC5823691 DOI: 10.1021/acs.jmedchem.7b01154] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Costimulatory interactions are required for T cell activation and development of an effective immune response; hence, they are valuable therapeutic targets for immunomodulation. However, they, as all other protein-protein interactions, are difficult to target by small molecules. Here, we report the identification of novel small-molecule inhibitors of the CD40-CD40L interaction designed starting from the chemical space of organic dyes. For the most promising compounds such as DRI-C21045, activity (IC50) in the low micromolar range has been confirmed in cell assays including inhibition of CD40L-induced activation in NF-κB sensor cells, THP-1 myeloid cells, and primary human B cells as well as in murine allogeneic skin transplant and alloantigen-induced T cell expansion in draining lymph node experiments. Specificity versus other TNF-superfamily interactions (TNF-R1-TNF-α) and lack of cytotoxicity have also been confirmed at these concentrations. These novel compounds provide proof-of-principle evidence for the possibility of small-molecule inhibition of costimulatory protein-protein interactions, establish the structural requirements needed for efficient CD40-CD40L inhibition, and serve to guide the search for such immune therapeutics.
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Affiliation(s)
- Jinshui Chen
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Yun Song
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
- Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Damir Bojadzic
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Alejandro Tamayo-Garcia
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Ana Marie Landin
- Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Bonnie B. Blomberg
- Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
| | - Peter Buchwald
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
- Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA
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Abstract
PURPOSE OF REVIEW About 50% of the heritability of type 1 diabetes (T1D) is attributed to human leukocyte antigen (HLA) alleles and the remainder to several (close to 50) non-HLA loci. A current challenge in the field of the genetics of T1D is to apply the knowledge accumulated in the last 40 years towards differential diagnosis and risk assessment. RECENT FINDINGS T1D genetic risk scores seek to combine the information from HLA and non-HLA alleles to improve the accuracy of diagnosis, prediction, and prognosis. Here, we describe genetic risk scores that have been developed and validated in various settings and populations. Several genetic scores have been proposed that merge disease risk information from multiple genetic factors to optimize the use of genetic information and ultimately improve prediction and diagnosis of T1D.
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Affiliation(s)
- Maria J Redondo
- Texas Children's Hospital/Baylor College of Medicine, 6701 Fannin Street, CC1020, Houston, TX, 77030, USA.
| | - Richard A Oram
- University of Exeter Medical School, Institute of Biomedical and Clinical Science, RILD Building, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK
| | - Andrea K Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, 1775 Aurora Ct, Aurora, CO, 80045, USA
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20
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Abstract
Type 1 diabetes mellitus is a chronic state of insulin deficiency which results from destruction of beta cells by the immune system. The long term microvascular and macrovascular complications can be devastating. Since the discovery of insulin almost 100 years ago new medical therapies have improved the long-term survival for people with type 1 diabetes. Each year we come closer to discovering a cure but much work still needs to be done to eliminate this disease.
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Affiliation(s)
- Melanie Copenhaver
- Division of Pediatric Endocrinology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - Robert P Hoffman
- Division of Pediatric Endocrinology, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
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21
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Abstract
Underlying type 1 diabetes is a genetic aetiology dominated by the influence of specific HLA haplotypes involving primarily the class II DR-DQ region. In genetically predisposed children with the DR4-DQ8 haplotype, exogenous factors, yet to be identified, are thought to trigger an autoimmune reaction against insulin, signalled by insulin autoantibodies as the first autoantibody to appear. In children with the DR3-DQ2 haplotype, the triggering reaction is primarily against GAD signalled by GAD autoantibodies (GADA) as the first-appearing autoantibody. The incidence rate of insulin autoantibodies as the first-appearing autoantibody peaks during the first years of life and declines thereafter. The incidence rate of GADA as the first-appearing autoantibody peaks later but does not decline. The first autoantibody may variably be followed, in an apparently non-HLA-associated pathogenesis, by a second, third or fourth autoantibody. Although not all persons with a single type of autoantibody progress to diabetes, the presence of multiple autoantibodies seems invariably to be followed by loss of functional beta cell mass and eventually by dysglycaemia and symptoms. Infiltration of mononuclear cells in and around the islets appears to be a late phenomenon appearing in the multiple-autoantibody-positive with dysglycaemia. As our understanding of the aetiology and pathogenesis of type 1 diabetes advances, the improved capability for early prediction should guide new strategies for the prevention of type 1 diabetes.
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Affiliation(s)
- Simon E Regnell
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden
| | - Åke Lernmark
- Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital, Jan Waldenströms gata 35, SE-20502, Malmö, Sweden.
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22
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Ganugula R, Arora M, Jaisamut P, Wiwattanapatapee R, Jørgensen HG, Venkatpurwar VP, Zhou B, Rodrigues Hoffmann A, Basu R, Guo S, Majeti NVRK. Nano-curcumin safely prevents streptozotocin-induced inflammation and apoptosis in pancreatic beta cells for effective management of Type 1 diabetes mellitus. Br J Pharmacol 2017; 174:2074-2084. [PMID: 28409821 PMCID: PMC5466524 DOI: 10.1111/bph.13816] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 03/14/2017] [Accepted: 04/01/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE Approaches to prevent selective and progressive loss of insulin-producing beta cells in Type 1 diabetes mellitus (T1DM) will help to manage this prevalent and devastating disease. Curcumin (CUR), a natural anti-inflammatory substance, suppresses diabetes-associated inflammation and cell death. However, very high doses need to be used because of poor oral bioavailability, making it difficult to translate the anti-inflammatory actions to clinical situations. EXPERIMENTAL APPROACH We have prepared biodegradable nanosystems encapsulating curcumin (nCUR), resulting in at least nine-fold improvement in oral bioavailability. Here, we tested the ability of nCUR to prevent streptozotocin (STZ)-induced inflammation and apoptosis in pancreatic islets and beta cells, in rats. KEY RESULTS Non-fasted rats pretreated with 10 or 50 mg·kg-1 nCUR 6 h prior to STZ challenge had up to 37% reduction in the glucose levels, while plain CUR (50 mg·kg-1 ) results in 12% reduction. This treatment with nCUR was accompanied by decreased islet or beta cell death, as shown by TUNEL assay and H&E staining. Both CUR and nCUR significantly decreased levels of inflammatory cytokines in pancreatic tissue homogenates that correlated well with minimal histiocytic infiltration. Pre-treatment with nCUR, but not CUR, decreased 8-oxo-2'-deoxyguanosine, a sensitive biomarker of ROS-induced DNA damage, in pancreas. In normal rodents, daily dosing for 28 days, with nCUR (25-100 mg·kg-1 ) did not cause any deleterious health issues by the carrier. CONCLUSIONS AND IMPLICATIONS Together, these data indicate a potentially translatable dose of nCUR that is safe and efficacious in improving beta cell function, which could prevent T1DM.
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Affiliation(s)
- Raghu Ganugula
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of PharmacyTexas A&M UniversityCollege StationTXUSA
| | - Meenakshi Arora
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of PharmacyTexas A&M UniversityCollege StationTXUSA
| | - Patcharawalai Jaisamut
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of PharmacyTexas A&M UniversityCollege StationTXUSA
- Faculty of Traditional Thai MedicinePrince of Songkla UniversityHat‐YaiSongkhlaThailand
| | - Ruedeekorn Wiwattanapatapee
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical SciencesPrince of Songkla UniversityHat‐YaiSongkhlaThailand
| | - Heather G Jørgensen
- Paul O'Gorman Leukaemia Research Centre, Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Vinod P Venkatpurwar
- Strathclyde Institute of Pharmacy and Biomedical SciencesUniversity of StrathclydeGlasgowUK
| | - Beiyan Zhou
- Department of ImmunologyUniversity of Connecticut Health CenterFarmingtonCTUSA
| | | | - Rita Basu
- The Integrated Carbohydrate Physiology and Translation LaboratoryMayo ClinicRochesterMNUSA
| | - Shaodong Guo
- Department of Nutrition and Food ScienceTexas A&M UniversityCollege StationTXUSA
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Michels AW, Landry LG, McDaniel KA, Yu L, Campbell-Thompson M, Kwok WW, Jones KL, Gottlieb PA, Kappler JW, Tang Q, Roep BO, Atkinson MA, Mathews CE, Nakayama M. Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes. Diabetes 2017; 66:722-734. [PMID: 27920090 PMCID: PMC5319719 DOI: 10.2337/db16-1025] [Citation(s) in RCA: 150] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 12/01/2016] [Indexed: 12/16/2022]
Abstract
Type 1 diabetes results from chronic autoimmune destruction of insulin-producing β-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.
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Affiliation(s)
- Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Laurie G Landry
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Kristen A McDaniel
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Liping Yu
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - Martha Campbell-Thompson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - William W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Kenneth L Jones
- Department of Pediatrics, Section of Hematology, Oncology, and Bone Marrow Transplant, University of Colorado School of Medicine, Aurora, CO
| | - Peter A Gottlieb
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
| | - John W Kappler
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO
- Howard Hughes Medical Institute, Denver, CO
- Department of Biomedical Research, National Jewish Health, Denver, CO
- Program in Structural Biology and Biochemistry, University of Colorado School of Medicine, Aurora, CO
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA
- Diabetes Center, University of California, San Francisco, San Francisco, CA
| | - Bart O Roep
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA
| | - Mark A Atkinson
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Clayton E Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL
| | - Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO
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24
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Atypical presentations of celiac disease. ARS MEDICA TOMITANA 2017. [DOI: 10.1515/arsm-2016-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
In this study we evaluated the association of celiac disease in 81 children with autoimmune disease and genetic syndromes over a two years periods (January 2014 to July 2016) in Pediatric Clinic in Constanta. Because the extraintestinal symptoms are an atypical presentation of celiac disease we determined in these children the presence of celiac disease antibodies: Anti-tissue Transglutaminase Antibody IgA and IgA total serum level as a screening method followeds in selective cases by Anti-tissue Transglutaminase Antibody IgG, anti-endomysial antibodies, deamidated gliadin antibodies IgA and IgG and intestinal biopsia. In our study 8 patients had been diagnosed with celiac disease with extraintestinal symptoms, of which 4 with type 1 diabetes, 1 patient with ataxia, 2 patients with dermatitis herpetiformis and 1 patient with Down syndrome that associate also autoimmune thyroiditis, alopecia areata, enamel hypoplasia.
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Van Dalem A, Demeester S, Balti EV, Keymeulen B, Gillard P, Lapauw B, De Block C, Abrams P, Weber E, Vermeulen I, De Pauw P, Pipeleers D, Weets I, Gorus FK. Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio. PLoS One 2016; 11:e0166702. [PMID: 27907006 PMCID: PMC5131964 DOI: 10.1371/journal.pone.0166702] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 11/02/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin:C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release. METHODS Between-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive first-degree relatives (n = 49; age 5-39) were tested for fasting PI:C, HOMA2-IR and hyperglycemic clamp and followed for 20-57 months (interquartile range). RESULTS TT-TRFIA values for proinsulin, C-peptide and PI:C correlated significantly (r2 = 0.96-0.99; P<0.001) with results obtained with separate methods. TT-TRFIA achieved better between-day %CV for PI:C at three different levels (4.5-7.1 vs 6.7-9.5 for separate methods). In high-risk relatives fasting PI:C was significantly and inversely correlated (rs = -0.596; P<0.001) with first-phase C-peptide release during clamp (also with second phase release, only available for age 12-39 years; n = 31), but only after normalization for HOMA2-IR. In ROC- and Cox regression analysis, HOMA2-IR-corrected PI:C predicted 2-year progression to diabetes equally well as clamp-derived C-peptide release. CONCLUSIONS The reproducibility of PI:C benefits from the automated simultaneous determination of both hormones. HOMA2-IR-corrected PI:C may serve as a minimally invasive alternative to the more tedious hyperglycemic clamp test.
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Affiliation(s)
- Annelien Van Dalem
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Clinical Chemistry and Radio-immunology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Simke Demeester
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Clinical Chemistry and Radio-immunology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Eric V. Balti
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
| | - Bart Keymeulen
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Diabetology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Pieter Gillard
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Endocrinology, Universitair Ziekenhuis Leuven, Belgium
| | - Bruno Lapauw
- Department of Endocrinology, Universitair Ziekenhuis Gent, Ghent, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
| | - Pascale Abrams
- Department of Endocrinology and Diabetology, GZA Campus Sint Augustinus en Sint Vincentius, Wilrijk-Antwerp, Belgium
| | - Eric Weber
- Department of Endocrinology and Diabetology, Clinique du Sud Luxembourg et Clinique Saint Joseph, Arlon, Belgium
| | - Ilse Vermeulen
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
| | - Pieter De Pauw
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
| | - Daniël Pipeleers
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
| | - Ilse Weets
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Clinical Chemistry and Radio-immunology, Universitair Ziekenhuis Brussel, Brussels, Belgium
| | - Frans K. Gorus
- Diabetes Research Center, Brussels Free University—VUB, Brussels, Belgium
- Department of Clinical Chemistry and Radio-immunology, Universitair Ziekenhuis Brussel, Brussels, Belgium
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Thorsen SU, Pipper CB, Eising S, Skogstrand K, Hougaard DM, Svensson J, Pociot F. Neonatal levels of adiponectin, interleukin-10 and interleukin-12 are associated with the risk of developing type 1 diabetes in childhood and adolescence: A nationwide Danish case-control study. Clin Immunol 2016; 174:18-23. [PMID: 27871914 DOI: 10.1016/j.clim.2016.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 11/11/2016] [Accepted: 11/13/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIM An in-depth understanding of the early phase of type 1 diabetes (T1D) pathogenesis is important for targeting primary prevention. We examined if 14 preselected mediators of immune responses differed in neonates that later developed T1D compared to control neonates. METHODS The study is a case-control study with a 1:2 matching. The individuals were born between 1981 through 2002. Cases were validated using the National Patient Register and the Danish Childhood Diabetes Register. Interleukin(IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-12p70, interferon gamma, tumor necrosis factor alpha, transforming growth factor beta 1 (active form), leptin, adiponectin, c-reactive protein, mannose-binding lectin and soluble triggering receptor expressed on myeloid cells-1 were measured by using a flowmetric Luminex xMAP® technology. We tested two models both including a number of possible confounders. In the first model (model 1) we also adjusted for HLA-DQB1 genotype. A total of 1930 groups of assay-matched cases and controls (4746 individuals) were included in the statistical analyses. RESULTS Adiponectin was negatively associated with later risk of T1D in both models (relative change (RC), model 1: 0.95, P=0.046 and model 2: 0.95, P=0.006). IL-10 and IL-12 were both positively associated with T1D risk in the model 2 (RC, 1.19, P=0.006 and 1.07, P=0.02, respectively)-these results were borderline significant in model 1, but showed the same direction as the results from model 2. CONCLUSIONS Our results indicate that specific immunological signatures are already present at time of birth in children developing T1D before the age of 18years.
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Affiliation(s)
- Steffen U Thorsen
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev. Denmark.
| | - Christian B Pipper
- Department of Public Health, Section of Biostatistics, University of Copenhagen, Oester Farimagsgade 5, 1710 Copenhagen K, Denmark
| | - Stefanie Eising
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev. Denmark
| | - Kristin Skogstrand
- Department of Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut Artillerivej 5, 2300 Copenhagen S, Denmark
| | - David M Hougaard
- Department of Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut Artillerivej 5, 2300 Copenhagen S, Denmark
| | - Jannet Svensson
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev. Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
| | - Flemming Pociot
- Copenhagen Diabetes Research Center (CPH-DIRECT), Department of Paediatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev. Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
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Balazard F, Le Fur S, Valtat S, Valleron AJ, Bougnères P, Thevenieau D, Chatel CF, Desailloud R, Bony-Trifunovic H, Ducluzeau PH, Coutant R, Caudrelier S, Pambou A, Dubosclard E, Joubert F, Jan P, Marcoux E, Bertrand AM, Mignot B, Penformis A, Stuckens C, Piquemal R, Barat P, Rigalleau V, Stheneur C, Fournier S, Kerlan V, Metz C, Fargeot-Espaliat A, Reznic Y, Olivier F, Gueorguieva I, Monier A, Radet C, Gajdos V, Terral D, Vervel C, Bendifallah D, Signor CB, Dervaux D, Benmahammed A, Loeuille GA, Popelard F, Guillou A, Benhamou PY, Khoury J, Brossier JP, Bassil J, Clavel S, Le Luyer B, Bougnères P, Labay F, Guemas I, Weill J, Cappoen JP, Nadalon S, Lienhardt-Roussie A, Paoli A, Kerouedan C, Yollin E, Nicolino M, Simonin G, Cohen J, Atlan C, Tamboura A, Dubourg H, Pignol ML, Talon P, Jellimann S, Chaillous L, Baron S, Bortoluzzi MN, Baechler E, Salet R, Zelinsky-Gurung A, Dallavale F, Larger E, Laloi-Michelin M, Gautier JF, Guérin B, Oilleau L, Pantalone L, Lukas C, Guilhem I, De Kerdanet M, Wielickzo MC, Priou-Guesdon M, Richard O, Kurtz F, Laisney N, Ancelle D, Parlier G, Boniface C, Bockel DP, Dufillot D, Razafimahefa B, Gourdy P, Lecomte P, Pepin-Donat M, Combes-Moukhovsky ME, et alBalazard F, Le Fur S, Valtat S, Valleron AJ, Bougnères P, Thevenieau D, Chatel CF, Desailloud R, Bony-Trifunovic H, Ducluzeau PH, Coutant R, Caudrelier S, Pambou A, Dubosclard E, Joubert F, Jan P, Marcoux E, Bertrand AM, Mignot B, Penformis A, Stuckens C, Piquemal R, Barat P, Rigalleau V, Stheneur C, Fournier S, Kerlan V, Metz C, Fargeot-Espaliat A, Reznic Y, Olivier F, Gueorguieva I, Monier A, Radet C, Gajdos V, Terral D, Vervel C, Bendifallah D, Signor CB, Dervaux D, Benmahammed A, Loeuille GA, Popelard F, Guillou A, Benhamou PY, Khoury J, Brossier JP, Bassil J, Clavel S, Le Luyer B, Bougnères P, Labay F, Guemas I, Weill J, Cappoen JP, Nadalon S, Lienhardt-Roussie A, Paoli A, Kerouedan C, Yollin E, Nicolino M, Simonin G, Cohen J, Atlan C, Tamboura A, Dubourg H, Pignol ML, Talon P, Jellimann S, Chaillous L, Baron S, Bortoluzzi MN, Baechler E, Salet R, Zelinsky-Gurung A, Dallavale F, Larger E, Laloi-Michelin M, Gautier JF, Guérin B, Oilleau L, Pantalone L, Lukas C, Guilhem I, De Kerdanet M, Wielickzo MC, Priou-Guesdon M, Richard O, Kurtz F, Laisney N, Ancelle D, Parlier G, Boniface C, Bockel DP, Dufillot D, Razafimahefa B, Gourdy P, Lecomte P, Pepin-Donat M, Combes-Moukhovsky ME, Zymmermann B, Raoulx M, Dumont AGEC. Association of environmental markers with childhood type 1 diabetes mellitus revealed by a long questionnaire on early life exposures and lifestyle in a case-control study. BMC Public Health 2016; 16:1021. [PMID: 27682602 PMCID: PMC5041527 DOI: 10.1186/s12889-016-3690-9] [Show More Authors] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 09/20/2016] [Indexed: 12/22/2022] Open
Abstract
Background The incidence of childhood type 1 diabetes (T1D) incidence is rising in many countries, supposedly because of changing environmental factors, which are yet largely unknown. The purpose of the study was to unravel environmental markers associated with T1D. Methods Cases were children with T1D from the French Isis-Diab cohort. Controls were schoolmates or friends of the patients. Parents were asked to fill a 845-item questionnaire investigating the child’s environment before diagnosis. The analysis took into account the matching between cases and controls. A second analysis used propensity score methods. Results We found a negative association of several lifestyle variables, gastroenteritis episodes, dental hygiene, hazelnut cocoa spread consumption, wasp and bee stings with T1D, consumption of vegetables from a farm and death of a pet by old age. Conclusions The found statistical association of new environmental markers with T1D calls for replication in other cohorts and investigation of new environmental areas. Trial registration Clinical-Trial.gov NCT02212522. Registered August 6, 2014. Electronic supplementary material The online version of this article (doi:10.1186/s12889-016-3690-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- F Balazard
- Sorbonne Universités, UPMC Univ Paris 06, CNRS, Paris, France. .,INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.
| | - S Le Fur
- INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.,Department of pediatric endocrinology, Hôpital Bicêtre, Kremlin-Bicêtre, France
| | - S Valtat
- INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France
| | - A J Valleron
- INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France
| | - P Bougnères
- INSERM U1169, Hôpital Bicêtre, Université Paris-Sud, Kremlin-Bicêtre, France.,Department of pediatric endocrinology, Hôpital Bicêtre, Kremlin-Bicêtre, France
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Effect of Associated Autoimmune Diseases on Type 1 Diabetes Mellitus Incidence and Metabolic Control in Children and Adolescents. BIOMED RESEARCH INTERNATIONAL 2016; 2016:6219730. [PMID: 27525273 PMCID: PMC4971288 DOI: 10.1155/2016/6219730] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Revised: 04/06/2016] [Accepted: 04/19/2016] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases developing in childhood. The incidence of the disease in children increases for unknown reasons at a rate from 3 to 5% every year worldwide. The background of T1DM is associated with the autoimmune process of pancreatic beta cell destruction, which leads to absolute insulin deficiency and organ damage. Complex interactions between environmental and genetic factors contribute to the development of T1DM in genetically predisposed patients. The T1DM-inducing autoimmune process can also affect other organs, resulting in development of additional autoimmune diseases in the patient, thereby impeding diabetes control. The most common T1DM comorbidities include autoimmune thyroid diseases, celiac disease, and autoimmune gastritis; additionally, diabetes can be a component of PAS (Polyglandular Autoimmune Syndrome). The aim of this review is to assess the prevalence of T1DM-associated autoimmune diseases in children and adolescents and their impact on the course of T1DM. We also present suggestions concerning screening tests.
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McLaughlin RJ, Spindler MP, van Lummel M, Roep BO. Where, How, and When: Positioning Posttranslational Modification Within Type 1 Diabetes Pathogenesis. Curr Diab Rep 2016; 16:63. [PMID: 27168063 PMCID: PMC4863913 DOI: 10.1007/s11892-016-0752-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Autoreactive T cells specific for islet autoantigens develop in type 1 diabetes (T1D) by escaping central as well as peripheral tolerance. The current paradigm for development of islet autoimmunity is just beginning to include the contribution of posttranslationally modified (PTM) islet autoantigens, for which the immune system may be ignorant rather than tolerant. As a result, PTM is the latest promising lead in the quest to understand how the break in peripheral tolerance occurs in T1D. However, it is not completely clear how, where, or when these modifications take place. Currently, only a few PTM antigens have been well-thought-out or identified in T1D, and methods for identifying and characterizing new PTM antigens are rapidly improving. This review will address both reported and potential new sources of modified islet autoantigens and discuss how islet neo-autoantigen generation may contribute to the development and progression of T1D.
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Affiliation(s)
- Rene J McLaughlin
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, E3-Q, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Matthew P Spindler
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, E3-Q, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Menno van Lummel
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, E3-Q, PO Box 9600, 2300 RC, Leiden, The Netherlands
| | - Bart O Roep
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, E3-Q, PO Box 9600, 2300 RC, Leiden, The Netherlands.
- Department of Diabetes Immunology, Diabetes & Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
- Danish Diabetes Academy, Søndre Blvd. 29, 5000, Odense, Denmark.
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30
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Deng X, Cheng J, Shen M. Vitamin D improves diabetic nephropathy in rats by inhibiting renin and relieving oxidative stress. J Endocrinol Invest 2016; 39:657-66. [PMID: 26691308 DOI: 10.1007/s40618-015-0414-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 11/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND It is well established that the activation of the renin-angiotensin system (RAS) and the oxidative stress caused by hyperglycemia are major mediators of the development and progression of diabetic nephropathy (DN). Vitamin D may be important in maintaining podocyte health, preventing epithelial-to-mesenchymal transformation, and suppressing renin gene expression and inflammation, but its mechanism requires clarification. This study evaluated the specific mechanism of vitamin D to DN improvement. METHODS We induced a rat model of diabetes with an intraperitoneal injection of streptozotocin (60 mg/kg). The streptozotocin-induced diabetic rats were fed normal chow for about 2 months to induce the DN model. The DN rats were then treated with irbesartan and/or calcitriol, administered intragastrically about 1 month. RESULTS The rats displayed the early characteristics of DN, including increased microalbuminuria, obvious hypertrophic kidney, and a markedly increased kidney weight/bodyweight ratio. Vitamin D inhibited the compensatory increase in renin expression. Malondialdehyde, which reflects oxidative stress levels, was elevated in the DN group rats and their antioxidant capacity was significantly reduced. The irbesartan and calcitriol interventions markedly improved the renal pathology and pathophysiological changes. Irbesartan combined with vitamin D (calcitriol) more effectively ameliorated DN than irbesartan alone. CONCLUSIONS Vitamin D combined with angiotensin II type 1 receptor blockers exerts a synergistic effect on the treatment of DN, not only by inhibiting renin but also by reducing oxidative stress and increasing the renal antioxidant capacity.
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Affiliation(s)
- X Deng
- Department of Endocrinology, Wuhan Third Hospital, Wuhan University, 430062, Wuhan, China.
| | - J Cheng
- Department of Endocrinology, Changzhou No. 2 People's Hospital, Nanjing Medical University, 213003, Changzhou, China
| | - M Shen
- Department of Endocrinology, Changzhou No. 2 People's Hospital, Nanjing Medical University, 213003, Changzhou, China
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31
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McLaughlin KA, Richardson CC, Ravishankar A, Brigatti C, Liberati D, Lampasona V, Piemonti L, Morgan D, Feltbower RG, Christie MR. Identification of Tetraspanin-7 as a Target of Autoantibodies in Type 1 Diabetes. Diabetes 2016; 65:1690-8. [PMID: 26953162 DOI: 10.2337/db15-1058] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 03/01/2016] [Indexed: 01/25/2023]
Abstract
The presence of autoantibodies to multiple-islet autoantigens confers high risk for the development of type 1 diabetes. Four major autoantigens are established (insulin, glutamate decarboxylase, IA2, and zinc transporter-8), but the molecular identity of a fifth, a 38-kDa membrane glycoprotein (Glima), is unknown. Glima antibodies have been detectable only by immunoprecipitation from extracts of radiolabeled islet or neuronal cells. We sought to identify Glima to enable efficient assay of these autoantibodies. Mouse brain and lung were shown to express Glima. Membrane glycoproteins from extracts of these organs were enriched by detergent phase separation, lectin affinity chromatography, and SDS-PAGE. Proteins were also immunoaffinity purified from brain extracts using autoantibodies from the sera of patients with diabetes before SDS-PAGE. Eluates from gel regions equivalent to 38 kDa were analyzed by liquid chromatography-tandem mass spectrometry for protein identification. Three proteins were detected in samples from the brain and lung extracts, and in the immunoaffinity-purified sample, but not in the negative control. Only tetraspanin-7, a multipass transmembrane glycoprotein with neuroendocrine expression, had physical characteristics expected of Glima. Tetraspanin-7 was confirmed as an autoantigen by demonstrating binding to autoantibodies in type 1 diabetes. We identify tetraspanin-7 as a target of autoimmunity in diabetes, allowing its exploitation for diabetes prediction and immunotherapy.
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Affiliation(s)
- Kerry A McLaughlin
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K
| | - Carolyn C Richardson
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K. School of Life Sciences, University of Lincoln, Lincoln, U.K
| | - Aarthi Ravishankar
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K
| | - Cristina Brigatti
- Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Daniela Liberati
- Division of Genetics and Cellular Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Vito Lampasona
- Division of Genetics and Cellular Biology, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy
| | - Diana Morgan
- Division of Epidemiology & Biostatistics, School of Medicine, University of Leeds, Leeds, U.K
| | - Richard G Feltbower
- Division of Epidemiology & Biostatistics, School of Medicine, University of Leeds, Leeds, U.K
| | - Michael R Christie
- Diabetes Research Group, Division of Diabetes & Nutritional Sciences, King's College London, London, U.K. School of Life Sciences, University of Lincoln, Lincoln, U.K.
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32
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Juan-Mateu J, Villate O, Eizirik DL. MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research. Eur J Endocrinol 2016; 174:R225-38. [PMID: 26628584 PMCID: PMC5331159 DOI: 10.1530/eje-15-0916] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Accepted: 12/01/2015] [Indexed: 12/30/2022]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in T cells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.
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Affiliation(s)
- Jonàs Juan-Mateu
- Medical FacultyULB Center for Diabetes Research and Welbio, Université Libre de Bruxelles (ULB), Route de Lennik, 808 - CP618, B-1070 Brussels, Belgium
| | - Olatz Villate
- Medical FacultyULB Center for Diabetes Research and Welbio, Université Libre de Bruxelles (ULB), Route de Lennik, 808 - CP618, B-1070 Brussels, Belgium
| | - Décio L Eizirik
- Medical FacultyULB Center for Diabetes Research and Welbio, Université Libre de Bruxelles (ULB), Route de Lennik, 808 - CP618, B-1070 Brussels, Belgium
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Abstract
Type 1 diabetes is a chronic autoimmune disease resulting from T cell-mediated destruction of insulin-producing beta cells within pancreatic islets. Disease incidence has increased significantly in the last two decades, especially in young children. Type 1 diabetes is now predictable in humans with the measurement of serum islet autoantibodies directed against insulin and beta cell proteins. Knowledge regarding the presentation of insulin and islet antigens to T cells has increased dramatically over the last several years. Here, we review the trimolecular complex in diabetes, which consists of a major histocompatibility molecule,self-peptide, and T cell receptor, with a focus on insulin peptide presentation to T cells. With this increased understanding of how antigens are presented to T cells comes the hope for improved therapies for type 1 diabetes prevention.
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Affiliation(s)
- Maki Nakayama
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Kimberly M Simmons
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA.
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Abstract
Type 1 diabetes (T1D) affects 1.93 in 1000 youth in the USA. Over the last 40 years, a combination of genetic and immunological markers has been developed allowing for the accurate prediction of progression to T1D. Despite our abilities to predict disease and the marked improvement in our understanding of the natural history of T1D, therapies capable of preventing or reversing T1D remain elusive. This article will review recent and ongoing efforts to understand the causes of T1D and related efforts to study potential therapies aimed at preventing T1D.
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Affiliation(s)
| | - Michael J Haller
- University of Florida, PO Box 100296, Gainesville, FL, 32610, USA.
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Atkinson MA, von Herrath M, Powers AC, Clare-Salzler M. Current concepts on the pathogenesis of type 1 diabetes--considerations for attempts to prevent and reverse the disease. Diabetes Care 2015; 38:979-88. [PMID: 25998290 PMCID: PMC4439528 DOI: 10.2337/dc15-0144] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Mark A Atkinson
- Department of Pathology, University of Florida, Gainesville, FL Department of Pediatrics, University of Florida, Gainesville, FL
| | - Matthias von Herrath
- La Jolla Institute for Allergy and Immunology, San Diego, CA Novo Nordisk R&D Center, Seattle, WA
| | - Alvin C Powers
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University, Nashville, TN Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN VA Tennessee Valley Healthcare System, Nashville, TN
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Simmons KM, Michels AW. Type 1 diabetes: A predictable disease. World J Diabetes 2015; 6:380-390. [PMID: 25897349 PMCID: PMC4398895 DOI: 10.4239/wjd.v6.i3.380] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 11/26/2014] [Accepted: 01/12/2015] [Indexed: 02/05/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin producing beta cells and reliance on exogenous insulin for survival. T1D is one of the most common chronic diseases in childhood and the incidence is increasing, especially in children less than 5 years of age. In individuals with a genetic predisposition, an unidentified trigger initiates an abnormal immune response and the development of islet autoantibodies directed against proteins in insulin producing beta cells. There are currently four biochemical islet autoantibodies measured in the serum directed against insulin, glutamic decarboxylase, islet antigen 2, and zinc transporter 8. Development of islet autoantibodies occurs before clinical diagnosis of T1D, making T1D a predictable disease in an individual with 2 or more autoantibodies. Screening for islet autoantibodies is still predominantly done through research studies, but efforts are underway to screen the general population. The benefits of screening for islet autoantibodies include decreasing the incidence of diabetic ketoacidosis that can be life threatening, initiating insulin therapy sooner in the disease process, and evaluating safe and specific therapies in large randomized clinical intervention trials to delay or prevent progression to diabetes onset.
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Role of nutritional factors at the early life stages in the pathogenesis and clinical course of type 1 diabetes. BIOMED RESEARCH INTERNATIONAL 2015; 2015:382165. [PMID: 25883958 PMCID: PMC4391527 DOI: 10.1155/2015/382165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 11/02/2014] [Accepted: 11/03/2014] [Indexed: 02/06/2023]
Abstract
Nutrition has been suggested as an important environmental factor other than viruses and chemicals in the pathogenesis of type 1 diabetes (T1D). Whereas various maternal dietary nutritional elements have been suggested and examined in T1D of both humans and experimental animals, the results largely remain controversial. In a series of studies using T1D model nonobese diabetic (NOD) mice, maternal dietary n-6/n-3 essential fatty acid ratio during pregnancy and lactation period, that is, early life stages of the offspring, has been shown to affect pathogenesis of insulitis and strongly prevent overt T1D of the offspring, which is consistent with its preventive effects on other allergic diseases.
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Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects. Proc Natl Acad Sci U S A 2015; 112:4429-34. [PMID: 25831495 DOI: 10.1073/pnas.1502967112] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Certain class II MHC (MHCII) alleles in mice and humans confer risk for or protection from type 1 diabetes (T1D). Insulin is a major autoantigen in T1D, but how its peptides are presented to CD4 T cells by MHCII risk alleles has been controversial. In the mouse model of T1D, CD4 T cells respond to insulin B-chain peptide (B:9-23) mimotopes engineered to bind the mouse MHCII molecule, IA(g7), in an unfavorable position or register. Because of the similarities between IA(g7) and human HLA-DQ T1D risk alleles, we examined control and T1D subjects with these risk alleles for CD4 T-cell responses to the same natural B:9-23 peptide and mimotopes. A high proportion of new-onset T1D subjects mounted an inflammatory IFN-γ response much more frequently to one of the mimotope peptides than to the natural peptide. Surprisingly, the control subjects bearing an HLA-DQ risk allele also did. However, these control subjects, especially those with only one HLA-DQ risk allele, very frequently made an IL-10 response, a cytokine associated with regulatory T cells. T1D subjects with established disease also responded to the mimotope rather than the natural B:9-23 peptide in proliferation assays and the proliferating cells were highly enriched in certain T-cell receptor sequences. Our results suggest that the risk of T1D may be related to how an HLA-DQ genotype determines the balance of T-cell inflammatory vs. regulatory responses to insulin, having important implications for the use and monitoring of insulin-specific therapies to prevent diabetes onset.
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Balti EV, Vandemeulebroucke E, Weets I, Van De Velde U, Van Dalem A, Demeester S, Verhaeghen K, Gillard P, De Block C, Ruige J, Keymeulen B, Pipeleers DG, Decochez K, Gorus FK. Hyperglycemic clamp and oral glucose tolerance test for 3-year prediction of clinical onset in persistently autoantibody-positive offspring and siblings of type 1 diabetic patients. J Clin Endocrinol Metab 2015; 100:551-60. [PMID: 25405499 DOI: 10.1210/jc.2014-2035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
CONTEXT AND OBJECTIVE In preparation of future prevention trials, we aimed to identify predictors of 3-year diabetes onset among oral glucose tolerance test (OGTT)- and hyperglycemic clamp-derived metabolic markers in persistently islet autoantibody positive (autoAb(+)) offspring and siblings of patients with type 1 diabetes (T1D). DESIGN The design is a registry-based study. SETTING Functional tests were performed in a hospital setting. PARTICIPANTS Persistently autoAb(+) first-degree relatives of patients with T1D (n = 81; age 5-39 years). MAIN OUTCOME MEASURES We assessed 3-year predictive ability of OGTT- and clamp-derived markers using receiver operating characteristics (ROC) and Cox regression analysis. Area under the curve of clamp-derived first-phase C-peptide release (AUC(5-10 min); min 5-10) was determined in all relatives and second-phase release (AUC(120-150 min); min 120-150) in those aged 12-39 years (n = 62). RESULTS Overall, the predictive ability of AUC(5-10 min) was better than that of peak C-peptide, the best predictor among OGTT-derived parameters (ROC-AUC [95%CI]: 0.89 [0.80-0.98] vs 0.81 [0.70-0.93]). Fasting blood glucose (FBG) and AUC(5-10 min) provided the best combination of markers for prediction of diabetes within 3 years; (ROC-AUC [95%CI]: 0.92 [0.84-1.00]). In multivariate Cox regression analysis, AUC(5-10 min)) (P = .001) was the strongest independent predictor and interacted significantly with all tested OGTT-derived parameters. AUC(5-10 min) below percentile 10 of controls was associated with 50-70% progression to T1D regardless of age. Similar results were obtained for AUC(120-150 min). CONCLUSIONS Clamp-derived first-phase C-peptide release can be used as an efficient and simple screening strategy in persistently autoAb(+) offspring and siblings of T1D patients to predict impending diabetes.
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Affiliation(s)
- Eric V Balti
- Diabetes Research Center (E.V.B., E.V., I.W., A.V., S.D., P.G., B.K., D.G.P., K.D., F.K.G.), Brussels Free University-VUB, Brussels, Belgium; Department of Clinical Chemistry and Radio-Immunology (E.V.B., I.W., A.V., S.D., K.V., F.K.G.), University Hospital Brussels-UZ Brussel, Brussels, Belgium; Diabetes Clinic (E.V., U.V., B.K., K.D.), University Hospital Brussels-UZ Brussel, Brussels, Belgium; Department of Clinical and Experimental Medicine (P.G.), University of Leuven-KUL and University Hospital Leuven, Leuven, Belgium; Department of Endocrinology (C.D.), Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium; and Department of Endocrinology (J.R.), University of Ghent, Ghent, Belgium
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Ilonen J, Knip M, Vaarala O. Heterogeneity in diabetes-associated autoantibodies and susceptibility to Type 1 diabetes: lessons for disease prevention. Expert Rev Endocrinol Metab 2015; 10:25-34. [PMID: 30289041 DOI: 10.1586/17446651.2015.955474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Autoantibodies against pancreatic islets are strong predictors of Type 1 diabetes. When persistent β-cell autoantibodies against at least two autoantigens are detected, the probability of diabetes is extremely high, although the time period before disease development can vary from days up to more than 20 years. Insulin autoantibodies or antibodies specific to glutamate decarboxylase 65 enzyme are in most cases, the first autoantibodies to appear. Insulin autoantibodies typically emerge very early with a peak at the age of 1.5 years, whereas the onset of glutamic acid decarboxylase 65 antibody positivity has a more even distribution, peaking later in childhood. These differences in the timing of appearance suggest that different environmental factors might be involved in the initiation of β-cell autoimmunity beginning either already in infancy or later on. This should be taken into account in studies aimed at identifying environmental factors triggering islet cell-specific autoimmunity and also in the design of prevention trials.
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Affiliation(s)
- Jorma Ilonen
- a 1 Immunogenetics Laboratory, University of Turku, Turku, Finland
- b 2 Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland
| | - Mikael Knip
- c 3 Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- d 4 Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland
- e 5 Folkhälsan Research Center, Helsinki, Finland
- f 6 Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Outi Vaarala
- g 7 Department of Vaccination and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland
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Szablewski L. Role of immune system in type 1 diabetes mellitus pathogenesis. Int Immunopharmacol 2014; 22:182-91. [PMID: 24993340 DOI: 10.1016/j.intimp.2014.06.033] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Revised: 06/16/2014] [Accepted: 06/18/2014] [Indexed: 12/26/2022]
Abstract
The immune system is the body's natural defense system against invading pathogens. It protects the body from infection and works to communicate an individual's well-being through a complex network of interconnected cells and cytokines. This system is an associated host defense. An uncontrolled immune system has the potential to trigger negative complications in the host. Type 1 diabetes results from the destruction of pancreatic β-cells by a β-cell-specific autoimmune process. Examples of β-cell autoantigens are insulin, glutamic acid decarboxylase, tyrosine phosphatase, and insulinoma antigen. There are many autoimmune diseases, but type 1 diabetes mellitus is one of the well-characterized autoimmune diseases. The mechanisms involved in the β-cell destruction are still not clear; it is generally believed that β-cell autoantigens, macrophages, dendritic cells, B lymphocytes, and T lymphocytes are involved in the β-cell-specific autoimmune process. It is necessary to determine what exact factors are causing the immune system to become unregulated in such a manner as to promote an autoimmune response.
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Affiliation(s)
- Leszek Szablewski
- General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, 5 Chalubinskiego Str., 02-004 Warsaw, Poland.
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43
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Hunt L, Emery P. Defining populations at risk of rheumatoid arthritis: the first steps to prevention. Nat Rev Rheumatol 2014; 10:521-30. [DOI: 10.1038/nrrheum.2014.82] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Raab J, Giannopoulou EZ, Schneider S, Warncke K, Krasmann M, Winkler C, Ziegler AG. Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression. Diabetologia 2014; 57:902-8. [PMID: 24531263 DOI: 10.1007/s00125-014-3181-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 01/21/2014] [Indexed: 12/31/2022]
Abstract
AIMS/HYPOTHESIS Vitamin D deficiency is common in people with type 1 diabetes, but its role in disease progression is unclear. Our aim was to assess the prevalence of vitamin D deficiency in prediabetes (defined as the presence of multiple islet autoantibodies), and investigate whether or not progression to type 1 diabetes is faster in children with vitamin D deficiency and multiple islet autoantibodies. METHODS Levels of 25-hydroxyvitamin D [25(OH)D] were measured in 108 children with multiple islet autoantibodies within 2 years of islet autoantibody seroconversion, in 406 children who remained islet autoantibody-negative and in 244 patients with newly diagnosed type 1 diabetes. Children with multiple islet autoantibodies were prospectively followed for a median of 5.8 years (interquartile range 3.4-8.6 years) to monitor progression to type 1 diabetes. RESULTS In the cross-sectional analysis, 25(OH)D levels were lower and the prevalence of vitamin D deficiency (<50 nmol/l) was higher in children with prevalent multiple islet autoantibodies than in islet autoantibody-negative children (59.9 ± 3.0 vs 71.9 ± 1.5 nmol/l; p < 0.001; 39.8% vs 28.3%; p = 0.021). The differences in vitamin D levels between the groups were greatest in summer. The cumulative incidence of type 1 diabetes at 10 years after seroconversion was similar between children with vitamin D deficiency and those with sufficient vitamin D levels (51.8% [95% CI 29.3, 74.3] vs 55.4% [95% CI 35.5, 72.3], p = 0.8). CONCLUSIONS/INTERPRETATION Vitamin D levels were lower in children with multiple islet autoantibodies and in children with type 1 diabetes than in autoantibody-negative children. However, vitamin D deficiency was not associated with faster progression to type 1 diabetes in children with multiple islet autoantibodies.
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Abstract
Cell therapy in the form of human islet transplantation has been a successful form of treatment for patients with type 1 diabetes for over 10 years, but is significantly limited by lack of suitable donor material. A replenishable supply of insulin-producing cells has the potential to address this problem; however to date success has been limited to a few preclinical studies. Two of the most promising strategies include differentiation of embryonic stem cells and induced pluripotent stem cells towards insulin-producing cells and transdifferentiation of acinar or other closely related cell types towards β-cells. Here, we discuss recent progress and challenges that need to be overcome in taking cell therapy to the clinic.
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Affiliation(s)
- K R Muir
- School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
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46
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Collier RJ, Bauman DE. Update on human health concerns of recombinant bovine somatotropin use in dairy cows. J Anim Sci 2014; 92:1800-7. [DOI: 10.2527/jas.2013-7383] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- R. J. Collier
- School of Animal and Comparative Biomedical Sciences University of Arizona, Tucson 85719
| | - D. E. Bauman
- Department of Animal Science, Cornell University, Ithaca, NY 14853
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Gorus FK, Keymeulen B, Veld PAI, Pipeleers DG. Predictors of progression to Type 1 diabetes: preparing for immune interventions in the preclinical disease phase. Expert Rev Clin Immunol 2014; 9:1173-83. [DOI: 10.1586/1744666x.2013.856757] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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DiaPep277® and immune intervention for treatment of type 1 diabetes. Clin Immunol 2013; 149:307-16. [DOI: 10.1016/j.clim.2013.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Revised: 09/01/2013] [Accepted: 09/03/2013] [Indexed: 11/24/2022]
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Tagore S, De RK. Simulating an infection growth model in certain healthy metabolic pathways of Homo sapiens for highlighting their role in Type I Diabetes mellitus using fire-spread strategy, feedbacks and sensitivities. PLoS One 2013; 8:e69724. [PMID: 24039701 PMCID: PMC3767837 DOI: 10.1371/journal.pone.0069724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 06/12/2013] [Indexed: 11/18/2022] Open
Abstract
Disease Systems Biology is an area of life sciences, which is not very well understood to date. Analyzing infections and their spread in healthy metabolite networks can be one of the focussed areas in this regard. We have proposed a theory based on the classical forest fire model for analyzing the path of infection spread in healthy metabolic pathways. The theory suggests that when fire erupts in a forest, it spreads, and the surrounding trees also catch fire. Similarly, when we consider a metabolic network, the infection caused in the metabolites of the network spreads like a fire. We have constructed a simulation model which is used to study the infection caused in the metabolic networks from the start of infection, to spread and ultimately combating it. For implementation, we have used two approaches, first, based on quantitative strategies using ordinary differential equations and second, using graph-theory based properties. Furthermore, we are using certain probabilistic scores to complete this task and for interpreting the harm caused in the network, given by a 'critical value' to check whether the infection can be cured or not. We have tested our simulation model on metabolic pathways involved in Type I Diabetes mellitus in Homo sapiens. For validating our results biologically, we have used sensitivity analysis, both local and global, as well as for identifying the role of feedbacks in spreading infection in metabolic pathways. Moreover, information in literature has also been used to validate the results. The metabolic network datasets have been collected from the Kyoto Encyclopedia of Genes and Genomes (KEGG).
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Affiliation(s)
- Somnath Tagore
- Department of Biotechnology and Bioinformatics, Padmashree Dr. D. Y. Patil University, Navi Mumbai, India
| | - Rajat K. De
- Machine Intelligence Unit, Indian Statistical Institute, Kolkata, India
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Salvatoni A, Baj A, Bianchi G, Federico G, Colombo M, Toniolo A. Intrafamilial spread of enterovirus infections at the clinical onset of type 1 diabetes. Pediatr Diabetes 2013; 14:407-16. [PMID: 23763622 DOI: 10.1111/pedi.12056] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/25/2013] [Accepted: 05/14/2013] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND At the clinical onset of type 1 diabetes mellitus (T1D), enterovirus (EV) infections are suspected to play a role. EVs in blood are seen as a possible biomarker of T1D. EV infections may occur in temporal and geographic clusters and may spread within families. OBJECTIVE We checked whether EVs were present in the blood of newly diagnosed diabetic probands and of their consenting siblings and parents. We aimed at evaluating the frequency of EV infection, whether infections were spreading within families, and which EV species were involved. SUBJECTS AND METHODS Blood was drawn from 24 newly diagnosed diabetic children/adolescents and their family members (20 siblings and 41 parents). Blood donors and non-diabetic children/adolescents diagnosed with overweight/short stature were used as controls. RNA was extracted from plasma/leukocytes. Reverse-transcription polymerase chain reaction assays capable of detecting virtually all EV types and of giving preliminary species identification were used. RESULTS AND CONCLUSIONS EV genomes were found in the blood of 19 of 24 (79%) diabetics, 12 of 20 (60%) non-diabetic siblings, 26 of 41 (63%) parents, and 1 of 29 (3%) pediatric controls. EVs of the A, B, C, and D species were detected, with the B and C species more prevalent. Probands and virus-positive members of each family consistently shared the same EV species. During follow-up, 4 of 20 (20%) siblings of diabetic probands developed T1D with a latency of 3-25 months. In conclusion, infection by different EV species is highly prevalent at the clinical onset and extends to family members. EV may represent a precipitating factor of T1D. However, the disease only develops in a subset of infected individuals.
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Affiliation(s)
- Alessandro Salvatoni
- Pediatric Diabetes Unit, Department of Clinical and Experimental Medicine, University of Insubria Medical School, Varese, Italy.
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