|
1
|
van Tienhoven R, O'Meally D, Scott TA, Morris KV, Williams JC, Kaddis JS, Zaldumbide A, Roep BO. Genetic protection from type 1 diabetes resulting from accelerated insulin mRNA decay. Cell 2025; 188:2407-2416.e9. [PMID: 40112799 DOI: 10.1016/j.cell.2025.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/07/2025] [Accepted: 02/21/2025] [Indexed: 03/22/2025]
Abstract
Insulin gene (INS) variation and beta-cell stress are associated with the risk of development of type 1 diabetes (T1D) and autoimmunity against insulin. The unfolded protein response alleviating endoplasmic reticulum (ER) stress involves activation of inositol-requiring enzyme 1α (IRE1α) that impedes translation by mRNA decay. We discover that the IRE1α digestion motif is present in insulin mRNA carrying SNP rs3842752 (G>A). This SNP in the 3' untranslated region of INS associates with protection from T1D (INSP). ER stress in beta cells with INSP led to accelerated insulin mRNA decay compared with the susceptible INS variant (INSS). Human islets with INSP showed improved vitality and function and reversed diabetes more rapidly when transplanted into diabetic mice than islets carrying INSS only. Surrogate beta cells with INSP expressed less ER stress and INS-DRiP neoantigen. This explanation for genetic protection from T1D may act instead of or in concert with the previously proposed mechanism attributed to INS promoter polymorphism.
Collapse
Affiliation(s)
- René van Tienhoven
- Department of Diabetes Immunology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA; Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Denis O'Meally
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Tristan A Scott
- Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Kevin V Morris
- Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Kelvin Grove, Brisbane, QLD 4059, Australia
| | - John C Williams
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Arnaud Zaldumbide
- Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden 2333ZA, the Netherlands
| | - Bart O Roep
- Department of Internal Medicine, Leiden University Medical Center, Leiden 2333ZA, the Netherlands.
| |
Collapse
|
|
2
|
Mavridou M, Pearce SH. Exploring antigenic variation in autoimmune endocrinopathy. Front Immunol 2025; 16:1561455. [PMID: 40093006 PMCID: PMC11906412 DOI: 10.3389/fimmu.2025.1561455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Accepted: 02/07/2025] [Indexed: 03/19/2025] Open
Abstract
Autoimmune disorders develop owing to a misdirected immune response against self-antigen. Genetic studies have revealed that numerous variants in genes encoding immune system proteins are associated with the development of autoimmunity. Indeed, many of these genetic variants in key immune receptors or transcription factors are common in the pathogenesis of several different autoimmune conditions. In contrast, the proclivity to develop autoimmunity to any specific target organ or tissue is under-researched. This has particular relevance to autoimmune endocrine conditions, where organ-specific involvement is the rule. Genetic polymorphisms in the genes encoding the targets of autoimmune responses have been shown to be associated with predisposition to several autoimmune diseases, including type 1 diabetes, autoimmune thyroid disease and Addison's disease. Mechanistically, variations leading to decreased intrathymic expression, overexpression, different localisation, alternative splicing or post-translational modifications can interfere in the tolerance induction process. This review will summarise the different ways genetic variations in certain genes encoding endocrine-specific antigens (INS, TSHR, TPO, CYP21A2, PIT-1) may predispose to different autoimmune endocrine conditions.
Collapse
Affiliation(s)
- Maria Mavridou
- Translational and Clinical Research Institute, Newcastle University, BioMedicine
West, Newcastle-upon-Tyne, United Kingdom
| | - Simon H. Pearce
- Translational and Clinical Research Institute, Newcastle University, BioMedicine
West, Newcastle-upon-Tyne, United Kingdom
- Endocrine Unit, Royal Victoria Infirmary,
Newcastle-upon-Tyne, United Kingdom
| |
Collapse
|
|
3
|
Du M, Li S, Jiang J, Ma X, Liu L, Wang T, Zhang J, Niu D. Advances in the Pathogenesis and Treatment Strategies for Type 1 Diabetes Mellitus. Int Immunopharmacol 2025; 148:114185. [PMID: 39893858 DOI: 10.1016/j.intimp.2025.114185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/26/2025] [Accepted: 01/26/2025] [Indexed: 02/04/2025]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disorder distinguished by the infiltration of immune cells into pancreatic islets, primarily resulting in damage to pancreatic β-cells. Despite extensive research, the precise pathogenesis of T1D remains elusive, with its etiology linked to a complex interplay of genetic, immune, and environmental factors. While genetic predispositions, such as HLA and other susceptibility genes, are necessary, they do not fully account for disease development. Environmental influences such as viral infections and dietary factors may contribute to the disease by affecting the immune system and epigenetic modifications. Additionally, endogenous retroviruses (ERVs) might play a role in T1D pathogenesis. Current therapeutic approaches, including insulin replacement therapy, immune omodulatory therapy, autoantigen immunotherapy, organ transplantation, and genetic modification, offer potential to alter disease progression but are still constrained by limitations. This review presents updated knowledge on T1D, with a focus on risk factors, predisposing hypotheses, and recent advancements in therapeutic strategies.
Collapse
Affiliation(s)
- Meiheng Du
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China
| | - Sihong Li
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China
| | - Jun Jiang
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China
| | - Xiang Ma
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China
| | - Lu Liu
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China
| | - Tao Wang
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, Jiangsu 211300, China
| | - Jufang Zhang
- Department of Plastic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang 310006, China.
| | - Dong Niu
- College of Animal Science and Technology & College of Veterinary Medicine, Zhejiang A&F University, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Hangzhou, Zhejiang 311300, China.
| |
Collapse
|
|
4
|
Zhou Y, Chen X, Zu X. ZBTB7A as a therapeutic target for cancer. Biochem Biophys Res Commun 2024; 736:150888. [PMID: 39490153 DOI: 10.1016/j.bbrc.2024.150888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/23/2024] [Accepted: 10/23/2024] [Indexed: 11/05/2024]
Abstract
ZBTB7A, alternatively referred to Pokemon, FBI-1, LRF, and OCZF, is classified as a member of POK/ZBTB protein family of transcriptional repressors. ZBTB7A binds to targeted DNA via C-terminal zinc fingers and recruits co-compression complexes through N-terminal BTB ⁄ POZ domain to impede transcription. ZBTB7A regulates a range of fundamental biological processes such as cell proliferation, differentiation and apoptosis, B- and T-lymphocyte fate determination and thymic insulin expression and self-tolerance. Accumulating evidence has demonstrated an important role of ZBTB7A in the initiation and advancement of tumors, thus making ZBTB7A emerge as an appealing target. This review examines the functions and regulatory mechanisms of ZBTB7A in a range of common solid tumors, including hepatocellular carcinoma, breast cancer, prostate cancer and lung cancer, as well as hematological malignancies. Notably, the review concludes with a summary of the recent applications of targeting ZBTB7A in clinical treatments through gene silencing, immunotherapy and chemotherapeutic approaches to halt or slow tumor progression. We focus on the functional role and regulatory mechanisms of ZBTB7A in cancer with the goal of providing new insights for the development of more effective cancer therapeutic strategies.
Collapse
Affiliation(s)
- Ying Zhou
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
| | - Xisha Chen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; Hunan Provincial Clinical Medical Research Center for Drug Evaluation of Major Chronic Diseases, China.
| |
Collapse
|
|
5
|
Liquat N, Hassan MU, Shafique F, Khan S, Alanzi AR, Khan NU. Investigating the role of keratin proteins and microbial associations in hereditary and pathogenic alopecia. Arch Dermatol Res 2024; 316:718. [PMID: 39460809 DOI: 10.1007/s00403-024-03436-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/16/2024] [Accepted: 09/30/2024] [Indexed: 10/28/2024]
Abstract
The purpose of this research was to identify the role of keratin proteins in causing inherited as well as pathogenic alopecia, pinpoint deleterious SNPs, and predict structural changes affecting protein-protein interactions in hair disorders. To elucidate the role of keratin proteins and genetic mutations in alopecia by analyzing protein structures through bioinformatics and identifying a mutation in the LPAR6 gene. It sought to identify the microorganisms linked to alopecia and conducted a comprehensive bioinformatics analysis of proteins with unknown experimental structures and molecular simulation analysis. The study identified a genetic mutation (c.188 A > T, p.Asp63Val) in the LPAR6 gene associated with hereditary hair loss. Pathogenic alopecia was identified to be associated with S. aureus and two ic keratinophilic fungi namely M. canis, and T. violaceum. Additionally, among 14 proteins lacking prior structural information, four proteins namely Keratin, type II cuticular Hb3 (KR1), Keratin, type II cuticular Hb6 (KR2), Keratin, type II cytoskeletal 74 (KR3) and Keratin, type II cuticular Hb1 (KR4) exhibited common 'K-head' and 'F' domains. Docking analysis revealed five distinct binding sites (C1-C5) for each protein. The 'K-head' displayed the highest predicted binding affinities with Vina scores of -5.6 for KR2 and - 4.7 for KR4 whereas the 'F' domain showed Vina scores of -6.0 for KR3 and - 5.7 for KR2. This research underscores the crucial role of keratin proteins in both hereditary and pathogenic alopecia, emphasizing their significance for future investigations.
Collapse
Affiliation(s)
- Nadia Liquat
- Department of Microbiology, Shaheed Benazir Bhutto Women University Peshawar, Pakhtunkhwa, Pakistan
| | - Mahreen Ul Hassan
- Department of Microbiology, Shaheed Benazir Bhutto Women University Peshawar, Pakhtunkhwa, Pakistan
| | - Farheen Shafique
- Department of Zoology, Faculty of Science, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
| | - Sana Khan
- Combinatorial Tumor Immunotherapy MRC, Chonnam National University Medical School, Hwasun-gun, Jeollanam-do, South Korea
| | - Abdullah R Alanzi
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Najeeb Ullah Khan
- Institute of Biotechnology and Genetic Engineering, The University of Agriculture Peshawar, Pakhtunkhwa, Pakistan.
| |
Collapse
|
|
6
|
Roy S, Pokharel P, Piganelli JD. Decoding the immune dance: Unraveling the interplay between beta cells and type 1 diabetes. Mol Metab 2024; 88:101998. [PMID: 39069156 PMCID: PMC11342121 DOI: 10.1016/j.molmet.2024.101998] [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: 05/11/2024] [Revised: 07/12/2024] [Accepted: 07/23/2024] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by the specific destruction of insulin-producing beta cells in the pancreas by the immune system, including CD4 cells which orchestrate the attack and CD8 cells which directly destroy the beta cells, resulting in the loss of glucose homeostasis. SCOPE OF REVIEW This comprehensive document delves into the complex interplay between the immune system and beta cells, aiming to shed light on the mechanisms driving their destruction in T1D. Insights into the genetic predisposition, environmental triggers, and autoimmune responses provide a foundation for understanding the autoimmune attack on beta cells. From the role of viral infections as potential triggers to the inflammatory response of beta cells, an intricate puzzle starts to unfold. This exploration highlights the importance of beta cells in breaking immune tolerance and the factors contributing to their targeted destruction. Furthermore, it examines the potential role of autophagy and the impact of cytokine signaling on beta cell function and survival. MAJOR CONCLUSIONS This review collectively represents current research findings on T1D which offers valuable perspectives on novel therapeutic approaches for preserving beta cell mass, restoring immune tolerance, and ultimately preventing or halting the progression of T1D. By unraveling the complex dynamics between the immune system and beta cells, we inch closer to a comprehensive understanding of T1D pathogenesis, paving the way for more effective treatments and ultimately a cure.
Collapse
Affiliation(s)
- Saptarshi Roy
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Pravil Pokharel
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States
| | - Jon D Piganelli
- Department of Endocrinology, Indiana University School of Medicine, Indianapolis, IN, 46202, United States.
| |
Collapse
|
|
7
|
Guneri D, Alexandrou E, El Omari K, Dvořáková Z, Chikhale RV, Pike DTS, Waudby CA, Morris CJ, Haider S, Parkinson GN, Waller ZAE. Structural insights into i-motif DNA structures in sequences from the insulin-linked polymorphic region. Nat Commun 2024; 15:7119. [PMID: 39164244 PMCID: PMC11336075 DOI: 10.1038/s41467-024-50553-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 07/12/2024] [Indexed: 08/22/2024] Open
Abstract
The insulin-linked polymorphic region is a variable number of tandem repeats region of DNA in the promoter of the insulin gene that regulates transcription of insulin. This region is known to form the alternative DNA structures, i-motifs and G-quadruplexes. Individuals have different sequence variants of tandem repeats and although previous work investigated the effects of some variants on G-quadruplex formation, there is not a clear picture of the relationship between the sequence diversity, the DNA structures formed, and the functional effects on insulin gene expression. Here we show that different sequence variants of the insulin linked polymorphic region form different DNA structures in vitro. Additionally, reporter genes in cellulo indicate that insulin expression may change depending on which DNA structures form. We report the crystal structure and dynamics of an intramolecular i-motif, which reveal sequences within the loop regions forming additional stabilising interactions that are critical to formation of stable i-motif structures. The outcomes of this work reveal the detail in formation of stable i-motif DNA structures, with potential for rational based drug design for compounds to target i-motif DNA.
Collapse
Affiliation(s)
- Dilek Guneri
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Effrosyni Alexandrou
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Kamel El Omari
- Diamond Light Source, Harwell Science and Innovation Campus, Chilton, Didcot, OX11 0DE, UK
| | - Zuzana Dvořáková
- Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 00, Brno, Czech Republic
| | - Rupesh V Chikhale
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Daniel T S Pike
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Christopher A Waudby
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Christopher J Morris
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
| | - Shozeb Haider
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
- UCL Centre for Advanced Research Computing, University College London, Gower Street, London, WC1E 6BT, UK.
| | - Gary N Parkinson
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
| | - Zoë A E Waller
- School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
| |
Collapse
|
|
8
|
Robertson CC, Elgamal RM, Henry-Kanarek BA, Arvan P, Chen S, Dhawan S, Eizirik DL, Kaddis JS, Vahedi G, Parker SCJ, Gaulton KJ, Soleimanpour SA. Untangling the genetics of beta cell dysfunction and death in type 1 diabetes. Mol Metab 2024; 86:101973. [PMID: 38914291 PMCID: PMC11283044 DOI: 10.1016/j.molmet.2024.101973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. SCOPE OF REVIEW Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. MAJOR CONCLUSIONS We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.
Collapse
Affiliation(s)
- Catherine C Robertson
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Ruth M Elgamal
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Belle A Henry-Kanarek
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Peter Arvan
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Center for Genomic Health, Weill Cornell Medicine, New York, NY, USA
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Golnaz Vahedi
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stephen C J Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
| | - Kyle J Gaulton
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
| | - Scott A Soleimanpour
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA.
| |
Collapse
|
|
9
|
Berumen J, Orozco L, Gallardo-Rincón H, Juárez-Torres E, Barrera E, Cruz-López M, Benuto RE, Ramos-Martinez E, Marin-Madina M, Alvarado-Silva A, Valladares-Salgado A, Peralta-Romero JJ, García-Ortiz H, Martinez-Juarez LA, Montoya A, Alvarez-Hernández DA, Alegre-Diaz J, Kuri-Morales P, Tapia-Conyer R. Association of tyrosine hydroxylase 01 (TH01) microsatellite and insulin gene (INS) variable number of tandem repeat (VNTR) with type 2 diabetes and fasting insulin secretion in Mexican population. J Endocrinol Invest 2024; 47:571-583. [PMID: 37624484 PMCID: PMC10904573 DOI: 10.1007/s40618-023-02175-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/05/2023] [Indexed: 08/26/2023]
Abstract
PURPOSE A variable number of tandem repeats (VNTR) in the insulin gene (INS) control region may be involved in type 2 diabetes (T2D). The TH01 microsatellite is near INS and may regulate it. We investigated whether the TH01 microsatellite and INS VNTR, assessed via the surrogate marker single nucleotide polymorphism rs689, are associated with T2D and serum insulin levels in a Mexican population. METHODS We analyzed a main case-control study (n = 1986) that used univariate and multivariate logistic regression models to calculate the risk conferred by TH01 and rs689 loci for T2D development; rs689 results were replicated in other case-control (n = 1188) and cross-sectional (n = 1914) studies. RESULTS TH01 alleles 6, 8, 9, and 9.3 and allele A of rs689 were independently associated with T2D, with differences between sex and age at diagnosis. TH01 alleles with ≥ 8 repeats conferred an increased risk for T2D in males compared with ≤ 7 repeats (odds ratio, ≥ 1.46; 95% confidence interval, 1.1-1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed ≥ 46 years but conferred protection when diagnosed ≤ 45 years. Similarly, rs689 allele A was associated with T2D in these groups. In males, larger TH01 alleles and the rs689 A allele were associated with a significant decrease in median fasting plasma insulin concentration with age in T2D cases; the reverse occurred in controls. CONCLUSION Larger TH01 alleles and rs689 A allele may potentiate insulin synthesis in males without T2D, a process disabled in those with T2D.
Collapse
Affiliation(s)
- J Berumen
- Facultad de Medicina, Unidad de Investigación en Medicina Experimental, Universidad Nacional Autónoma de México, 06720, Mexico City, México.
| | - L Orozco
- Laboratorio de Inmunogenómica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, Secretaria de Salud, 14610, Mexico City, México
| | - H Gallardo-Rincón
- Departamento de Soluciones Operativas, Fundación Carlos Slim, 11529, Mexico City, Mexico.
- Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, 44340, Guadalajara, Jalisco, México.
| | - E Juárez-Torres
- Laboratorio Huella Génica, Unidad de Diabetes, 06600, Mexico City, Mexico
| | - E Barrera
- Facultad de Medicina, Unidad de Investigación en Medicina Experimental, Universidad Nacional Autónoma de México, 06720, Mexico City, México
| | - M Cruz-López
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 06720, Mexico City, México
| | - R E Benuto
- Laboratorio Huella Génica, Unidad de Diabetes, 06600, Mexico City, Mexico
| | - E Ramos-Martinez
- Facultad de Medicina, Unidad de Investigación en Medicina Experimental, Universidad Nacional Autónoma de México, 06720, Mexico City, México
| | - M Marin-Madina
- Laboratorio Huella Génica, Unidad de Diabetes, 06600, Mexico City, Mexico
| | - A Alvarado-Silva
- Laboratorio Huella Génica, Unidad de Diabetes, 06600, Mexico City, Mexico
| | - A Valladares-Salgado
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 06720, Mexico City, México
| | - J J Peralta-Romero
- Unidad de Investigación Médica en Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, 06720, Mexico City, México
| | - H García-Ortiz
- Laboratorio de Inmunogenómica y Enfermedades Metabólicas, Instituto Nacional de Medicina Genómica, Secretaria de Salud, 14610, Mexico City, México
| | - L A Martinez-Juarez
- Departamento de Soluciones Operativas, Fundación Carlos Slim, 11529, Mexico City, Mexico
- Center for Humanitarian Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - A Montoya
- Departamento de Soluciones Operativas, Fundación Carlos Slim, 11529, Mexico City, Mexico
| | - D A Alvarez-Hernández
- Departamento de Soluciones Operativas, Fundación Carlos Slim, 11529, Mexico City, Mexico
| | - J Alegre-Diaz
- Facultad de Medicina, Unidad de Investigación en Medicina Experimental, Universidad Nacional Autónoma de México, 06720, Mexico City, México
| | - P Kuri-Morales
- Proyecto OriGen, Instituto Tecnologico y de Estudios Superiores de Monterrey, Monterrey, México
| | - R Tapia-Conyer
- Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, 04510, Mexico City, México
| |
Collapse
|
|
10
|
Ansari MA, Chauhan W, Shoaib S, Alyahya SA, Ali M, Ashraf H, Alomary MN, Al-Suhaimi EA. Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions. Int J Obes (Lond) 2023; 47:1179-1199. [PMID: 37696926 DOI: 10.1038/s41366-023-01369-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/04/2023] [Accepted: 08/17/2023] [Indexed: 09/13/2023]
Abstract
Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.
Collapse
Affiliation(s)
- Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia.
| | - Waseem Chauhan
- Department of Hematology, Duke University, Durham, NC, 27710, USA
| | - Shoaib Shoaib
- Department of Biochemistry, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Sami A Alyahya
- Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia
| | - Mubashshir Ali
- USF Health Byrd Alzheimer's Center and Neuroscience Institute, Department of Molecular Medicine, Tampa, FL, USA
| | - Hamid Ashraf
- Rajiv Gandhi Center for Diabetes and Endocrinology, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohammad N Alomary
- Advanced Diagnostic and Therapeutic Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia.
| | - Ebtesam A Al-Suhaimi
- King Abdulaziz & his Companions Foundation for Giftedness & Creativity, Riyadh, Saudi Arabia.
| |
Collapse
|
|
11
|
Allen LA, Taylor PN, Gillespie KM, Oram RA, Dayan CM. Maternal type 1 diabetes and relative protection against offspring transmission. Lancet Diabetes Endocrinol 2023; 11:755-767. [PMID: 37666263 DOI: 10.1016/s2213-8587(23)00190-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 09/06/2023]
Abstract
Type 1 diabetes is around twice as common in the offspring of men with type 1 diabetes than in the offspring of women with type 1 diabetes, but the reasons for this difference are unclear. This Review summarises the evidence on the rate of transmission of type 1 diabetes to the offspring of affected fathers compared with affected mothers. The findings of nine major studies are presented, describing the magnitude of the effect observed and the relative strengths and weaknesses of these studies. This Review also explores possible underlying mechanisms for this effect, such as genetic mechanisms (eg, the selective loss of fetuses with high-risk genes in mothers with type 1 diabetes, preferential transmission of susceptibility genes from fathers, and parent-of-origin effects influencing gene expression), environmental exposures (eg, exposure to maternal hyperglycaemia, exogenous insulin exposure, and transplacental antibody transfer), and maternal microchimerism. Understanding why type 1 diabetes is more common in the offspring of men versus women with type 1 diabetes will help in the identification of individuals at high risk of the disease and can pave the way in the development of interventions that mimic the protective elements of maternal type 1 diabetes to reduce the risk of disease in individuals at high risk.
Collapse
Affiliation(s)
- Lowri A Allen
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK.
| | - Peter N Taylor
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK
| | - Kathleen M Gillespie
- Diabetes and Metabolism, Bristol Medical School, University of Bristol, Southmead Hospital, Bristol, UK
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK
| | - Colin M Dayan
- Diabetes Research Group, Cardiff University, University Hospital of Wales, Cardiff, UK
| |
Collapse
|
|
12
|
Yang X, Hou X, Zhang J, Liu Z, Wang G. Research progress on the application of single-cell sequencing in autoimmune diseases. Genes Immun 2023; 24:220-235. [PMID: 37550409 DOI: 10.1038/s41435-023-00216-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/09/2023]
Abstract
Autoimmune diseases (AIDs) are caused by immune tolerance deficiency or abnormal immune regulation, leading to damage to host organs. The complicated pathogenesis and varied clinical symptoms of AIDs pose great challenges in diagnosing and monitoring this disease. Regrettably, the etiological factors and pathogenesis of AIDs are still not completely understood. It is noteworthy that the development of single-cell RNA sequencing (scRNA-seq) technology provides a new tool for analyzing the transcriptome of AIDs. In this essay, we have summarized the development of scRNA-seq technology, and made a relatively systematic review of the current research progress of scRNA-seq technology in the field of AIDs, providing a reference to preferably understand the pathogenesis, diagnosis, and treatment of AIDs.
Collapse
Affiliation(s)
- Xueli Yang
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Xianliang Hou
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China.
| | - Junning Zhang
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Zhenyu Liu
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| | - Guangyu Wang
- Central Laboratory, Guangxi Health Commission Key Laboratory of Glucose and Lipid Metabolism Disorders, The Second Affiliated Hospital of Guilin Medical University, Guilin, 541199, China
| |
Collapse
|
|
13
|
Mukamel RE, Handsaker RE, Sherman MA, Barton AR, Hujoel MLA, McCarroll SA, Loh PR. Repeat polymorphisms underlie top genetic risk loci for glaucoma and colorectal cancer. Cell 2023; 186:3659-3673.e23. [PMID: 37527660 PMCID: PMC10528368 DOI: 10.1016/j.cell.2023.07.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 04/07/2023] [Accepted: 07/03/2023] [Indexed: 08/03/2023]
Abstract
Many regions in the human genome vary in length among individuals due to variable numbers of tandem repeats (VNTRs). To assess the phenotypic impact of VNTRs genome-wide, we applied a statistical imputation approach to estimate the lengths of 9,561 autosomal VNTR loci in 418,136 unrelated UK Biobank participants and 838 GTEx participants. Association and statistical fine-mapping analyses identified 58 VNTRs that appeared to influence a complex trait in UK Biobank, 18 of which also appeared to modulate expression or splicing of a nearby gene. Non-coding VNTRs at TMCO1 and EIF3H appeared to generate the largest known contributions of common human genetic variation to risk of glaucoma and colorectal cancer, respectively. Each of these two VNTRs associated with a >2-fold range of risk across individuals. These results reveal a substantial and previously unappreciated role of non-coding VNTRs in human health and gene regulation.
Collapse
Affiliation(s)
- Ronen E Mukamel
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Robert E Handsaker
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
| | - Maxwell A Sherman
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alison R Barton
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Bioinformatics and Integrative Genomics Program, Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
| | - Margaux L A Hujoel
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Steven A McCarroll
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA.
| | - Po-Ru Loh
- Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| |
Collapse
|
|
14
|
Adashi EY, Cibula D, Peterson M, Azziz R. The polycystic ovary syndrome: the first 150 years of study. F S Rep 2023; 4:2-18. [PMID: 36959968 PMCID: PMC10028479 DOI: 10.1016/j.xfre.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open
Abstract
The communities of reproductive medicine and reproductive sciences have been witness to an enormous acceleration of interest in polycystic ovary syndrome (PCO) since the mid-19th century. Although progress has been increasingly palpable, the fundamentals of the etiology and pathophysiology of PCO remain as elusive as ever. Particularly lacking is a requisite understanding of events at the cellular and molecular levels. As we cross the millennial divide, it appears appropriate that an interim progress report be crafted. This treatise is attempting to meet this objective. What follows traces the chronology of the recorded history of PCO in 4 parts.
Collapse
Affiliation(s)
- Eli Y. Adashi
- Department of Medical Science, the Warren Alpert Medical School, Brown University, Providence, Rhode Island
- Correspondence: Eli Y. Adashi, M.D., MS, Brown University, 272 George St, Providence, Rhode Island 02906.
| | - David Cibula
- Gynecologic Oncology Center, Department of Obstetrics and Gynecology, First Faculty of Medicine, Charles University and General University Hospital (Central and Eastern European Gynecologic Oncology Group, CEEGOG), Prague, Czech Republic
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Matthew Peterson
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
| | | |
Collapse
|
|
15
|
Li H, Hu X, Li J, Jiang W, Wang L, Tan X. Identification of key regulatory genes and their working mechanisms in type 1 diabetes. BMC Med Genomics 2023; 16:8. [PMID: 36650594 PMCID: PMC9843847 DOI: 10.1186/s12920-023-01432-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 01/04/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of beta cells in pancreatic islets. Identification of the key genes involved in T1D progression and their mechanisms of action may contribute to a better understanding of T1D. METHODS The microarray profile of T1D-related gene expression was searched using the Gene Expression Omnibus (GEO) database. Then, the expression data of two messenger RNAs (mRNAs) were integrated for Weighted Gene Co-Expression Network Analysis (WGCNA) to generate candidate genes related to T1D. In parallel, T1D microRNA (miRNA) data were analyzed to screen for possible regulatory miRNAs and their target genes. An miRNA-mRNA regulatory network was then established to predict the key regulatory genes and their mechanisms. RESULTS A total of 24 modules (i.e., clusters/communities) were selected using WGCNA analysis, in which three modules were significantly associated with T1D. Further correlation analysis of the gene module revealed 926 differentially expressed genes (DEGs), of which 327 genes were correlated with T1D. Analysis of the miRNA microarray showed that 13 miRNAs had significant expression differences in T1D. An miRNA-mRNA network was established based on the prediction of miRNA target genes and the combined analysis of mRNA, in which the target genes of two miRNAs were found in T1D correlated genes. CONCLUSION An miRNA-mRNA network for T1D was established, based on which 2 miRNAs and 12 mRNAs were screened, suggesting that they may play key regulatory roles in the initiation and development of T1D.
Collapse
Affiliation(s)
- Hui Li
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| | - Xiao Hu
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| | - Jieqiong Li
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| | - Wen Jiang
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| | - Li Wang
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| | - Xin Tan
- grid.508008.50000 0004 4910 8370Pediatric Department, The First Hospital of Changsha, No. 311, Yingpan Road, Kaifu District, Changsha, 410000 Hunan People’s Republic of China
| |
Collapse
|
|
16
|
van Tienhoven R, Vu AN, Kaddis JS, Roep BO. Low risk for diabetic complications in type 1 diabetes patients carrying a protective insulin gene variant. PLoS One 2023; 18:e0280872. [PMID: 36701305 PMCID: PMC9879388 DOI: 10.1371/journal.pone.0280872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 01/10/2023] [Indexed: 01/27/2023] Open
Abstract
Type 1 diabetes patients carrying a 'protective' insulin gene (INS) variant present a disease endotype with reduced insulin antibody titers, preserved beta cell function and improved glycemic control. We tested whether this protective INS variant associated with lowered risk for development of proliferative diabetic retinopathy (PDR) and diabetic kidney disease (DKD) as long-term diabetic complications. Insulin gene polymorphisms were evaluated in 1,363 type 1 diabetes patients participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study that compared intensive versus conventional insulin therapy in relation with development of PDR and DKD with a follow-up of over two decades. PDR and DKD were absent in type 1 diabetes patients carrying the protective INS variant and receiving intensive insulin therapy (the current standard of clinical care) 1-5 years from their diagnosis (n = 67; mean post-diagnosis follow up of 20.4 ± 1.6 years), versus 11 of 258 patients (4.3%) lacking this variant (20.4 ± 1.8 years follow up). In the secondary intervention group of the intensive therapy arm (1-15 years of disease), PDR was significantly less frequent in carriers of the protective INS variant than those without it (4 of 83 [4.8%] vs. 31 of 260 [11.9%]; p = 0.032; 26.1 ± 3.9 and 26.3 ± 4.1 years follow-up, respectively), whereas DKD frequencies were no different between those with or without this variant (5 of 83 [6.0%] vs. 11 of 260 [4.2%]). Carrying a copy of this protective INS variant further reduces the risk of diabetic complications achieved by intensive insulin therapy and marks a disease endotype with superior glycemic control, increased and extended beta cell function, and prevention of DKD and PDR.
Collapse
Affiliation(s)
- René van Tienhoven
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, California, United States America
| | - Anh Nguyet Vu
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, California, United States America
| | - John S. Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, California, United States America
| | - Bart O. Roep
- Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
- * E-mail:
| |
Collapse
|
|
17
|
Harrison LC. Type 1 Diabetes. Clin Immunol 2023. [DOI: 10.1016/b978-0-7020-8165-1.00071-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
|
|
18
|
Pang H, Lin J, Luo S, Huang G, Li X, Xie Z, Zhou Z. The missing heritability in type 1 diabetes. Diabetes Obes Metab 2022; 24:1901-1911. [PMID: 35603907 PMCID: PMC9545639 DOI: 10.1111/dom.14777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/04/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1D are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1D, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called 'missing heritability' phenomenon. While the gap between known heritability and true heritability in T1D is small compared with that in other complex traits and disorders, further elucidation of T1D genetics has the potential to bring novel insights into its aetiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants and structural variants) and interactions (gene-gene and gene-environment interactions; e.g. epigenetic effects). In the following review, we introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1D.
Collapse
Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| |
Collapse
|
|
19
|
Liu QR, Aseer KR, Yao Q, Zhong X, Ghosh P, O’Connell JF, Egan JM. Anti-Inflammatory and Pro-Autophagy Effects of the Cannabinoid Receptor CB2R: Possibility of Modulation in Type 1 Diabetes. Front Pharmacol 2022; 12:809965. [PMID: 35115945 PMCID: PMC8804091 DOI: 10.3389/fphar.2021.809965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/21/2021] [Indexed: 11/13/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from loss of insulin-secreting β-cells in islets of Langerhans. The loss of β-cells is initiated when self-tolerance to β-cell-derived contents breaks down, which leads to T cell-mediated β-cell damage and, ultimately, β-cell apoptosis. Many investigations have demonstrated the positive effects of antagonizing cannabinoid receptor 1 (CB1R) in metabolic diseases such as fatty liver disease, obesity, and diabetes mellitus, but the role of cannabinoid receptor 2 (CB2R) in such diseases is relatively unknown. Activation of CB2R is known for its immunosuppressive roles in multiple sclerosis, rheumatoid arthritis, Crohn’s, celiac, and lupus diseases, and since autoimmune diseases can share common environmental and genetic factors, we propose CB2R specific agonists may also serve as disease modifiers in diabetes mellitus. The CNR2 gene, which encodes CB2R protein, is the result of a gene duplication of CNR1, which encodes CB1R protein. This ortholog evolved rapidly after transitioning from invertebrates to vertebrate hundreds of million years ago. Human specific CNR2 isoforms are induced by inflammation in pancreatic islets, and a CNR2 nonsynonymous SNP (Q63R) is associated with autoimmune diseases. We collected evidence from the literature and from our own studies demonstrating that CB2R is involved in regulating the inflammasome and especially release of the cytokine interleukin 1B (IL-1β). Furthermore, CB2R activation controls intracellular autophagy and may regulate secretion of extracellular vesicles from adipocytes that participate in recycling of lipid droplets, dysregulation of which induces chronic inflammation and obesity. CB2R activation may play a similar role in islets of Langerhans. Here, we will discuss future strategies to unravel what roles, if any, CB2R modifiers potentially play in T1DM.
Collapse
Affiliation(s)
- Qing-Rong Liu
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
- *Correspondence: Qing-Rong Liu, ; Josephine M. Egan,
| | - Kanikkai Raja Aseer
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Qin Yao
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Xiaoming Zhong
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, United States
| | - Paritosh Ghosh
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Jennifer F. O’Connell
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Josephine M. Egan
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
- *Correspondence: Qing-Rong Liu, ; Josephine M. Egan,
| |
Collapse
|
|
20
|
Pathophysiologic Mechanisms of Insulin Secretion and Signaling-Related Genes in Etiology of Polycystic Ovary Syndrome. Genet Res (Camb) 2021; 2021:7781823. [PMID: 34949963 PMCID: PMC8668318 DOI: 10.1155/2021/7781823] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/06/2021] [Accepted: 11/17/2021] [Indexed: 12/14/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women. PCOS is characterized by anovulation, hyperandrogenism, polycystic ovaries, insulin resistance, and obesity. Despite the finding that the genetic origin of PCOS is well demonstrated in previous twin and familial clustering studies, genes and factors that can exactly explain the PCOS pathophysiology are not known. Objective(s). In this review, we attempted to identify genes related to secretion and signaling of insulin aspects of PCOS and their physiological functions in order to explain the pathways that are regulated by these genes which can be a prominent function in PCOS predisposition. Materials and Methods. For this purpose, published articles and reviews dealing with genetic evaluation of PCOS in women from peer-reviewed journals in PubMed and Google Scholar databases were included in this review. Results. The genomic investigations in women of different populations identified many candidate genes and loci that are associated with PCOS. The most important of them are INSR, IRS1-2, MTNR1A, MTNR1B, THADA, PPAR-γ2, ADIPOQ, and CAPN10. These are mainly associated with metabolic aspects of PCOS. Conclusions. In this review, we proposed that each of these genes may interrupt specific physiological pathways by affecting them and contribute to PCOS initiation. It is clear that the role of genes involved in insulin secretion and signaling is more critical than other pathways.
Collapse
|
|
21
|
Huda N, Yasmin T, Nabi AHMN. MNS16A VNTR polymorphism of human telomerase gene: Elucidation of a gender specific potential allele associated with type 2 diabetes in Bangladeshi population. J Diabetes Complications 2021; 35:108018. [PMID: 34404572 DOI: 10.1016/j.jdiacomp.2021.108018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/11/2021] [Accepted: 08/07/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND Type 2 diabetes (T2D) is a multifactorial disorder that affects multi-organ and can alter telomerase (encoded by hTERT gene) activity and thus, may affect telomere length. The variable number of tandem repeats MNS16A in hTERT gene facilitates extension of telomeres by regulating telomerase. In the present study, genetic analysis of MNS16A tandem repeats in hTERT gene was performed with the aim of finding out any association of allelic and genotypic variations with the risk of T2D in Bangladeshi population. METHODS A total of unrelated 395 individuals with T2D and 247 healthy individuals were included in the study. The genotypic and allelic frequencies were determined using allele specific polymerase chain reaction. The association of allelic and genotypic frequencies with risk of T2D was analyzed using logistic regression analysis on the basis of odds ratio at 95% confidence interval. Hardy-Weinberg equilibrium (HWE) test was performed to evaluate the uniformity of the genotypic frequencies and deviation from the HWE was tested using Chi-square test. RESULTS Logistic regression analyses revealed significant association of short allele containing 243 bp (OR: 1.37 and p = 0.03) with T2D, when the long alleles (commonly found) were considered as reference. The heterozygous genotype 272/302 was significantly associated with the decreased risk of T2D (OR: 0.33, p = 0.001). The combined results of genotypes indicated that the MNS16A polymorphism was significantly associated with the increased risk of T2D under the dominant model (LL vs SL + SS; OR: 2.62, p < 0.0001). Interestingly, short allele 243 was associated with the risk of disease only in male population (OR: 1.62, p = 0.02). The genotype 272/302 was also found to be associated with the decreased risk of T2D when respective data for male was analyzed individually. CONCLUSIONS We have identified four variable number of tandem repeats with varying patterns of association with T2D in Bangladeshi population and to extend our knowledge of understanding regarding these VNTRs, further large-scale studies are warranted.
Collapse
Affiliation(s)
- Nafiul Huda
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh
| | - Tahirah Yasmin
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh
| | - A H M Nurun Nabi
- Laboratory of Population Genetics, Department of Biochemistry and Molecular Biology, University of Dhaka, Bangladesh.
| |
Collapse
|
|
22
|
Musthaffa Y, Hamilton-Williams EE, Nel HJ, Bergot AS, Mehdi AM, Harris M, Thomas R. Proinsulin-specific T-cell responses correlate with estimated c-peptide and predict partial remission duration in type 1 diabetes. Clin Transl Immunology 2021; 10:e1315. [PMID: 34336205 PMCID: PMC8312239 DOI: 10.1002/cti2.1315] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/20/2021] [Accepted: 06/27/2021] [Indexed: 12/11/2022] Open
Abstract
Objective Type 1 diabetes (T1D) is an autoimmune disorder in which autoreactive T cells destroy insulin-producing β-cells. Interventions that preserve β-cell function represent a fundamental therapeutic goal in T1D and biomarkers that predict and monitor β-cell function, and changes in islet autoantigenic signatures are needed. As proinsulin and neoantigens derived from proinsulin peptides (hybrid insulin peptides, HIPs) are important T1D autoantigens, we analysed peripheral blood CD4+ T-cell autoantigen-specific proliferative responses and their relationship to estimated β-cell function. Methods We recruited 72 people with and 42 without T1D, including 17 pre-diabetic islet antibody-positive and 9 antibody-negative first-degree relatives and 16 unrelated healthy controls with T1D-risk HLA types. We estimated C-peptide level at 3-month intervals for 2 years post-diagnosis and measured CD4+ T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay. Results We show that CD4+ T-cell proliferation to any islet peptide and to multiple epitopes were significantly more frequent in pre-diabetic islet antibody-positive siblings and participants with T1D ≤ 3 months of duration, than in participants with T1D > 3 months or healthy controls. Among participants with T1D and first-degree relatives, CD4+ T-cell proliferation occurred most frequently in response to proinsulin33-63 (full-length C-peptide). Proinsulin33-63-specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/DQ8. In children with T1D, proinsulin33-63-specific T-cell proliferation positively associated with concurrent estimated C-peptide and predicted survival in honeymoon. Conclusion CD4+ T-cell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin33-63-specific CD4+ T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.
Collapse
Affiliation(s)
- Yassmin Musthaffa
- Department of Endocrinology and Diabetes Queensland Children's Hospital South Brisbane QLD Australia.,The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Emma E Hamilton-Williams
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Hendrik J Nel
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Anne-Sophie Bergot
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Ahmed M Mehdi
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Mark Harris
- Department of Endocrinology and Diabetes Queensland Children's Hospital South Brisbane QLD Australia.,The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| | - Ranjeny Thomas
- The University of Queensland Diamantina Institute The University of Queensland Brisbane QLD Australia
| |
Collapse
|
|
23
|
Large parental differences in chromatin organization in pancreatic beta cell line explaining diabetes susceptibility effects. Nat Commun 2021; 12:4338. [PMID: 34267199 PMCID: PMC8282625 DOI: 10.1038/s41467-021-24635-2] [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: 07/29/2020] [Accepted: 06/28/2021] [Indexed: 12/26/2022] Open
Abstract
Previous GWAS studies identified non-coding loci with parent-of-origin-specific effects on Type 2 diabetes susceptibility. Here we report the molecular basis for one such locus near the KRTAP5-6 gene on chromosome 11. We determine the pattern of long-range contacts between an enhancer in this locus and the human INS promoter 460 kb away, in the human pancreatic β-cell line, EndoC-βH1. 3C long range contact experiments distinguish contacts on the two sister chromosomes. Coupling with allele-specific SNPs allows construction of maps revealing marked differences in organization of the two sister chromosomes in the entire region between KRTAP5-6 and INS. Further mapping distinguishes maternal and paternal alleles. This reveals a domain of parent-of-origin-specific chromatin structure extending in the telomeric direction from the INS locus. This suggests more generally that imprinted loci may extend their influence over gene expression beyond those loci through long range chromatin structure, resulting in parent-of-origin-biased expression patterns over great distances. A SNP distant from the human insulin (INS) gene near the KRTAP5-6 gene confers increased susceptibility to type 2 diabetes when present on the paternal allele while decreased susceptibility when on the maternal allele. Here the authors show that long-range contacts between the INS locus and the KRTAP5-6 gene locus distinguish paternal and maternal alleles.
Collapse
|
|
24
|
The dark side of insulin: A primary autoantigen and instrument of self-destruction in type 1 diabetes. Mol Metab 2021; 52:101288. [PMID: 34242821 PMCID: PMC8513143 DOI: 10.1016/j.molmet.2021.101288] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/27/2021] [Accepted: 07/02/2021] [Indexed: 12/12/2022] Open
Abstract
Background Since its discovery 100 years ago, insulin, as the ‘cure’ for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged. Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent (e.g., virus). Nevertheless, direct, interventional studies in non-obese diabetic (NOD) mouse models of type 1 diabetes point to a critical role for (pro)insulin as a primary autoantigen that drives beta cell pathology. Scope of review Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of (pro)insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed. Evidence in humans remains circumstantial. Additionally, as (pro)insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed. Major conclusions Paradoxically, insulin is both a ‘cure’ and a potential ‘cause’ of type 1 diabetes, actively participating as an autoantigen to drive autoimmune destruction of beta cells - the instrument of its own destruction.
Collapse
|
|
25
|
Sims EK, Carr ALJ, Oram RA, DiMeglio LA, Evans-Molina C. 100 years of insulin: celebrating the past, present and future of diabetes therapy. Nat Med 2021; 27:1154-1164. [PMID: 34267380 PMCID: PMC8802620 DOI: 10.1038/s41591-021-01418-2] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/28/2021] [Indexed: 02/04/2023]
Abstract
The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
Collapse
Affiliation(s)
- Emily K Sims
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alice L J Carr
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
- The Academic Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Linda A DiMeglio
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Carmella Evans-Molina
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Center for Diabetes & Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, USA.
- The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Roudebush VA Medical Center, Indianapolis, IN, USA.
| |
Collapse
|
|
26
|
Assfalg R, Knoop J, Hoffman KL, Pfirrmann M, Zapardiel-Gonzalo JM, Hofelich A, Eugster A, Weigelt M, Matzke C, Reinhardt J, Fuchs Y, Bunk M, Weiss A, Hippich M, Halfter K, Hauck SM, Hasford J, Petrosino JF, Achenbach P, Bonifacio E, Ziegler AG. Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial. Diabetologia 2021; 64:1079-1092. [PMID: 33515070 PMCID: PMC8012335 DOI: 10.1007/s00125-020-05376-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.).
Collapse
Affiliation(s)
- Robin Assfalg
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
| | - Jan Knoop
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Kristi L Hoffman
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Markus Pfirrmann
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jose Maria Zapardiel-Gonzalo
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Anna Hofelich
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
| | - Anne Eugster
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Marc Weigelt
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Claudia Matzke
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Julia Reinhardt
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Yannick Fuchs
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
| | - Melanie Bunk
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Andreas Weiss
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Markus Hippich
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Kathrin Halfter
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
| | - Jörg Hasford
- Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Joseph F Petrosino
- Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Peter Achenbach
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany
- German Center for Diabetes Research (DZD), Munich, Germany
| | - Ezio Bonifacio
- German Center for Diabetes Research (DZD), Munich, Germany
- Technische Universität Dresden, Center for Regenerative Therapies Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden, Dresden, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Munich-Neuherberg, Germany
| | - Anette-Gabriele Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.
- Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany.
- German Center for Diabetes Research (DZD), Munich, Germany.
| |
Collapse
|
|
27
|
Mannering SI, Rubin AF, Wang R, Bhattacharjee P. Identifying New Hybrid Insulin Peptides (HIPs) in Type 1 Diabetes. Front Immunol 2021; 12:667870. [PMID: 33995402 PMCID: PMC8120023 DOI: 10.3389/fimmu.2021.667870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/15/2021] [Indexed: 11/13/2022] Open
Abstract
In 2016 Delong et al. discovered a new type of neoepitope formed by the fusion of two unrelated peptide fragments. Remarkably these neoepitopes, called hybrid insulin peptides, or HIPs, are recognized by pathogenic CD4+ T cells in the NOD mouse and human pancreatic islet-infiltrating T cells in people with type 1 diabetes. Current data implicates CD4+ T-cell responses to HIPs in the immune pathogenesis of human T1D. Because of their role in the immune pathogenesis of human T1D it is important to identify new HIPs that are recognized by CD4+ T cells in people at risk of, or with, T1D. A detailed knowledge of T1D-associated HIPs will allow HIPs to be used in assays to monitor changes in T cell mediated beta-cell autoimmunity. They will also provide new targets for antigen-specific therapies for T1D. However, because HIPs are formed by the fusion of two unrelated peptides there are an enormous number of potential HIPs which makes it technically challenging to identify them. Here we review the discovery of HIPs, how they form and discuss approaches to identifying new HIPs relevant to the immune pathogenesis of human type 1 diabetes.
Collapse
Affiliation(s)
- Stuart I Mannering
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia.,Department of Medicine, University of Melbourne, St. Vincent's Hospital, Melbourne, VIC, Australia
| | - Alan F Rubin
- Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.,Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
| | - Ruike Wang
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia
| | - Pushpak Bhattacharjee
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Melbourne, VIC, Australia
| |
Collapse
|
|
28
|
Rodriguez-Calvo T, Johnson JD, Overbergh L, Dunne JL. Neoepitopes in Type 1 Diabetes: Etiological Insights, Biomarkers and Therapeutic Targets. Front Immunol 2021; 12:667989. [PMID: 33953728 PMCID: PMC8089389 DOI: 10.3389/fimmu.2021.667989] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/29/2021] [Indexed: 12/12/2022] Open
Abstract
The mechanisms underlying type 1 diabetes (T1D) pathogenesis remain largely unknown. While autoantibodies to pancreatic beta-cell antigens are often the first biological response and thereby a useful biomarker for identifying individuals in early stages of T1D, their role in T1D pathogenesis is not well understood. Recognition of these antigenic targets by autoreactive T-cells plays a pathological role in T1D development. Recently, several beta-cell neoantigens have been described, indicating that both neoantigens and known T1D antigens escape central or peripheral tolerance. Several questions regarding the mechanisms by which tolerance is broken in T1D remain unanswered. Further delineating the timing and nature of antigenic responses could allow their use as biomarkers to improve staging, as targets for therapeutic intervention, and lead to a better understanding of the mechanisms leading to loss of tolerance. Multiple factors that contribute to cellular stress may result in the generation of beta-cell derived neoepitopes and contribute to autoimmunity. Understanding the cellular mechanisms that induce beta-cells to produce neoantigens has direct implications on development of therapies to intercept T1D disease progression. In this perspective, we will discuss evidence for the role of neoantigens in the pathogenesis of T1D, including antigenic responses and cellular mechanisms. We will additionally discuss the pathways leading to neoepitope formation and the cross talk between the immune system and the beta-cells in this regard. Ultimately, delineating the timing of neoepitope generation in T1D pathogenesis will determine their role as biomarkers as well as therapeutic targets.
Collapse
Affiliation(s)
- Teresa Rodriguez-Calvo
- Institute of Diabetes Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Munich, Germany
| | - James D. Johnson
- Diabetes Research Group, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lut Overbergh
- Laboratory Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium
| | - Jessica L. Dunne
- Janssen Research and Development, LLC, Raritan, NJ, United States
| |
Collapse
|
|
29
|
A New Hypothesis for Type 1 Diabetes Risk: The At-Risk Allele at rs3842753 Associates With Increased Beta-cell INS Messenger RNA in a Meta-Analysis of Single-Cell RNA-Sequencing Data. Can J Diabetes 2021; 45:775-784.e2. [PMID: 34052132 DOI: 10.1016/j.jcjd.2021.03.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/26/2022]
Abstract
OBJECTIVES Type 1 diabetes is characterized by the autoimmune destruction of insulin-secreting beta cells. Genetic variants upstream at the insulin (INS) locus contribute to ∼10% of type 1 diabetes heritable risk. Previous studies showed an association between rs3842753 C/C genotype and type 1 diabetes susceptibility, but the molecular mechanisms remain unclear. To date, no large-scale studies have looked at the effect of genetic variation at rs3842753 on INS mRNA at the single-cell level. METHODS We aligned all human islet single-cell RNA sequencing data sets available to us in year 2020 to the reference genome GRCh38.98 and genotyped rs3842753, integrating 2,315 β cells and 1,223 β-like cells from 13 A/A protected donors, 23 A/C heterozygous donors and 35 C/C at-risk donors, including adults without diabetes and with type 2 diabetes. RESULTS INS expression mean and variance were significantly higher in single β cells from females compared with males. On comparing across β cells and β-like cells, we found that rs3842753 C‒containing cells (either homozygous or heterozygous) had the highest INS expression. We also found that β cells with the rs3842753 C allele had significantly higher endoplasmic reticulum stress marker gene expression compared with the A/A homozygous genotype. CONCLUSIONS These findings support the emerging concept that inherited risk of type 1 diabetes may be associated with inborn, persistent elevated insulin production, which may lead to β-cell endoplasmic reticulum stress and fragility.
Collapse
|
|
30
|
Mannering SI, Bhattacharjee P. Insulin's other life: an autoantigen in type 1 diabetes. Immunol Cell Biol 2021; 99:448-460. [PMID: 33524197 DOI: 10.1111/imcb.12442] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 12/21/2020] [Accepted: 01/28/2021] [Indexed: 12/14/2022]
Abstract
One hundred years ago, Frederick Banting, John Macleod, Charles Best and James Collip, and their collaborators, discovered insulin. This discovery paved the way to saving countless lives and ushered in the "Insulin Era." Since the discovery of insulin, we have made enormous strides in understanding its role in metabolism and diabetes. Insulin has played a dramatic role in the treatment of people with diabetes; particularly type 1 diabetes (T1D). Insulin replacement is a life-saving therapy for people with T1D and some with type 2 diabetes. T1D is an autoimmune disease caused by the T-cell-mediated destruction of the pancreatic insulin-producing beta cells that leads to a primary insulin deficiency. It has become increasingly clear that insulin, and its precursors preproinsulin (PPI) and proinsulin (PI), can play another role-not as a hormone but as an autoantigen in T1D. Here we review the role played by the products of the INS gene as autoantigens in people with T1D. From many elegant animal studies, it is clear that T-cell responses to insulin, PPI and PI are essential for T1D to develop. Here we review the evidence that autoimmune responses to insulin and PPI arise in people with T1D and discuss the recently described neoepitopes derived from the products of the insulin gene. Finally, we look forward to new approaches to deliver epitopes derived from PPI, PI and insulin that may allow immune tolerance to pancreatic beta cells to be restored in people with, or at risk of, T1D.
Collapse
Affiliation(s)
- Stuart I Mannering
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia.,Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia
| | - Pushpak Bhattacharjee
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
| |
Collapse
|
|
31
|
Type 1 diabetes: genes associated with disease development. Cent Eur J Immunol 2021; 45:439-453. [PMID: 33658892 PMCID: PMC7882399 DOI: 10.5114/ceji.2020.103386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 01/02/2020] [Indexed: 11/17/2022] Open
Abstract
Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Based on the World Health Organization (WHO) report from 2014 the number of people suffering from all types of diabetes ascended to 422 million, compared to 108 million in 1980. It was calculated that this number will double by the end of 2030. In 2015 American Diabetes Association (ADA) announced that 30.3 million Americans (that is 9.4% of the overall population) had diabetes of which only approximately 1.25 million had T1D. Nowadays, T1D represents roughly 10% of adult diabetes cases total. Multiple genetic abnormalities at different loci have been found to contribute to type 1 diabetes development. The analysis of genome-wide association studies (GWAS) of T1D has identified over 50 susceptible regions (and genes within these regions). Many of these regions are defined by single nucleotide polymorphisms (SNPs) but molecular mechanisms through which they increase or lower the risk of diabetes remain unknown. Genetic factors (in existence since birth) can be detected long before the emergence of immunological or clinical markers. Therefore, a comprehensive understanding of the multiple genetic factors underlying T1D is extremely important for further clinical trials and development of personalized medicine for diabetic patients. We present an overview of current studies and information about regions in the human genome associated with T1D. Moreover, we also put forward information about epigenetic modifications, non-coding RNAs and environmental factors involved in T1D development and onset.
Collapse
|
|
32
|
Denyer AL, Catchpole B, Davison LJ. Genetics of canine diabetes mellitus part 2: Current understanding and future directions. Vet J 2021; 270:105612. [PMID: 33641811 DOI: 10.1016/j.tvjl.2021.105612] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 02/08/2023]
Abstract
Part 1 of this 2-part review outlined the importance of disease classification in diabetes genetic studies, as well as the ways in which genetic variants may contribute to risk of a complex disease within an individual, or within a particular group of individuals. Part 2, presented here, describes in more detail our current understanding of the genetics of canine diabetes mellitus compared to our knowledge of the human disease. Ongoing work to improve our knowledge, using new technologies, is also introduced.
Collapse
Affiliation(s)
- Alice L Denyer
- Department of Pathology and Pathogen Biology, Royal Veterinary College, Hatfield, UK
| | - Brian Catchpole
- Department of Pathology and Pathogen Biology, Royal Veterinary College, Hatfield, UK
| | - Lucy J Davison
- Department of Clinical Sciences and Services, Royal Veterinary College, Hatfield, UK; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
| | | |
Collapse
|
|
33
|
Ramos-Rodríguez M, Pérez-González B, Pasquali L. The β-Cell Genomic Landscape in T1D: Implications for Disease Pathogenesis. Curr Diab Rep 2021; 21:1. [PMID: 33387073 PMCID: PMC7778620 DOI: 10.1007/s11892-020-01370-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/19/2020] [Indexed: 11/15/2022]
Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) develops as a consequence of a combination of genetic predisposition and environmental factors. Combined, these events trigger an autoimmune disease that results in progressive loss of pancreatic β cells, leading to insulin deficiency. This article reviews the current knowledge on the genetics of T1D with a specific focus on genetic variation in pancreatic islet regulatory networks and its implication to T1D risk and disease development. RECENT FINDINGS Accumulating evidence suggest an active role of β cells in T1D pathogenesis. Based on such observation several studies aimed in mapping T1D risk variants acting at the β cell level. Such studies unravel T1D risk loci shared with type 2 diabetes (T2D) and T1D risk variants potentially interfering with β-cell responses to external stimuli. The characterization of regulatory genomics maps of disease-relevant states and cell types can be used to elucidate the mechanistic role of β cells in the pathogenesis of T1D.
Collapse
Affiliation(s)
- Mireia Ramos-Rodríguez
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain
| | - Beatriz Pérez-González
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain
| | - Lorenzo Pasquali
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain.
| |
Collapse
|
|
34
|
Abstract
PURPOSE OF REVIEW Diabetes is a spectrum of clinical manifestations, including latent autoimmune diabetes in adults (LADA). However, it has been questioned whether LADA exists or simply is a group of misclassified type 1 diabetes (T1D) and type 2 diabetes (T2D) patients. This review will provide an updated overview of the genetics of LADA, highlight what genetics tell us about LADA as a diabetes subtype, and point to future directions in the study of LADA. RECENT FINDINGS Recent studies have verified the genetic overlap between LADA and both T1D and T2D and have contributed identification of a novel LADA-specific locus, namely, PFKFB3, and subtype-specific signatures in the HLA region. Genetic risk scores comprising T1D-risk variants have been shown to be a promising tool for discriminating diabetes subtypes and identifying patients rapidly progressing to insulin dependence. Genetic data support the existence of LADA, but further studies are needed to fully determine the place of LADA in the diabetes spectrum.
Collapse
Affiliation(s)
- Mette K Andersen
- The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200, Copenhagen N, Denmark.
| |
Collapse
|
|
35
|
Carry PM, Vanderlinden LA, Johnson RK, Dong F, Steck AK, Frohnert BI, Rewers M, Yang IV, Kechris K, Norris JM. DNA methylation near the INS gene is associated with INS genetic variation (rs689) and type 1 diabetes in the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes 2020; 21:597-605. [PMID: 32061050 PMCID: PMC7378362 DOI: 10.1111/pedi.12995] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 02/06/2020] [Accepted: 02/12/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Mechanisms underlying the role of non-human leukocyte antigen (HLA) genetic risk variants in type 1 diabetes (T1D) are poorly understood. We aimed to test the association between methylation and non-HLA genetic risk. METHODS We conducted a methylation quantitative trait loci (mQTL) analysis in a nested case-control study from the Dietary Autoimmunity Study in the Young. Controls (n = 83) were frequency-matched to T1D cases (n = 83) based on age, race/ethnicity, and sample availability. We evaluated 13 non-HLA genetic markers known be associated with T1D. Genome-wide methylation profiling was performed on peripheral blood samples collected prior to T1D using the Illumina 450 K (discovery set) and infinium methylation EPIC beadchip (EPIC validation) platforms. Linear regression models, adjusting for age and sex, were used to test to each single nucleotide polymorphism (SNP) -probe combination. Logistic regression models were used to test the association between T1D and methylation levels among probes with a significant mQTL. A meta-analysis was used to combine odds ratios from the two platforms. RESULTS We identified 10 SNP-methylation probe pairs (false discovery rate (FDR) adjusted P < .05 and validation P < .05). Probes were associated with the GSDMB, C1QTNF6, IL27, and INS genes. The cg03366382 (OR: 1.9, meta-P = .0495), cg21574853 (OR: 2.5, meta-P = .0232), and cg25336198 (odds ratio: 6.6, meta-P = .0081) probes were significantly associated with T1D. The three probes were located upstream from the INS transcription start site. CONCLUSIONS We confirmed an association between DNA methylation and rs689 that has been identified in related studies. Measurements in our study preceded the onset of T1D suggesting methylation may have a role in the relationship between INS variation and T1D development.
Collapse
Affiliation(s)
- Patrick M. Carry
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Lauren A. Vanderlinden
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Randi K. Johnson
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Fran Dong
- Barbara Davis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Andrea K. Steck
- Barbara Davis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado,University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Brigitte I. Frohnert
- Barbara Davis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado,University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Marian Rewers
- Barbara Davis Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado,University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Ivana V. Yang
- University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, Colorado
| | - Katerina Kechris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| |
Collapse
|
|
36
|
Ihantola EL, Ilmonen H, Kailaanmäki A, Rytkönen-Nissinen M, Azam A, Maillère B, Lindestam Arlehamn CS, Sette A, Motwani K, Seay HR, Brusko TM, Knip M, Veijola R, Toppari J, Ilonen J, Kinnunen T. Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules. THE JOURNAL OF IMMUNOLOGY 2020; 204:2349-2359. [PMID: 32229538 DOI: 10.4049/jimmunol.1901079] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 02/22/2020] [Indexed: 12/21/2022]
Abstract
Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which the insulin-producing β cells within the pancreas are destroyed. Identification of target Ags and epitopes of the β cell-reactive T cells is important both for understanding T1D pathogenesis and for the rational development of Ag-specific immunotherapies for the disease. Several studies suggest that proinsulin is an early and integral target autoantigen in T1D. However, proinsulin epitopes recognized by human CD4+ T cells have not been comprehensively characterized. Using a dye dilution-based T cell cloning method, we generated and characterized 24 unique proinsulin-specific CD4+ T cell clones from the peripheral blood of 17 individuals who carry the high-risk DR3-DQ2 and/or DR4-DQ8 HLA class II haplotypes. Some of the clones recognized previously reported DR4-restricted epitopes within the C-peptide (C25-35) or A-chain (A1-15) of proinsulin. However, we also characterized DR3-restricted epitopes within both the B-chain (B16-27 and B22-C3) and C-peptide (C25-35). Moreover, we identified DQ2-restricted epitopes within the B-chain and several DQ2- or DQ8-restricted epitopes within the C-terminal region of C-peptide that partially overlap with previously reported DQ-restricted epitopes. Two of the DQ2-restricted epitopes, B18-26 and C22-33, were shown to be naturally processed from whole human proinsulin. Finally, we observed a higher frequency of CDR3 sequences matching the TCR sequences of the proinsulin-specific T cell clones in pancreatic lymph node samples compared with spleen samples. In conclusion, we confirmed several previously reported epitopes but also identified novel (to our knowledge) epitopes within proinsulin, which are presented by HLA class II molecules associated with T1D risk.
Collapse
Affiliation(s)
- Emmi-Leena Ihantola
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Henna Ilmonen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Anssi Kailaanmäki
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Marja Rytkönen-Nissinen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland
| | - Aurélien Azam
- Commissariat à l'Energie Atomique et aux Energies Alternatives-Saclay, Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif Sur Yvette, France
| | - Bernard Maillère
- Commissariat à l'Energie Atomique et aux Energies Alternatives-Saclay, Université Paris-Saclay, Service d'Ingénierie Moléculaire des Protéines, 91191 Gif Sur Yvette, France
| | | | - Alessandro Sette
- La Jolla Institute for Immunology, La Jolla, CA 92037.,Department of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Keshav Motwani
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32610
| | - Howard R Seay
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32610
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32610.,Department of Pediatrics, University of Florida, College of Medicine Gainesville, FL 32610
| | - Mikael Knip
- Tampere Center for Child Health Research, Tampere University Hospital, FI-33520 Tampere, Finland.,Children's Hospital, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, FI-00014 Helsinki, Finland.,Folkhälsan Research Center, FI-00290 Helsinki, Finland
| | - Riitta Veijola
- PEDEGO Research Unit, Department of Pediatrics, Medical Research Center, Oulu University Hospital and University of Oulu, FI-90014 Oulu, Finland
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, FI-20521 Turku, Finland.,Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, University of Turku, FI-20520 Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, FI-20520 Turku, Finland.,Clinical Microbiology, Turku University Hospital, FI-20521 Turku, Finland; and
| | - Tuure Kinnunen
- Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland; .,Eastern Finland Laboratory Centre (ISLAB), FI-70210 Kuopio, Finland
| |
Collapse
|
|
37
|
Martinov T, Fife BT. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance. Ann N Y Acad Sci 2020; 1461:73-103. [PMID: 31025378 PMCID: PMC6994200 DOI: 10.1111/nyas.14106] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/25/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) affects over a million Americans, and disease incidence is on the rise. Despite decades of research, there is still no cure for this disease. Exciting beta cell replacement strategies are being developed, but in order for such approaches to work, targeted immunotherapies must be designed. To selectively halt the autoimmune response, researchers must first understand how this response is regulated and which tolerance checkpoints fail during T1D development. Herein, we discuss the current understanding of T1D pathogenesis in humans, genetic and environmental risk factors, presumed roles of CD4+ and CD8+ T cells as well as B cells, and implicated autoantigens. We also highlight studies in non-obese diabetic mice that have demonstrated the requirement for CD4+ and CD8+ T cells and B cells in driving T1D pathology. We present an overview of central and peripheral tolerance mechanisms and comment on existing controversies in the field regarding central tolerance. Finally, we discuss T cell- and B cell-intrinsic tolerance mechanisms, with an emphasis on the roles of inhibitory receptors in maintaining islet tolerance in humans and in diabetes-prone mice, and strategies employed to date to harness inhibitory receptor signaling to prevent or reverse T1D.
Collapse
Affiliation(s)
- Tijana Martinov
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Brian T Fife
- Department of Medicine, Center for Immunology, University of Minnesota Medical School, Minneapolis, Minnesota
| |
Collapse
|
|
38
|
Constantinou C, Spella M, Chondrou V, Patrinos GP, Papachatzopoulou A, Sgourou A. The multi-faceted functioning portrait of LRF/ZBTB7A. Hum Genomics 2019; 13:66. [PMID: 31823818 PMCID: PMC6905007 DOI: 10.1186/s40246-019-0252-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 11/26/2019] [Indexed: 12/19/2022] Open
Abstract
Transcription factors (TFs) consisting of zinc fingers combined with BTB (for broad-complex, tram-track, and bric-a-brac) domain (ZBTB) are a highly conserved protein family that comprises a multifunctional and heterogeneous group of TFs, mainly modulating cell developmental events and cell fate. LRF/ZBTB7A, in particular, is reported to be implicated in a wide variety of physiological and cancer-related cell events. These physiological processes include regulation of erythrocyte maturation, B/T cell differentiation, adipogenesis, and thymic insulin expression affecting consequently insulin self-tolerance. In cancer, LRF/ZBTB7A has been reported to act either as oncogenic or as oncosuppressive factor by affecting specific cell processes (proliferation, apoptosis, invasion, migration, metastasis, etc) in opposed ways, depending on cancer type and molecular interactions. The molecular mechanisms via which LRF/ZBTB7A is known to exert either physiological or cancer-related cellular effects include chromatin organization and remodeling, regulation of the Notch signaling axis, cellular response to DNA damage stimulus, epigenetic-dependent regulation of transcription, regulation of the expression and activity of NF-κB and p53, and regulation of aerobic glycolysis and oxidative phosphorylation (Warburg effect). It is a pleiotropic TF, and thus, alterations to its expression status become detrimental for cell survival. This review summarizes its implication in different cellular activities and the commonly invoked molecular mechanisms triggered by LRF/ZBTB7A’s orchestrated action.
Collapse
Affiliation(s)
- Caterina Constantinou
- Biology laboratory, School of Science and Technology, Hellenic Open University, Patras, Greece.,Laboratory of Pharmacology, Department of Medicine, University of Patras, Patras, Greece
| | - Magda Spella
- Biology laboratory, School of Science and Technology, Hellenic Open University, Patras, Greece.,Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Medical Faculty, University of Patras, Patras, Greece
| | - Vasiliki Chondrou
- Biology laboratory, School of Science and Technology, Hellenic Open University, Patras, Greece
| | - George P Patrinos
- Laboratory of Pharmacogenomics and Individualized Therapy, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.,Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, UAE.,Zayed Center of Health Sciences, United Arab Emirates University, Al-Ain, UAE
| | | | - Argyro Sgourou
- Biology laboratory, School of Science and Technology, Hellenic Open University, Patras, Greece.
| |
Collapse
|
|
39
|
Kamel AM, Mira MF, Ebid GTA, Kassem SH, Radwan ER, Mamdouh M, Amin M, Badawy N, Bazaraa H, Ibrahim A, Salah N. Association of insulin gene VNTR INS -23/Hph1 A>T (rs689) polymorphism with type 1 diabetes mellitus in Egyptian children. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2019. [DOI: 10.1186/s43042-019-0017-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Type1 diabetes mellitus (T1DM) has a multi-factorial pathogenesis; the interplay between genetic susceptibility and environmental factors is thought to provide the fundamental element for the disease. Apart from HLA, more than 50 genetic variants are associated with T1DM. INS -23/Hph1 A>T (rs689) is one of the effective loci with inconsistent reports in the literature. Accordingly, this study was designed to define the frequencies of INS -23/Hph1 A>T polymorphism and its association with T1DM in Egyptian diabetic children and their non-diabetic family members as compared to healthy controls.
Methods
Using polymerase chain reaction-restriction fragment length polymorphism methodology, analysis of insulin gene VNTR polymorphism was performed for 496 samples (91 patients, 179 parents, 130 siblings, and 96 controls); parents and siblings were apparently healthy.
Results
INS genotypes and allele frequencies were comparable between patients, non-diabetic siblings, and parents (p = 0.97 and 0.77, respectively). However, the TT/AT genotype and T allele were over-presented in the three family groups compared to controls (p = 0.0015 and 0.0029, respectively).
Comparing patients to controls, the T allele is considered a risk factor for the development of TIDM (OR 2.56, 95% CI 1.42–4.62, p = 0.0017).
INS -23/Hph1 A>T polymorphism showed concordance between patients and their mothers (Kappa = 0.446, p = 0.000) but not with their fathers (Kappa = 0.031, p = 0.765).
Conclusions
INS -23/Hph1 A>T gene polymorphism was shown to be a risk factor for the development of TIDM. This is in agreement with some and in disagreement with other reports. Studies of risk susceptibility factors have to be carried out locally in each community; results cannot be extrapolated from one ethnic group to another.
Collapse
|
|
40
|
De novo emergence and potential function of human-specific tandem repeats in brain-related loci. Hum Genet 2019; 138:661-672. [PMID: 31069507 DOI: 10.1007/s00439-019-02017-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Accepted: 04/16/2019] [Indexed: 01/02/2023]
Abstract
Tandem repeats (TRs) are widespread in the genomes of all living organisms. In eukaryotes, they are found in both coding and noncoding regions and have potential roles in the regulation of cellular processes such as transcription, translation and in the modification of protein structure. Recent studies have highlighted TRs as a key regulator of gene expression and a potential contributor to human evolution. Thus, TRs are emerging as an important source of variation that can result in differential gene expression at intra- and inter-species levels. In this study, we performed a genome-wide survey to identify TRs that have emerged in the human lineage. We further examined these loci to explore their potential functional significance for human evolution. We identified 152 human-specific TR (HSTR) loci containing a repeat unit of more than ten bases, with most of them showing a repeat count of two. Gene set enrichment analysis showed that HSTR-associated genes were associated with biological functions in brain development and synapse function. In addition, we compared gene expression of human HSTR loci with orthologues from non-human primates (NHP) in seven different tissues. Strikingly, the expression level of HSTR-associated genes in brain tissues was significantly higher in human than in NHP. These results suggest the possibility that de novo emergence of TRs could have resulted in altered gene expression in humans within a short-time frame and contributed to the rapid evolution of human brain function.
Collapse
|
|
41
|
Mannering SI, Di Carluccio AR, Elso CM. Neoepitopes: a new take on beta cell autoimmunity in type 1 diabetes. Diabetologia 2019; 62:351-356. [PMID: 30402774 DOI: 10.1007/s00125-018-4760-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 10/08/2018] [Indexed: 01/13/2023]
Abstract
Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of pancreatic insulin-producing beta cells. The epitopes recognised by pathogenic T cells in human type 1 diabetes are poorly defined; however, a growing body of evidence suggests that T cell responses against neoepitopes contribute to beta cell destruction in type 1 diabetes. Neoepitopes are formed when self-proteins undergo post-translational modification to create a new epitope that is recognised by T- or B cells. Here we review the role of human T cell responses against neoepitopes in the immune pathogenesis of type 1 diabetes. Specifically, we review the different approaches to identifying neoepitopes relevant to human type 1 diabetes and outline several advances in this field that have occurred over the past few years. We also discuss the application of neoepitopes to the development of antigen-specific therapies for type 1 diabetes and the unresolved challenges that need to be overcome before the full repertoire of neoepitopes recognised by pathogenic human T cells in type 1 diabetes can be determined. This information may then be used to develop antigen-specific therapies for type 1 diabetes and assays to monitor changes in pathogenic, beta cell-specific T cell responses.
Collapse
Affiliation(s)
- Stuart I Mannering
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Melbourne, VIC, 3065, Australia.
- Department of Medicine, University of Melbourne, Fitzroy, Melbourne, VIC, Australia.
| | - Anthony R Di Carluccio
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Melbourne, VIC, 3065, Australia
| | - Colleen M Elso
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Melbourne, VIC, 3065, Australia
- Department of Medicine, University of Melbourne, Fitzroy, Melbourne, VIC, Australia
| |
Collapse
|
|
42
|
Nyaga DM, Vickers MH, Jefferies C, Perry JK, O'Sullivan JM. The genetic architecture of type 1 diabetes mellitus. Mol Cell Endocrinol 2018; 477:70-80. [PMID: 29913182 DOI: 10.1016/j.mce.2018.06.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 05/14/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023]
Abstract
Type 1 diabetes mellitus (T1D) is a complex autoimmune disorder characterised by loss of the insulin-producing pancreatic beta cells in genetically predisposed individuals, ultimately resulting in insulin deficiency and hyperglycaemia. T1D is most common among children and young adults, and the incidence is on the rise across the world. The aetiology of T1D is hypothesized to involve genetic and environmental factors that result in the T-cell mediated destruction of pancreatic beta cells. There is a strong genetic risk to T1D; with genome-wide association studies (GWAS) identifying over 60 susceptibility regions within the human genome which are marked by single nucleotide polymorphisms (SNPs). Here, we review what is currently known about the genetics of T1D. We argue that advancing our understanding of the aetiology and pathogenesis of T1D will require the integration of genome biology (omics-data) with GWAS data, thereby making it possible to elucidate the putative gene regulatory networks modulated by disease-associated SNPs. This approach has a potential to revolutionize clinical management of T1D in an era of precision medicine.
Collapse
Affiliation(s)
- Denis M Nyaga
- The Liggins Institute, The University of Auckland, New Zealand
| | - Mark H Vickers
- The Liggins Institute, The University of Auckland, New Zealand
| | - Craig Jefferies
- The Liggins Institute, The University of Auckland, New Zealand; Starship Children's Health, Auckland, New Zealand
| | - Jo K Perry
- The Liggins Institute, The University of Auckland, New Zealand
| | | |
Collapse
|
|
43
|
Alswat KA, Nasr A, Al Dubayee MS, Talaat IM, Alsulaimani AA, Mohamed IAA, Allam G. The Potential Role of PTPN-22 C1858T Gene Polymorphism in the Pathogenesis of Type 1 Diabetes in Saudi Population. Immunol Invest 2018; 47:521-533. [PMID: 29611765 DOI: 10.1080/08820139.2018.1458109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Recent investigations have reported an association between protein tyrosine phosphatase non-receptor type-22 (PTPN-22) gene polymorphism and susceptibility to the development of type 1 diabetes (T1D) in some populations and not in others. In this study, we aimed to investigate the association of PTPN-22 C1858T polymorphism with T1D in Saudi children. METHODS A cohort of 372 type 1 diabetic children and 372 diabetes-free subjects was enrolled in the current investigation. The PTPN-22 C1858T polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS Our data showed that the frequency of CT and TT genotypes of PTPN-22 C1858T was higher in T1D children (17.7% and 4.3%, respectively) compared to healthy controls (4.8% and 1.6%, respectively), and both genotypes were statistically associated with T1D patients (OR = 4.4, 95% CI: 2.55-7.58, p < 0.001; and OR = 3.2, 95% CI: 1.23-8.28, p = 0.017, respectively). Moreover, the 1858T allele was significantly associated with T1D patients compared to the C allele (OR = 3.2, 95% CI: 1.59-6.88, p < 0.001). In addition, the T allele was significantly associated with elevated levels of HbA1c, anti-GAD, and anti-insulin antibodies (p < 0.001) and a lower concentration of C-peptide (p < 0.001) in T1D children. CONCLUSION The data presented here suggests that the T allele of PTPN-22 C1858T polymorphism might be a risk factor for T1D development in Saudi children.
Collapse
Affiliation(s)
- Khaled A Alswat
- a Department of Internal Medicine , College of Medicine, Taif University , Taif , Saudi Arabia.,b Diabetic Center , Prince Mansour Military Community Hospital , Taif , Saudi Arabia
| | - Amre Nasr
- c King Saud bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia.,d King Abdullah International Medical Research Center KAIMRC , Riyadh , Saudi Arabia
| | - Mohammed S Al Dubayee
- c King Saud bin Abdulaziz University for Health Sciences , Riyadh , Saudi Arabia.,d King Abdullah International Medical Research Center KAIMRC , Riyadh , Saudi Arabia.,e King Abdulaziz Medical City , Saudi Arabia
| | - Iman M Talaat
- f Department of Pediatrics, Faculty of Medicine , Ain Shams University , Cairo , Egypt
| | - Adnan A Alsulaimani
- b Diabetic Center , Prince Mansour Military Community Hospital , Taif , Saudi Arabia.,g Department of Pediatrics , College of Medicine, Taif University , Taif , Saudi Arabia
| | - Imad A A Mohamed
- h Department of Microbiology, Faculty of Veterinary Medicine , Zagazig University , Sharkia , Egypt.,i Department of Microbiology and Immunology , College of Medicine, Taif University , Taif , Saudi Arabia
| | - Gamal Allam
- i Department of Microbiology and Immunology , College of Medicine, Taif University , Taif , Saudi Arabia.,j Immunology Section, Department of Zoology, Faculty of Science , Beni-Suef University , Beni-Suef , Egypt
| |
Collapse
|
|
44
|
Kent SC, Mannering SI, Michels AW, Babon JAB. Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the "Scene of the Crime". Curr Diab Rep 2017; 17:95. [PMID: 28864875 PMCID: PMC5600889 DOI: 10.1007/s11892-017-0915-y] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Autoimmune-mediated destruction of insulin-producing β-cells within the pancreas results in type 1 diabetes (T1D), which is not yet preventable or curable. Previously, our understanding of the β-cell specific T cell repertoire was based on studies of autoreactive T cell responses in the peripheral blood of patients at risk for, or with, T1D; more recently, investigations have included immunohistochemical analysis of some T cell specificities in the pancreas from organ donors with T1D. Now, we are able to examine live, islet-infiltrating T cells from donors with T1D. RECENT FINDINGS Analysis of the T cell repertoire isolated directly from the pancreatic islets of donors with T1D revealed pro-inflammatory T cells with targets of known autoantigens, including proinsulin and glutamic acid decarboxylase, as well as modified autoantigens. We have assayed the islet-infiltrating T cell repertoire for autoreactivity and function directly from the inflamed islets of T1D organ donors. Design of durable treatments for prevention of or therapy for T1D requires understanding this repertoire.
Collapse
Affiliation(s)
- Sally C Kent
- Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, ASC7-2041, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
| | - Stuart I Mannering
- Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria, 3065, Australia
- Department of Medicine, University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, 3065, Australia
| | - Aaron W Michels
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Jenny Aurielle B Babon
- Department of Medicine, Division of Diabetes, Diabetes Center of Excellence, ASC7-2041, University of Massachusetts Medical School, Worcester, MA, 01605, USA
| |
Collapse
|
|
45
|
Lee T, Sprouse ML, Banerjee P, Bettini M, Bettini ML. Ectopic Expression of Self-Antigen Drives Regulatory T Cell Development and Not Deletion of Autoimmune T Cells. THE JOURNAL OF IMMUNOLOGY 2017; 199:2270-2278. [PMID: 28835461 DOI: 10.4049/jimmunol.1700207] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 07/27/2017] [Indexed: 01/18/2023]
Abstract
Type 1 diabetes is a T cell-mediated autoimmune disease that is characterized by Ag-specific targeting and destruction of insulin-producing β cells. Although multiple studies have characterized the pathogenic potential of β cell-specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. In this study, we demonstrate that ectopic expression of insulin epitope B:9-23 (InsB9-23) by thymic APCs is insufficient to induce deletion of high- or low-affinity InsB9-23-reactive CD4+ T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3+ regulatory T cells. In contrast, the MHC stable insulin mimetope (InsB9-23 R22E) efficiently deletes insulin-specific T cells and prevents escape of high-affinity thymocytes. Collectively, these results suggest that Ag dose and peptide-MHC complex stability can lead to multiple fates of insulin-reactive CD4+ T cell development and autoimmune disease outcome.
Collapse
Affiliation(s)
- Thomas Lee
- Section of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030; and
| | - Maran L Sprouse
- Section of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030; and
| | - Pinaki Banerjee
- Center for Human Immunobiology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030
| | - Maria Bettini
- Section of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030; and
| | - Matthew L Bettini
- Section of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030; and
| |
Collapse
|
|
46
|
Jerram ST, Leslie RD. The Genetic Architecture of Type 1 Diabetes. Genes (Basel) 2017; 8:genes8080209. [PMID: 28829396 PMCID: PMC5575672 DOI: 10.3390/genes8080209] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 08/07/2017] [Accepted: 08/16/2017] [Indexed: 12/13/2022] Open
Abstract
Type 1 diabetes (T1D) is classically characterised by the clinical need for insulin, the presence of disease-associated serum autoantibodies, and an onset in childhood. The disease, as with other autoimmune diseases, is due to the interaction of genetic and non-genetic effects, which induce a destructive process damaging insulin-secreting cells. In this review, we focus on the nature of this interaction, and how our understanding of that gene-environment interaction has changed our understanding of the nature of the disease. We discuss the early onset of the disease, the development of distinct immunogenotypes, and the declining heritability with increasing age at diagnosis. Whilst Human Leukocyte Antigens (HLA) have a major role in causing T1D, we note that some of these HLA genes have a protective role, especially in children, whilst other non-HLA genes are also important. In adult-onset T1D, the disease is often not insulin-dependent at diagnosis, and has a dissimilar immunogenotype with reduced genetic predisposition. Finally, we discuss the putative nature of the non-genetic factors and how they might interact with genetic susceptibility, including preliminary studies of the epigenome associated with T1D.
Collapse
Affiliation(s)
- Samuel T Jerram
- Bart's and the London School of Medicine and Dentistry, QMUL, London E1 2AT, UK.
| | - Richard David Leslie
- Bart's and the London School of Medicine and Dentistry, QMUL, London E1 2AT, UK.
| |
Collapse
|
|
47
|
Galvani G, Fousteri G. PTPN22 and islet-specific autoimmunity: What have the mouse models taught us? World J Diabetes 2017; 8:330-336. [PMID: 28751955 PMCID: PMC5507829 DOI: 10.4239/wjd.v8.i7.330] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2016] [Revised: 04/11/2017] [Accepted: 05/15/2017] [Indexed: 02/05/2023] Open
Abstract
An allelic variant of the protein tyrosin phosphatase non-receptor 22 (PTPN22) gene, PTPN22 R620W, constitutes the strongest non-HLA genetic risk factor for the development of type 1 diabetes (T1D). A number of studies using mouse models have addressed how PTPN22 predisposes to T1D. PTPN22 downmodulation, overexpression or expression of the variant gene in genetically manipulated mice has generated controversial results. These discrepancies probably derive from the fact that PTPN22 has differential effects on innate and adaptive immune responses. Moreover, the effects of PTPN22 are dependent on other genetic variables. Here we discuss these findings and try to explain the discrepancies. Exploring the mechanism by which PTPN22 contributes to islet-specific autoimmunity could help us understand its role in T1D pathogenesis and exploit it as a potential therapeutic target to prevent the disease.
Collapse
|
|
48
|
The influence of genetic predisposition and autoimmune hepatitis inducing antigens in disease development. J Autoimmun 2017; 78:39-45. [DOI: 10.1016/j.jaut.2016.12.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 11/07/2016] [Accepted: 12/04/2016] [Indexed: 12/31/2022]
|
|
49
|
Investigation of coordination and order in transcription regulation of innate and adaptive immunity genes in type 1 diabetes. BMC Med Genomics 2017; 10:7. [PMID: 28143555 PMCID: PMC5282641 DOI: 10.1186/s12920-017-0243-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 01/25/2017] [Indexed: 01/19/2023] Open
Abstract
Background Type 1 diabetes (T1D) is an autoimmune disease and extensive evidence has indicated a critical role of both the innate and the adaptive arms of immune system in disease development. To date most clinical trials of immunomodulation therapies failed to show efficacy. A number of gene expression studies of T1D have been carried out. However, a systems analysis of the expression variations of the innate and adaptive immunity gene sets, or their co-expression network structures in cohorts at different disease states or of different disease risks, is not available till now. Methods We utilized data from a large gene expression study that included transcription profiles of control peripheral blood mononuclear cells (PBMC) exposed to plasma of 148 human subjects from four cohorts that included unrelated healthy controls (uHC), recent onset T1D patients (RO-T1D), and healthy siblings of probands that possess high (HRS, High Risk Sibling) or low (LRS, Low Risk Sibling) risk HLA haplotypes. Both weighted and non-weighted co-expression networks were constructed in each cohort separately, and edge weight distribution and the activation of known protein complexes were examined. The co-expression networks of the innate and adaptive immunity genes were further examined in more detail through a number of network measures that included network density, Shannon entropy, h-index, and the scaling exponent γ of degree distribution. Pathway analysis was carried out using CoGA, a tool for detecting significant network structural changes of a gene set. Results Weighted network edge distribution revealed a globally weakened co-expression network induced by the RO-T1D cohort as compared to that by the uHC, suggesting a broad spectrum loss of transcriptional coordination. The two healthy T1D family cohorts (HRS and LRS) induced more active but heterogeneous transcription coordination globally, and among both the innate and the adaptive immunity genes, than the uHC. This finding is consistent with our previous report of these cohorts sharing a heightened innate inflammatory state. The spike-in of IL-1RA to RO-T1D sera improved co-expression network strength of both the innate and the adaptive immunity genes, and enabled a global order recovery in transcription regulation that resulted in significantly increased number of activated protein complexes. Many of the top pathways that showed significant difference in co-expression network structures and order between RO-T1D and uHC have strong links to T1D. Conclusions Network level analysis of the innate and adaptive immunity genes, and the whole genome, revealed striking cohort-dependent differences in co-expression network structural measures, suggesting their potential in cohort classification and disease-relevant pathway identification. The results demonstrated the advantages of systems analysis in defining molecular signatures as well as in predicting targets in future research. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0243-8) contains supplementary material, which is available to authorized users.
Collapse
|
|
50
|
Bettini ML, Bettini M. Understanding Autoimmune Diabetes through the Prism of the Tri-Molecular Complex. Front Endocrinol (Lausanne) 2017; 8:351. [PMID: 29312143 PMCID: PMC5735072 DOI: 10.3389/fendo.2017.00351] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022] Open
Abstract
The strongest susceptibility allele for Type 1 Diabetes (T1D) is human leukocyte antigen (HLA), which supports a central role for T cells as the drivers of autoimmunity. However, the precise mechanisms that allow thymic escape and peripheral activation of beta cell antigen-specific T cells are still largely unknown. Studies performed with the non-obese diabetic (NOD) mouse have challenged several immunological dogmas, and have made the NOD mouse a key experimental system to study the steps of immunodysregulation that lead to autoimmune diabetes. The structural similarities between the NOD I-Ag7 and HLA-DQ8 have revealed the stability of the T cell receptor (TCR)/HLA/peptide tri-molecular complex as an important parameter in the development of autoimmune T cells, as well as afforded insights into the key antigens targeted in T1D. In this review, we will provide a summary of the current understanding with regard to autoimmune T cell development, the significance of the antigens targeted in T1D, and the relationship between TCR affinity and immune regulation.
Collapse
Affiliation(s)
- Matthew L. Bettini
- Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, McNair Medical Institute, Houston, TX, United States
- *Correspondence: Matthew L. Bettini, ; Maria Bettini,
| | - Maria Bettini
- Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, McNair Medical Institute, Houston, TX, United States
- *Correspondence: Matthew L. Bettini, ; Maria Bettini,
| |
Collapse
|