Skip to main content
SpringerLink
Log in

A Role for lncRNAs in Regulating Inflammatory and Autoimmune Responses Underlying Type 1 Diabetes

  • Chapter
  • First Online:
Long Noncoding RNA

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1363))

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which immune cells mediate the specific destruction of the insulin-producing β cells in the pancreatic islets. Genetic and transcriptome studies for T1D indicate that a relatively large number of long noncoding RNAs (lncRNAs), detected in both immune cells and β cells, contribute to the underlying inflammation and autoimmune pathology. Although lncRNAs do not encode proteins, their biochemical versatility as RNA molecules enables them to interact with proteins, DNA or RNA to exert regulatory effects on various cellular processes. Recent studies have begun to determine these effects for a small number of lncRNAs in modulating specific immune cell and β-cell responses to elevated glucose levels and pro-inflammatory cytokines that are present within the islets during T1D pathogenesis. These findings are reviewed here and highlight the potential for different lncRNAs to act in concert to inhibit or exacerbate inflammatory and autoimmune responses. Despite this progress to date, additional investigations are required for a more in-depth understanding of their individual functional roles in this interplay, as well as identifying which lncRNAs are likely diagnostic biomarkers or therapeutic targets for autoimmune diseases such as T1D.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 179.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Nolan CJ, Prentki M (2008) The islet β-cell: fuel responsive and vulnerable. Trends Endocrinol Metab 19:285–291. https://doi.org/10.1016/j.tem.2008.07.006

    Article  CAS  PubMed  Google Scholar 

  2. Regazzi R, Rodriguez-Trejo A, Jacovetti C (2016) Insulin secretion in health and disease: nutrients dictate the pace. Proc Nutr Soc 75:19–29. https://doi.org/10.1017/S0029665115004152

    Article  CAS  PubMed  Google Scholar 

  3. Eizirik DL, Pasquali L, Cnop M (2020) Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 16:349–362. https://doi.org/10.1038/s41574-020-0355-7

    Article  CAS  PubMed  Google Scholar 

  4. Usmani-Brown S et al (2019) β-cell responses to inflammation. Mol Metab 27S:S104–S113. https://doi.org/10.1016/j.molmet.2019.06.013

    Article  CAS  PubMed  Google Scholar 

  5. DeFronzo RA et al (2015) Type 2 diabetes mellitus. Nat Rev Dis Primers 1:15019. https://doi.org/10.1038/nrdp.2015.19

    Article  PubMed  Google Scholar 

  6. DiMeglio LA, Evans-Molina C, Oram RA (2018) Type 1 diabetes. Lancet 391:2449–2462. https://doi.org/10.1016/S0140-6736(18)31320-5

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cole JB, Florez JC (2020) Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol 16:377–390. https://doi.org/10.1038/s41581-020-0278-5

    Article  PubMed  Google Scholar 

  8. Pullen TJ, Rutter GA (2014) Roles of lncRNAs in pancreatic β cell identity and diabetes susceptibility. Front Genet 5:193. https://doi.org/10.3389/fgene.2014.00193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Motterle A, Gattesco S, Caille D, Meda P, Regazzi R (2015) Involvement of long non-coding RNAs in β cell failure at the onset of type 1 diabetes in NOD mice. Diabetologia 58:1827–1835. https://doi.org/10.1007/s00125-015-3641-5

    Article  CAS  PubMed  Google Scholar 

  10. Motterle A et al (2017) Identification of islet-enriched long non-coding RNAs contributing to β-cell failure in type 2 diabetes. Mol Metab 6:1407–1418. https://doi.org/10.1016/j.molmet.2017.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Singer RA, Sussel L (2018) Islet long noncoding RNAs: a playbook for discovery and characterization. Diabetes 67:1461–1470. https://doi.org/10.2337/dbi18-0001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ravasi T et al (2006) Experimental validation of the regulated expression of large numbers of non-coding RNAs from the mouse genome. Genome Res 16:11–19. https://doi.org/10.1101/gr.4200206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guttman M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227. https://doi.org/10.1038/nature07672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iyer MK et al (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47:199–208. https://doi.org/10.1038/ng.3192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136:629–641. https://doi.org/10.1016/j.cell.2009.02.006

    Article  CAS  PubMed  Google Scholar 

  16. Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62. https://doi.org/10.1038/nrg.2015.10

    Article  CAS  PubMed  Google Scholar 

  17. Gloss BS, Dinger ME (2016) The specificity of long noncoding RNA expression. Biochim Biophys Acta 1859:16–22. https://doi.org/10.1016/j.bbagrm.2015.08.005

    Article  CAS  PubMed  Google Scholar 

  18. Mattick JS, Rinn JL (2015) Discovery and annotation of long noncoding RNAs. Nat Struct Mol Biol 22:5–7. https://doi.org/10.1038/nsmb.2942

    Article  CAS  PubMed  Google Scholar 

  19. Jarroux J, Morillon A, Pinskaya M (2017) History, discovery, and classification of lncRNAs. Adv Exp Med Biol 1008:1–46. https://doi.org/10.1007/978-981-10-5203-3_1

    Article  CAS  PubMed  Google Scholar 

  20. Guttman M, Rinn JL (2012) Modular regulatory principles of large non-coding RNAs. Nature 482:339–346. https://doi.org/10.1038/nature10887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Geisler S, Coller J (2013) RNA in unexpected places: long non-coding RNA functions in diverse cellular contexts. Nat Rev Mol Cell Biol 14:699–712. https://doi.org/10.1038/nrm3679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yao RW, Wang Y, Chen LL (2019) Cellular functions of long noncoding RNAs. Nat Cell Biol 21:542–551. https://doi.org/10.1038/s41556-019-0311-8

    Article  CAS  PubMed  Google Scholar 

  23. Shields EJ, Petracovici AF, Bonasio R (2019) lncRedibly versatile: biochemical and biological functions of long noncoding RNAs. Biochem J 476:1083–1104. https://doi.org/10.1042/BCJ20180440

    Article  CAS  PubMed  Google Scholar 

  24. Pervouchine DD et al (2015) Enhanced transcriptome maps from multiple mouse tissues reveal evolutionary constraint in gene expression. Nat Commun 6:5903. https://doi.org/10.1038/ncomms6903

    Article  CAS  PubMed  Google Scholar 

  25. Moran I et al (2012) Human β cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab 16:435–448. https://doi.org/10.1016/j.cmet.2012.08.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Benner C et al (2014) The transcriptional landscape of mouse β cells compared to human β cells reveals notable species differences in long non-coding RNA and protein-coding gene expression. BMC Genomics 15:620. https://doi.org/10.1186/1471-2164-15-620

    Article  PubMed  PubMed Central  Google Scholar 

  27. Akerman I et al (2017) Human pancreatic β cell lncRNAs control cell-specific regulatory networks. Cell Metab 25:400–411. https://doi.org/10.1016/j.cmet.2016.11.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mirza AH, Kaur S, Pociot F (2017) Long non-coding RNAs as novel players in β cell function and type 1 diabetes. Hum Genomics 11:17. https://doi.org/10.1186/s40246-017-0113-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Motterle A, Sanchez-Parra C, Regazzi R (2016) Role of long non-coding RNAs in the determination of β-cell identity. Diabetes Obes Metab 18 S3uppl 1:41–50. https://doi.org/10.1111/dom.12714

    Article  CAS  Google Scholar 

  30. Carpenter S (2016) Long noncoding RNA: novel links between gene expression and innate immunity. Virus Res 212:137–145. https://doi.org/10.1016/j.virusres.2015.08.019

    Article  CAS  PubMed  Google Scholar 

  31. Atianand MK, Caffrey DR, Fitzgerald KA (2017) Immunobiology of long noncoding RNAs. Annu Rev Immunol 35:177–198. https://doi.org/10.1146/annurev-immunol-041015-055459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wong WKM, Sorensen AE, Joglekar MV, Hardikar AA, Dalgaard LT (2018) Non-coding RNA in pancreas and β-cell development. Noncoding RNA 4:41. https://doi.org/10.3390/ncrna4040041

    Article  CAS  PubMed Central  Google Scholar 

  33. Bluestone JA, Herold K, Eisenbarth G (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464:1293–1300. https://doi.org/10.1038/nature08933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Coppieters KT et al (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209:51–60. https://doi.org/10.1084/jem.20111187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Patterson CC et al (2019) Worldwide estimates of incidence, prevalence and mortality of type 1 diabetes in children and adolescents: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract 157:107842. https://doi.org/10.1016/j.diabres.2019.107842

    Article  PubMed  Google Scholar 

  36. Bizzarri C et al (2010) Clinical presentation and autoimmune characteristics of very young children at the onset of type 1 diabetes mellitus. J Pediatr Endocrinol Metab 23:1151–1157. https://doi.org/10.1515/jpem.2010.180

    Article  CAS  PubMed  Google Scholar 

  37. Nyenwe EA, Kitabchi AE (2016) The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism 65:507–521. https://doi.org/10.1016/j.metabol.2015.12.007

    Article  CAS  PubMed  Google Scholar 

  38. de Ferranti SD et al (2014) Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Circulation 130:1110–1130. https://doi.org/10.1161/CIR.0000000000000034

    Article  PubMed  Google Scholar 

  39. Monti MC et al (2007) Familial risk factors for microvascular complications and differential male-female risk in a large cohort of American families with type 1 diabetes. J Clin Endocrinol Metab 92:4650–4655. https://doi.org/10.1210/jc.2007-1185

    Article  CAS  PubMed  Google Scholar 

  40. Fong DS, Aiello LP, Ferris FL 3rd, Klein R (2004) Diabetic retinopathy. Diabetes Care 27:2540–2553. https://doi.org/10.2337/diacare.27.10.2540

    Article  PubMed  Google Scholar 

  41. Finne P, Reunanen A, Stenman S, Groop PH, Gronhagen-Riska C (2005) Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 294:1782–1787. https://doi.org/10.1001/jama.294.14.1782

    Article  CAS  PubMed  Google Scholar 

  42. Knip M, Simell O (2012) Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med 2:a007690. https://doi.org/10.1101/cshperspect.a007690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hamilton-Williams EE, Lorca GL, Norris JM, Dunne JL (2021) A triple threat? The role of diet, nutrition, and the microbiota in T1D pathogenesis. Front Nutr 8:600756. https://doi.org/10.3389/fnut.2021.600756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Eizirik DL, Colli ML, Ortis F (2009) The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nat Rev Endocrinol 5:219–226. https://doi.org/10.1038/nrendo.2009.21

    Article  CAS  PubMed  Google Scholar 

  45. Mannering SI, Pathiraja V, Kay TW (2016) The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol 183:8–15. https://doi.org/10.1111/cei.12699

    Article  CAS  PubMed  Google Scholar 

  46. Atkinson MA et al (2011) How does type 1 diabetes develop?: the notion of homicide or β-cell suicide revisited. Diabetes 60:1370–1379. https://doi.org/10.2337/db10-1797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Yang J et al (2006) Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol 176:2781–2789. https://doi.org/10.4049/jimmunol.176.5.2781

    Article  CAS  PubMed  Google Scholar 

  48. Palmer JP et al (1983) Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337–1339. https://doi.org/10.1126/science.6362005

    Article  CAS  PubMed  Google Scholar 

  49. Baekkeskov S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156. https://doi.org/10.1038/347151a0

    Article  CAS  PubMed  Google Scholar 

  50. Solimena M et al (1996) ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J 15:2102–2114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wenzlau JM et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045. https://doi.org/10.1073/pnas.0705894104

    Article  PubMed  PubMed Central  Google Scholar 

  52. Ahmed S et al (2019) Standardizing T-cell biomarkers in type 1 diabetes: challenges and recent advances. Diabetes 68:1366–1379. https://doi.org/10.2337/db19-0119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pathiraja V et al (2015) Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes 64:172–182. https://doi.org/10.2337/db14-0858

    Article  CAS  PubMed  Google Scholar 

  54. Mannering SI et al (2005) The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J Exp Med 202:1191–1197. https://doi.org/10.1084/jem.20051251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mannering SI et al (2009) The A-chain of insulin is a hot-spot for CD4+ T cell epitopes in human type 1 diabetes. Clin Exp Immunol 156:226–231. https://doi.org/10.1111/j.1365-2249.2009.03907.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Delong T et al (2016) Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351:711–714. https://doi.org/10.1126/science.aad2791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mallone R, Brezar V, Boitard C (2011) T cell recognition of autoantigens in human type 1 diabetes: clinical perspectives. Clin Dev Immunol 2011:513210. https://doi.org/10.1155/2011/513210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bonifacio E, Ziegler AG (2010) Advances in the prediction and natural history of type 1 diabetes. Endocrinol Metab Clin N Am 39:513–525. https://doi.org/10.1016/j.ecl.2010.05.007

    Article  Google Scholar 

  59. So M et al (2021) Advances in Type 1 diabetes prediction using islet autoantibodies: beyond a simple count. Endocr Rev. https://doi.org/10.1210/endrev/bnab013

  60. Sosenko JM et al (2010) Trends of earlier and later responses of C-peptide to oral glucose challenges with progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes Care 33:620–625. https://doi.org/10.2337/dc09-1770

    Article  CAS  PubMed  Google Scholar 

  61. Sosenko JM et al (2010) Glucose excursions between states of glycemia with progression to type 1 diabetes in the diabetes prevention trial-type 1 (DPT-1). Diabetes 59:2386–2389. https://doi.org/10.2337/db10-0534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Driver JP, Serreze DV, Chen YG (2011) Mouse models for the study of autoimmune type 1 diabetes: a NOD to similarities and differences to human disease. Semin Immunopathol 33:67–87. https://doi.org/10.1007/s00281-010-0204-1

    Article  CAS  PubMed  Google Scholar 

  63. Jayasimhan A, Mansour KP, Slattery RM (2014) Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse. Clin Sci (Lond) 126:1–18. https://doi.org/10.1042/CS20120627

    Article  CAS  Google Scholar 

  64. Diana J et al (2013) Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 19:65–73. https://doi.org/10.1038/nm.3042

    Article  CAS  PubMed  Google Scholar 

  65. Jansen A et al (1994) Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and β-cell destruction in NOD mice. Diabetes 43:667–675. https://doi.org/10.2337/diab.43.5.667

    Article  CAS  PubMed  Google Scholar 

  66. Dahlen E, Dawe K, Ohlsson L, Hedlund G (1998) Dendritic cells and macrophages are the first and major producers of TNF-α in pancreatic islets in the nonobese diabetic mouse. J Immunol 160:3585–3593

    CAS  PubMed  Google Scholar 

  67. Serreze DV, Leiter EH (2001) Genes and cellular requirements for autoimmune diabetes susceptibility in nonobese diabetic mice. Curr Dir Autoimmun 4:31–67. https://doi.org/10.1159/000060527

    Article  CAS  PubMed  Google Scholar 

  68. Lehuen A, Diana J, Zaccone P, Cooke A (2010) Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10:501–513. https://doi.org/10.1038/nri2787

    Article  CAS  PubMed  Google Scholar 

  69. Unanue ER, Ferris ST, Carrero JA (2016) The role of islet antigen presenting cells and the presentation of insulin in the initiation of autoimmune diabetes in the NOD mouse. Immunol Rev 272:183–201. https://doi.org/10.1111/imr.12430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bender C, Rajendran S, von Herrath MG (2020) New insights into the role of autoreactive CD8 T cells and cytokines in human type 1 diabetes. Front Endocrinol (Lausanne) 11:606434. https://doi.org/10.3389/fendo.2020.606434

    Article  Google Scholar 

  71. Morgan NG, Richardson SJ (2018) Fifty years of pancreatic islet pathology in human type 1 diabetes: insights gained and progress made. Diabetologia 61:2499–2506. https://doi.org/10.1007/s00125-018-4731-y

    Article  PubMed  PubMed Central  Google Scholar 

  72. Somoza N et al (1994) Pancreas in recent onset insulin-dependent diabetes mellitus. Changes in HLA, adhesion molecules and autoantigens, restricted T cell receptor V beta usage, and cytokine profile. J Immunol 153:1360–1377

    CAS  PubMed  Google Scholar 

  73. Uno S et al (2007) Macrophages and dendritic cells infiltrating islets with or without β cells produce tumour necrosis factor-α in patients with recent-onset type 1 diabetes. Diabetologia 50:596–601. https://doi.org/10.1007/s00125-006-0569-9

    Article  CAS  PubMed  Google Scholar 

  74. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2009) Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol 155:173–181. https://doi.org/10.1111/j.1365-2249.2008.03860.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Campbell-Thompson M et al (2016) Insulitis and β-cell mass in the natural history of type 1 diabetes. Diabetes 65:719–731. https://doi.org/10.2337/db15-0779

    Article  CAS  PubMed  Google Scholar 

  76. Lundberg M, Seiron P, Ingvast S, Korsgren O, Skog O (2017) Insulitis in human diabetes: a histological evaluation of donor pancreases. Diabetologia 60:346–353. https://doi.org/10.1007/s00125-016-4140-z

    Article  CAS  PubMed  Google Scholar 

  77. Shapiro MR et al (2021) De-coding genetic risk variants in type 1 diabetes. Immunol Cell Biol 99:496–508. https://doi.org/10.1111/imcb.12438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Allen C, Palta M, D'Alessio DJ (1991) Risk of diabetes in siblings and other relatives of IDDM subjects. Diabetes 40:831–836. https://doi.org/10.2337/diab.40.7.831

    Article  CAS  PubMed  Google Scholar 

  79. Pociot F, Norgaard K, Hobolth N, Andersen O, Nerup J (1993) A nationwide population-based study of the familial aggregation of type 1 (insulin-dependent) diabetes mellitus in Denmark. Danish Study Group of Diabetes in Childhood. Diabetologia 36:870–875. https://doi.org/10.1007/BF00400364

    Article  CAS  PubMed  Google Scholar 

  80. Harjutsalo V, Podar T, Tuomilehto J (2005) Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. Diabetes 54:563–569. https://doi.org/10.2337/diabetes.54.2.563

    Article  CAS  PubMed  Google Scholar 

  81. Ferrannini E et al (2010) Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset. Diabetes 59:679–685. https://doi.org/10.2337/db09-1378

    Article  CAS  PubMed  Google Scholar 

  82. Todd JA, Bell JI, McDevitt HO (1987) HLA-DQ β gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329:599–604. https://doi.org/10.1038/329599a0

    Article  CAS  PubMed  Google Scholar 

  83. Erlich H et al (2008) HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes 57:1084–1092. https://doi.org/10.2337/db07-1331

    Article  CAS  PubMed  Google Scholar 

  84. Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33:176–183. https://doi.org/10.2337/diab.33.2.176

    Article  CAS  PubMed  Google Scholar 

  85. Lucassen AM et al (1993) Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet 4:305–310. https://doi.org/10.1038/ng0793-305

    Article  CAS  PubMed  Google Scholar 

  86. Ueda H et al (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506–511. https://doi.org/10.1038/nature01621

    Article  CAS  PubMed  Google Scholar 

  87. Bottini N et al (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338. https://doi.org/10.1038/ng1323

    Article  CAS  PubMed  Google Scholar 

  88. Vella A et al (2005) Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am J Hum Genet 76:773–779. https://doi.org/10.1086/429843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Barrett JC et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707. https://doi.org/10.1038/ng.381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bradfield JP et al (2011) A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet 7:e1002293. https://doi.org/10.1371/journal.pgen.1002293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Concannon P et al (2009) Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 58:1018–1022. https://doi.org/10.2337/db08-1551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cooper JD et al (2012) Confirmation of novel type 1 diabetes risk loci in families. Diabetologia 55:996–1000. https://doi.org/10.1007/s00125-012-2450-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hakonarson H et al (2007) A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448:591–594. https://doi.org/10.1038/nature06010

    Article  CAS  PubMed  Google Scholar 

  94. Howson JM, Walker NM, Smyth DJ, Todd JA, Type IDGC (2009) Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families. Genes Immun 10 Suppl 1:S74–S84. https://doi.org/10.1038/gene.2009.96

    Article  CAS  PubMed  Google Scholar 

  95. Onengut-Gumuscu S et al (2015) Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 47:381–386. https://doi.org/10.1038/ng.3245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Todd JA et al (2007) Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 39:857–864. https://doi.org/10.1038/ng2068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wellcome Trust Case Control, C (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678. https://doi.org/10.1038/nature05911

    Article  CAS  Google Scholar 

  98. Chiou J et al (2021) Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. Nature 594:398–402. https://doi.org/10.1038/s41586-021-03552-w

    Article  CAS  PubMed  Google Scholar 

  99. Zhu M et al (2019) Identification of novel T1D risk loci and their association with age and islet function at diagnosis in autoantibody-positive T1D individuals: based on a two-stage genome-wide association study. Diabetes Care 42:1414–1421. https://doi.org/10.2337/dc18-2023

    Article  CAS  PubMed  Google Scholar 

  100. Polychronakos C, Li Q (2011) Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet 12:781–792. https://doi.org/10.1038/nrg3069

    Article  CAS  PubMed  Google Scholar 

  101. Pociot F et al (2010) Genetics of type 1 diabetes: what's next? Diabetes 59:1561–1571. https://doi.org/10.2337/db10-0076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Castellanos-Rubio A, Ghosh S (2019) Disease-associated SNPs in inflammation-related lncRNAs. Front Immunol 10:420. https://doi.org/10.3389/fimmu.2019.00420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mirza AH, Kaur S, Brorsson CA, Pociot F (2014) Effects of GWAS-associated genetic variants on lncRNAs within IBD and T1D candidate loci. PLoS One 9:e105723. https://doi.org/10.1371/journal.pone.0105723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Li C, Wei B, Zhao J (2021) Competing endogenous RNA network analysis explores the key lncRNAs, miRNAs, and mRNAs in type 1 diabetes. BMC Med Genet 14:35. https://doi.org/10.1186/s12920-021-00877-3

    Article  CAS  Google Scholar 

  105. Smyth DJ et al (2008) Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 359:2767–2777. https://doi.org/10.1056/NEJMoa0807917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wallace C et al (2010) The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet 42:68–71. https://doi.org/10.1038/ng.493

    Article  CAS  PubMed  Google Scholar 

  107. Tan IK et al (2010) A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility. Genome Res 20:1629–1638. https://doi.org/10.1101/gr.101881.109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kumar V et al (2013) Human disease-associated genetic variation impacts large intergenic non-coding RNA expression. PLoS Genet 9:e1003201. https://doi.org/10.1371/journal.pgen.1003201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Orom UA et al (2010) Long noncoding RNAs with enhancer-like function in human cells. Cell 143:46–58. https://doi.org/10.1016/j.cell.2010.09.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Guttman M et al (2011) lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 477:295–300. https://doi.org/10.1038/nature10398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nyaga DM, Vickers MH, Jefferies C, Perry JK, O'Sullivan JM (2018) Type 1 diabetes mellitus-associated genetic variants contribute to overlapping immune regulatory networks. Front Genet 9:535. https://doi.org/10.3389/fgene.2018.00535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Guo H et al (2015) Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases. Hum Mol Genet 24:3305–3313. https://doi.org/10.1093/hmg/ddv077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hu X et al (2014) Regulation of gene expression in autoimmune disease loci and the genetic basis of proliferation in CD4+ effector memory T cells. PLoS Genet 10:e1004404. https://doi.org/10.1371/journal.pgen.1004404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. de Goede OM et al (2021) Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease. Cell 184:2633–2648 e2619. https://doi.org/10.1016/j.cell.2021.03.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mutskov V, Felsenfeld G (2009) The human insulin gene is part of a large open chromatin domain specific for human islets. Proc Natl Acad Sci U S A 106:17419–17424. https://doi.org/10.1073/pnas.0909288106

    Article  PubMed  PubMed Central  Google Scholar 

  116. Tomlinson MJ, t. et al (2014) Fine mapping and functional studies of risk variants for type 1 diabetes at chromosome 16p13.13. Diabetes 63:4360–4368. https://doi.org/10.2337/db13-1785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nieves-Bonilla JM, Kiaf B, Schuster C, Kissler S (2020) The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model. Genes Immun 21:71–77. https://doi.org/10.1038/s41435-019-0083-y

    Article  CAS  PubMed  Google Scholar 

  118. Trudeau JD et al (2000) Neonatal β-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49:1–7. https://doi.org/10.2337/diabetes.49.1.1

    Article  CAS  PubMed  Google Scholar 

  119. Turley S, Poirot L, Hattori M, Benoist C, Mathis D (2003) Physiological β cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 198:1527–1537. https://doi.org/10.1084/jem.20030966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Christen U, Bender C, von Herrath MG (2012) Infection as a cause of type 1 diabetes? Curr Opin Rheumatol 24:417–423. https://doi.org/10.1097/BOR.0b013e3283533719

    Article  PubMed  PubMed Central  Google Scholar 

  121. Hoglund P et al (1999) Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med 189:331–339. https://doi.org/10.1084/jem.189.2.331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gagnerault MC, Luan JJ, Lotton C, Lepault F (2002) Pancreatic lymph nodes are required for priming of β cell reactive T cells in NOD mice. J Exp Med 196:369–377. https://doi.org/10.1084/jem.20011353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Elling R et al (2018) Genetic models reveal cis and trans immune-regulatory activities for lincRNA-Cox2. Cell Rep 25:1511–1524 e1516. https://doi.org/10.1016/j.celrep.2018.10.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Carpenter S et al (2013) A long noncoding RNA mediates both activation and repression of immune response genes. Science 341:789–792. https://doi.org/10.1126/science.1240925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Li Z et al (2014) The long noncoding RNA THRIL regulates TNFα expression through its interaction with hnRNPL. Proc Natl Acad Sci U S A 111:1002–1007. https://doi.org/10.1073/pnas.1313768111

    Article  CAS  PubMed  Google Scholar 

  126. Chan J et al (2015) Cutting edge: a natural antisense transcript, AS-IL1α, controls inducible transcription of the proinflammatory cytokine IL-1α. J Immunol 195:1359–1363. https://doi.org/10.4049/jimmunol.1500264

    Article  CAS  PubMed  Google Scholar 

  127. Yang X, Bam M, Becker W, Nagarkatti PS, Nagarkatti M (2020) Long noncoding RNA AW112010 promotes the differentiation of inflammatory T cells by suppressing IL-10 expression through histone demethylation. J Immunol 205:987–993. https://doi.org/10.4049/jimmunol.2000330

    Article  CAS  PubMed  Google Scholar 

  128. Westra HJ et al (2018) Fine-mapping and functional studies highlight potential causal variants for rheumatoid arthritis and type 1 diabetes. Nat Genet 50:1366–1374. https://doi.org/10.1038/s41588-018-0216-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li R et al (2018) MEG3–4 is a miRNA decoy that regulates IL-1β abundance to initiate and then limit inflammation to prevent sepsis during lung infection. Sci Signal 11:eaao2387. https://doi.org/10.1126/scisignal.aao2387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. You L et al (2016) Downregulation of long noncoding RNA Meg3 affects insulin synthesis and secretion in mouse pancreatic β cells. J Cell Physiol 231:852–862. https://doi.org/10.1002/jcp.25175

    Article  CAS  PubMed  Google Scholar 

  131. Wang N et al (2018) Long noncoding RNA Meg3 regulates Mafa expression in mouse β cells by inactivating Rad21, Smc3 or Sin3α. Cell Physiol Biochem 45:2031–2043. https://doi.org/10.1159/000487983

    Article  CAS  PubMed  Google Scholar 

  132. Zhou Y et al (2007) Activation of p53 by MEG3 non-coding RNA. J Biol Chem 282:24731–24742. https://doi.org/10.1074/jbc.M702029200

    Article  CAS  PubMed  Google Scholar 

  133. Lu KH et al (2013) Long non-coding RNA MEG3 inhibits NSCLC cells proliferation and induces apoptosis by affecting p53 expression. BMC Cancer 13:461. https://doi.org/10.1186/1471-2407-13-461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Colombo T, Farina L, Macino G, Paci P (2015) PVT1: a rising star among oncogenic long noncoding RNAs. Biomed Res Int 2015:304208. https://doi.org/10.1155/2015/304208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Fu J et al (2020) LncRNA PVT1 links Myc to glycolytic metabolism upon CD4(+) T cell activation and Sjogren's syndrome-like autoimmune response. J Autoimmun 107:102358. https://doi.org/10.1016/j.jaut.2019.102358

    Article  CAS  PubMed  Google Scholar 

  136. Millis MP, Bowen D, Kingsley C, Watanabe RM, Wolford JK (2007) Variants in the plasmacytoma variant translocation gene (PVT1) are associated with end-stage renal disease attributed to type 1 diabetes. Diabetes 56:3027–3032. https://doi.org/10.2337/db07-0675

    Article  CAS  PubMed  Google Scholar 

  137. Jin K et al (2019) Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis. Cell Mol Life Sci 76:4275–4289. https://doi.org/10.1007/s00018-019-03222-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Tai N, Wong FS, Wen L (2016) The role of the innate immune system in destruction of pancreatic β cells in NOD mice and humans with type I diabetes. J Autoimmun 71:26–34. https://doi.org/10.1016/j.jaut.2016.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Stunault MI, Bories G, Guinamard RR, Ivanov S (2018) Metabolism plays a key role during macrophage activation. Mediat Inflamm 2018:2426138. https://doi.org/10.1155/2018/2426138

    Article  CAS  Google Scholar 

  140. Thayer TC et al (2011) Superoxide production by macrophages and T cells is critical for the induction of autoreactivity and type 1 diabetes. Diabetes 60:2144–2151. https://doi.org/10.2337/db10-1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shanmugam N, Reddy MA, Guha M, Natarajan R (2003) High glucose-induced expression of proinflammatory cytokine and chemokine genes in monocytic cells. Diabetes 52:1256–1264. https://doi.org/10.2337/diabetes.52.5.1256

    Article  CAS  PubMed  Google Scholar 

  142. Das S et al (2018) Diabetes mellitus-induced long noncoding RNA Dnm3os regulates macrophage functions and inflammation via nuclear mechanisms. Arterioscler Thromb Vasc Biol 38:1806–1820. https://doi.org/10.1161/ATVBAHA.117.310663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang H et al (2019) Cancer-associated fibroblast-promoted lncRNA DNM3OS confers radioresistance by regulating DNA damage response in esophageal squamous cell carcinoma. Clin Cancer Res 25:1989–2000. https://doi.org/10.1158/1078-0432.CCR-18-0773

    Article  CAS  PubMed  Google Scholar 

  144. Wang P et al (2016) miR-214/199a/199a* cluster levels predict poor survival in hepatocellular carcinoma through interference with cell-cycle regulators. Oncotarget 7:929–945. https://doi.org/10.18632/oncotarget.6137

    Article  PubMed  Google Scholar 

  145. el Azzouzi H et al (2013) The hypoxia-inducible microRNA cluster miR-199a approximately 214 targets myocardial PPARδ and impairs mitochondrial fatty acid oxidation. Cell Metab 18:341–354. https://doi.org/10.1016/j.cmet.2013.08.009

    Article  CAS  PubMed  Google Scholar 

  146. Lakhia R et al (2020) Interstitial microRNA miR-214 attenuates inflammation and polycystic kidney disease progression. JCI Insight 5:e133785. https://doi.org/10.1172/jci.insight.133785

    Article  PubMed Central  Google Scholar 

  147. Zgheib C, Hodges MM, Hu J, Liechty KW, Xu J (2017) Long non-coding RNA Lethe regulates hyperglycemia-induced reactive oxygen species production in macrophages. PLoS One 12:e0177453. https://doi.org/10.1371/journal.pone.0177453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Rapicavoli NA et al (2013) A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics. elife 2:e00762. https://doi.org/10.7554/eLife.00762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wu H, Wen F, Jiang M, Liu Q, Nie Y (2018) LncRNA uc.48+ is involved in the diabetic immune and inflammatory responses mediated by P2X7 receptor in RAW264.7 macrophages. Int J Mol Med 42:1152–1160. https://doi.org/10.3892/ijmm.2018.3661

    Article  CAS  PubMed  Google Scholar 

  150. Berghaus LJ et al (2010) Innate immune responses of primary murine macrophage-lineage cells and RAW 264.7 cells to ligands of Toll-like receptors 2, 3, and 4. Comp Immunol Microbiol Infect Dis 33:443–454. https://doi.org/10.1016/j.cimid.2009.07.001

    Article  PubMed  Google Scholar 

  151. Donath MY, Storling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T (2008) Cytokines and β-cell biology: from concept to clinical translation. Endocr Rev 29:334–350. https://doi.org/10.1210/er.2007-0033

    Article  CAS  PubMed  Google Scholar 

  152. Singh B, Nikoopour E, Huszarik K, Elliott JF, Jevnikar AM (2011) Immunomodulation and regeneration of islet β cells by cytokines in autoimmune type 1 diabetes. J Interf Cytokine Res 31:711–719. https://doi.org/10.1089/jir.2011.0025

    Article  CAS  Google Scholar 

  153. Kaminitz A, Stein J, Yaniv I, Askenasy N (2007) The vicious cycle of apoptotic β-cell death in type 1 diabetes. Immunol Cell Biol 85:582–589. https://doi.org/10.1038/sj.icb.7100093

    Article  CAS  PubMed  Google Scholar 

  154. Kim KA, Lee MS (2009) Recent progress in research on β-cell apoptosis by cytokines. Front Biosci (Landmark Ed) 14:657–664. https://doi.org/10.2741/3271

    Article  CAS  Google Scholar 

  155. Ramos-Rodriguez M et al (2019) The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat Genet 51:1588–1595. https://doi.org/10.1038/s41588-019-0524-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Kutlu B et al (2003) Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells. Diabetes 52:2701–2719. https://doi.org/10.2337/diabetes.52.11.2701

    Article  CAS  PubMed  Google Scholar 

  157. Ortis F et al (2010) Cytokines interleukin-1β and tumor necrosis factor-α regulate different transcriptional and alternative splicing networks in primary β-cells. Diabetes 59:358–374. https://doi.org/10.2337/db09-1159

    Article  CAS  PubMed  Google Scholar 

  158. Eizirik DL et al (2012) The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet 8:e1002552. https://doi.org/10.1371/journal.pgen.1002552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Li B et al (2014) RNA-seq methods for identifying differentially expressed gene in human pancreatic islet cells treated with pro-inflammatory cytokines. Mol Biol Rep 41:1917–1925. https://doi.org/10.1007/s11033-013-3016-2

    Article  CAS  PubMed  Google Scholar 

  160. Sun C et al (2016) Insights from lncRNAs profiling of MIN6 β cells undergoing inflammation. Mediat Inflamm 2016:9275106. https://doi.org/10.1155/2016/9275106

    Article  CAS  Google Scholar 

  161. Cianciaruso C et al (2017) Primary human and rat β-cells release the intracellular autoantigens GAD65, IA-2, and proinsulin in exosomes together with cytokine-induced enhancers of immunity. Diabetes 66:460–473. https://doi.org/10.2337/db16-0671

    Article  CAS  PubMed  Google Scholar 

  162. Guay C et al (2019) Lymphocyte-derived exosomal microRNAs promote pancreatic β cell death and may contribute to type 1 diabetes development. Cell Metab 29:348–361 e346. https://doi.org/10.1016/j.cmet.2018.09.011

    Article  CAS  PubMed  Google Scholar 

  163. Ribeiro D et al (2017) Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation. Proc Natl Acad Sci U S A 114:11127–11132. https://doi.org/10.1073/pnas.1711389114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Krishnan P, Syed F, Jiyun Kang N, Mirmira RG, Evans-Molina C (2019) Profiling of RNAs from human islet-derived exosomes in a model of type 1 diabetes. Int J Mol Sci 20:5903. https://doi.org/10.3390/ijms20235903

    Article  CAS  PubMed Central  Google Scholar 

  165. Ansari MJ et al (2003) The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 198:63–69. https://doi.org/10.1084/jem.20022125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fife BT et al (2006) Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203:2737–2747. https://doi.org/10.1084/jem.20061577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Guleria I et al (2007) Mechanisms of PDL1-mediated regulation of autoimmune diabetes. Clin Immunol 125:16–25. https://doi.org/10.1016/j.clim.2007.05.013

    Article  CAS  PubMed  Google Scholar 

  168. Osum KC et al (2018) Interferon-γ drives programmed death-ligand 1 expression on islet β cells to limit T cell function during autoimmune diabetes. Sci Rep 8:8295. https://doi.org/10.1038/s41598-018-26471-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Giannoukakis N, Rudert WA, Trucco M, Robbins PD (2000) Protection of human islets from the effects of interleukin-1β by adenoviral gene transfer of an Iκ B repressor. J Biol Chem 275:36509–36513. https://doi.org/10.1074/jbc.M005943200

    Article  CAS  PubMed  Google Scholar 

  170. Heimberg H et al (2001) Inhibition of cytokine-induced NF-κB activation by adenovirus-mediated expression of a NF-κB super-repressor prevents β-cell apoptosis. Diabetes 50:2219–2224. https://doi.org/10.2337/diabetes.50.10.2219

    Article  CAS  PubMed  Google Scholar 

  171. Eldor R et al (2006) Conditional and specific NF-κB blockade protects pancreatic β cells from diabetogenic agents. Proc Natl Acad Sci U S A 103:5072–5077. https://doi.org/10.1073/pnas.0508166103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ortis F et al (2006) Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-κB activation. Mol Endocrinol 20:1867–1879. https://doi.org/10.1210/me.2005-0268

    Article  CAS  PubMed  Google Scholar 

  173. Ortis F et al (2008) Induction of nuclear factor-κB and its downstream genes by TNF-α and IL-1β has a pro-apoptotic role in pancreatic β cells. Diabetologia 51:1213–1225. https://doi.org/10.1007/s00125-008-0999-7

    Article  CAS  PubMed  Google Scholar 

  174. Shan Z, Xu B, Mikulowska-Mennis A, Michie SA (2014) CCR7 directs the recruitment of T cells into inflamed pancreatic islets of nonobese diabetic (NOD) mice. Immunol Res 58:351–357. https://doi.org/10.1007/s12026-014-8500-9

    Article  CAS  PubMed  Google Scholar 

  175. Christen U, Kimmel R (2020) Chemokines as drivers of the autoimmune destruction in type 1 diabetes: opportunity for therapeutic intervention in consideration of an optimal treatment schedule. Front Endocrinol (Lausanne) 11:591083. https://doi.org/10.3389/fendo.2020.591083

    Article  Google Scholar 

  176. Gonzalez-Moro I et al (2020) The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA. Proc Natl Acad Sci U S A 117:9022–9031. https://doi.org/10.1073/pnas.1914353117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Castellanos-Rubio A et al (2016) A long noncoding RNA associated with susceptibility to celiac disease. Science 352:91–95. https://doi.org/10.1126/science.aad0467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Ding H et al (2020) LncRNA MALAT1 induces the dysfunction of β cells via reducing the histone acetylation of the PDX-1 promoter in type 1 diabetes. Exp Mol Pathol 114:104432. https://doi.org/10.1016/j.yexmp.2020.104432

    Article  CAS  PubMed  Google Scholar 

  179. Macfarlane WM et al (2000) Glucose modulation of insulin mRNA levels is dependent on transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+. Diabetes 49:418–423. https://doi.org/10.2337/diabetes.49.3.418

    Article  CAS  PubMed  Google Scholar 

  180. Melloul D (2004) Transcription factors in islet development and physiology: role of PDX-1 in β-cell function. Ann N Y Acad Sci 1014:28–37. https://doi.org/10.1196/annals.1294.003

    Article  CAS  PubMed  Google Scholar 

  181. Artner I, Hang Y, Guo M, Gu G, Stein R (2008) MafA is a dedicated activator of the insulin gene in vivo. J Endocrinol 198:271–279. https://doi.org/10.1677/JOE-08-0063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zatterale F et al (2019) Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes. Front Physiol 10:1607. https://doi.org/10.3389/fphys.2019.01607

    Article  PubMed  Google Scholar 

  183. Sladek R et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885. https://doi.org/10.1038/nature05616

    Article  CAS  PubMed  Google Scholar 

  184. Diabetes Genetics Initiative of Broad Institute of, H et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336. https://doi.org/10.1126/science.1142358

    Article  CAS  Google Scholar 

  185. Voight BF et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589. https://doi.org/10.1038/ng.609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Morris AP et al (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981–990. https://doi.org/10.1038/ng.2383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Pasquali L et al (2014) Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat Genet 46:136–143. https://doi.org/10.1038/ng.2870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Sathishkumar C, Prabu P, Mohan V, Balasubramanyam M (2018) Linking a role of lncRNAs (long non-coding RNAs) with insulin resistance, accelerated senescence, and inflammation in patients with type 2 diabetes. Hum Genomics 12:41. https://doi.org/10.1186/s40246-018-0173-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Dieter C, Lemos NE, Correa NRF, Assmann TS, Crispim D (2021) The impact of lncRNAs in diabetes mellitus: a systematic review and in silico analyses. Front Endocrinol (Lausanne) 12:602597. https://doi.org/10.3389/fendo.2021.602597

    Article  PubMed Central  Google Scholar 

  190. Reddy MA et al (2021) lncRNA DRAIR is downregulated in diabetic monocytes and modulates the inflammatory phenotype via epigenetic mechanisms. JCI Insight 6:143289. https://doi.org/10.1172/jci.insight.143289

    Article  PubMed  Google Scholar 

  191. Marchetti P et al (2020) A direct look at the dysfunction and pathology of the β cells in human type 2 diabetes. Semin Cell Dev Biol 103:83–93. https://doi.org/10.1016/j.semcdb.2020.04.005

    Article  CAS  PubMed  Google Scholar 

  192. Kameswaran V et al (2014) Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab 19:135–145. https://doi.org/10.1016/j.cmet.2013.11.016

    Article  CAS  PubMed  Google Scholar 

  193. Carter S, Miard S, Boivin L, Salle-Lefort S, Picard F (2018) Loss of Malat1 does not modify age- or diet-induced adipose tissue accretion and insulin resistance in mice. PLoS One 13:e0196603. https://doi.org/10.1371/journal.pone.0196603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Zhang Y, Fu Y, Zheng Y, Wen Z, Wang C (2020) Identification of differentially expressed mRNA and the Hub mRNAs modulated by lncRNA Meg3 as a competing endogenous RNA in brown adipose tissue of mice on a high-fat diet. Adipocytes 9:346–358. https://doi.org/10.1080/21623945.2020.1789283

    Article  CAS  Google Scholar 

  195. White RR et al (2015) Comprehensive transcriptional landscape of aging mouse liver. BMC Genomics 16:899. https://doi.org/10.1186/s12864-015-2061-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Mahpour A, Mullen AC (2021) Our emerging understanding of the roles of long non-coding RNAs in normal liver function, disease, and malignancy. JHEP Rep 3:100177. https://doi.org/10.1016/j.jhepr.2020.100177

    Article  PubMed  Google Scholar 

  197. Zhu X, Wu YB, Zhou J, Kang DM (2016) Upregulation of lncRNA MEG3 promotes hepatic insulin resistance via increasing FoxO1 expression. Biochem Biophys Res Commun 469:319–325. https://doi.org/10.1016/j.bbrc.2015.11.048

    Article  CAS  PubMed  Google Scholar 

  198. Zhu X et al (2019) lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression. Int J Mol Med 43:345–357. https://doi.org/10.3892/ijmm.2018.3975

    Article  CAS  PubMed  Google Scholar 

  199. Yan C, Chen J, Chen N (2016) Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. Sci Rep 6:22640. https://doi.org/10.1038/srep22640

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Ma Z et al (2019) LncRNA expression profile during autophagy and Malat1 function in macrophages. PLoS One 14:e0221104. https://doi.org/10.1371/journal.pone.0221104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Wu J et al (2018) The long noncoding RNA MALAT1 induces tolerogenic dendritic cells and regulatory T cells via miR155/dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin/IL10 axis. Front Immunol 9:1847. https://doi.org/10.3389/fimmu.2018.01847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hewitson JP et al (2020) Malat1 suppresses immunity to infection through promoting expression of Maf and IL-10 in Th cells. J Immunol 204:2949–2960. https://doi.org/10.4049/jimmunol.1900940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Murray PJ, Smale ST (2012) Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways. Nat Immunol 13:916–924. https://doi.org/10.1038/ni.2391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Robinson EK, Covarrubias S, Carpenter S (2020) The how and why of lncRNA function: an innate immune perspective. Biochim Biophys Acta Gene Regul Mech 1863:194419. https://doi.org/10.1016/j.bbagrm.2019.194419

    Article  CAS  PubMed  Google Scholar 

  205. Li L, Chang HY (2014) Physiological roles of long noncoding RNAs: insight from knockout mice. Trends Cell Biol 24:594–602. https://doi.org/10.1016/j.tcb.2014.06.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Kaddis JS, Pugliese A, Atkinson MA (2015) A run on the biobank: what have we learned about type 1 diabetes from the nPOD tissue repository? Curr Opin Endocrinol Diabetes Obes 22:290–295. https://doi.org/10.1097/MED.0000000000000171

    Article  CAS  PubMed  Google Scholar 

  207. Joshi K et al (2021) Modeling type 1 diabetes using pluripotent stem cell technology. Front Endocrinol (Lausanne) 12:635662. https://doi.org/10.3389/fendo.2021.635662

    Article  Google Scholar 

  208. Borkiewicz L, Kalafut J, Dudziak K, Przybyszewska-Podstawka A, Telejko I (2021) Decoding lncRNAs. Cancers (Basel) 13. https://doi.org/10.3390/cancers13112643

Download references

Acknowledgments

Various colleagues and past students provided informative discussions, in particular Colleen Elso, Leanne Mackin, Edward Po-Fan Chu, Michelle Papadimitriou (née Ashton), May Abdulaziz Alsayb, Stuart Mannering, Helen Thomas, Thomas Kay, Guarang Jhala, Balasubramanian Krishnamurthy, Pablo Silveira, Ashley Mansell and Meredith O’Keeffe. Any novel insights provided here were in part stimulated by those discussions, whereas any errors or failure to cite certain work rest solely with the author.

Author information

Authors and Affiliations

  1. St Vincent’s Institute, Fitzroy, VIC, Australia

    Thomas C. Brodnicki

  2. University of Melbourne, Department of Microbiology & Immunology, Department of Medicine, St Vincent’s Hospital, Fitzroy, VIC, Australia

    Thomas C. Brodnicki

Authors
  1. Thomas C. Brodnicki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas C. Brodnicki .

Editor information

Editors and Affiliations

  1. Molecular Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA, USA

    Susan Carpenter

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Brodnicki, T.C. (2022). A Role for lncRNAs in Regulating Inflammatory and Autoimmune Responses Underlying Type 1 Diabetes. In: Carpenter, S. (eds) Long Noncoding RNA. Advances in Experimental Medicine and Biology, vol 1363. Springer, Cham. https://doi.org/10.1007/978-3-030-92034-0_6

Download citation

Publish with us

Policies and ethics

Search

Navigation