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PATHOGENESIS OF TYPE 1 DIABETES

Pathogenesis of type 1 diabetes

GROUP LEADER: DECIO L. EIZIRIK, M.D., PH.D.

The “Pathogenesis of type 1 diabetes Laboratory” focuses on the mechanisms leading to pancreatic β-cell dysfunction and death in type 1 diabetes, and on the dialog between β-cells and the immune system that will eventually evolve to full autoimmunity and progressive β-cell loss.

Research Interests

The “Pathogenesis of type 1 diabetes Laboratory” focuses on the molecular pathways leading to β-cell dysfunction and death in type 1 diabetes. Work from the Eizirik Lab has led to fundamental concepts such as the dialogue between the immune system and β-cells that triggers and amplifies insulitis and β-cell damage, a finding recently extended by his group to other autoimmune diseases. He pioneered studies on global gene expression in pancreatic β-cells, clarifying the cytokine-, virus- and metabolically-regulated gene networks that define β-cell dysfunction and death in diabetes. This led to the discovery that key “β-cell gene modules” define the β-cell outcomes following injury and that >80% of the candidate genes for type 1 diabetes are expressed in human islets – expression of at least half of these candidate genes in β-cells is modified by cytokines or viral infections. The lab studied the function of several of these candidate genes, observing that most of them regulate local innate immune responses, particularly type I IFN signaling. Two other research lines from the Eizirik group focus on the role of endoplasmic reticulum (ER) stress and alternative splicing in β-cell dysfunction and death. They were the first to show that cytokines induce ER stress in β-cells and that ER stress markers are present in islets from type 1 diabetes individuals. Recent findings from his group identified the key role for IFNa in the induction of three hallmarks of early human b-cell dysfunction in type 1 diabetes, namely HLA class I overexpression, ER stress and apoptosis. He has mined alternative splice variants that are expressed preferentially at the β-cell surface and is using them as biomarkers for β-cell imaging or as targets to deliver therapeutic cargo.

Group Leader, Decio L. Eizirik, M.D., Ph.D.

Decio L. Eizirik, M.D., Ph.D., is Professor and former Director of the ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Belgium. He has published nearly 400 full papers and reviews in peer-reviewed international journals and has received several national and international prizes.

He is listed by the ISI Essential Science Indicators among the 1% most cited scientists in Clinical Medicine and Biology & Biochemistry, with an h-index of 87. Dr Eizirik has served as Honorary (Scientific) Secretary of the EASD and as Deputy Editor of Diabetologia.

 

 

Decio A.2022

Honours & Awards (selected)

  • “Postdoctoral Fellowship Award” from the Juvenile Diabetes Foundation International, USA, 07/89-07/91.

  • “Career Development Award” from the Juvenile Diabetes Foundation International (JDRF), USA, 1993-1996.

  • “Eli Lilly/EASD Research Fellowship Award in Diabetes and Metabolism” (EASD award “to encourage research in the field of diabetes”; 1993.

  • “Limbic Prize”, pedagogical prize awarded annually by students from the Biomedical Course, Uppsala University. The prize was awarded in 1997, for teaching in the 1996 course of Endocrine Function, Organ Function II, Biomedical Course.

  • “Research Prize Pharmacia & Upjohn”, awarded by the National Fund for Scientific Research, Flanders (Belgium)”, Brussels, 1998.

  • “Diabetes Care Research Award”, awarded by Juvenile Diabetes Foundation International/Roche Diagnostics, 1998.

  • “Glassman Lecture” of the Diabetes Research Center at the Hebrew University, Hadassah Medical School, Jerusalem, entitled “Molecular regulation of genes involved in beta-cell damage and repair”, 2000.

  • “Trondheim Honorary Lecture” (formerly “Millenium Lecture”), awarded every two years by the Faculty of Medicine at the Norwegian University of Science and Technology, Trondheim, Norway, entitled “The role of cytokines for type 1 diabetes”, 2004.

  • “Conference Mario Sanchez Medina”, Annual Award lecture from the Colombian Diabetes Association, presented at the annual congress of the Colombian Diabetes Association, entitled: “The role for ER stress in beta cell dysfunction and death”, Manizales, Colombia, 2009.

  • “2012 Albert Renold Prize Lecture for Outstanding Achievements in Research on the Islets of Langerhans”, awarded by the EASD, entitled: “Beta-cell apoptosis in diabetes: a complex road to disaster”, Berlin, 2012.

  • “2013 Rumbough Award for outstanding achievements in type 1 diabetes research”, awarded by the Juvenile Diabetes Foundation International, New York, 2013.

  • “2013 Albert Renold Lecture on Islet Research”, awarded by the Swiss Society for Endocrinology and Diabetology, entitled: “The crosstalk between ER stress, candidate genes for type 1 diabetes and beta cell apoptosis”, Bern, 2013

  • “George Eisenbarth Award and Memorial Lecture” at the 15th Annual Meeting of nPOD (Network for Pancreatic Organ donors with  Diabetes; www.jdrfnpod.org), Ferdinanda Beach, FL, USA, February 26-March 1st, 2023

     

Selected Publications

  1. Eizirik DL, Sandler S, Welsh N, Cetkovic-Cvrlje M, Niemann A, Geller DA, Pipeleers D, Bendtzen K, Hellerström C Cytokines suppress human islet function irrespective of their effects on nitric oxide generation. J Clin Invest, 93: 1698-1974, 1994 (https://www.jci.org/articles/view/117188)
  2. Eizirik DL, Pipeleers DG, Ling Z, Welsh N, Hellerström C, Andersson A Major species differences between man and rodents in the susceptibility to pancreatic β-cell injury. Proc Natl Acad Sci USA, 91: 9253-9256, 1994 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC44790/pdf/pnas01142-0066.pdf)
  3. Eldor R, Yeffet A, Baum K, Doviner V, Amar D, Christoferi G, Ben-Neriah Y, Carel JC, Boitard C, Klein T, Serup P, Eizirik DL, Melloul D Conditional and specific NF-κB blockade protects pancreatic beta cells against diabetogenic inducers. Proc Natl Acad Sci USA 103: 5072-5077, 2006 (http://www.pnas.org/content/103/13/5072.long)
  4. Eizirik DL, Cardozo AK, Cnop M The role for endoplasmic reticulum stress in diabetes. Endocrine Rev 29:42-61, 2008 (https://academic.oup.com/edrv/article/29/1/42/2354979)
  5. Gurzov E, Ortis F, Cunha DA, Gosset G, Li M, Cardozo AK, Eizirik Signaling by IL-1β + IFN-γ and ER stress converge on DP5/Hrk activation: novel mechanisms for pancreatic beta cell apoptosis. Cell Death Differ, 16, 1539–1550, 2009 (https://www.nature.com/articles/cdd200999)
  6. Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, Ortis F, Santin I, Colli ML, Barthson J, Bouwens L, Hughes L, Gregory L, Lunter G, Marselli L, Marchetti P, McCarthy MI, Cnop M The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genetics, 8: e1002552, 2012 (“Faculty of 1000 Recommended”) (http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002552)
  7. Nogueira TC, Paula FV, Villate O, Colli ML, Moura RF, Cunha DA, Marselli L, Marchetti P, Cnop M, Julier C, Eizirik DL GLIS3, a susceptibility gene for type 1 and 2 diabetes mellitus, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet, 9: e1003532, 2013 (http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003532)
  8. Marroqui L, Lopes M, Santos RSD, Roivainen M, Richardson S, Morgan N, Op de Beeck A, Eizirik DL Differential cell autonomous immune responses determine the outcome of coxsackievirus infections in pancreatic α and β cells. eLife, 4: e06990, 2015 (https://elifesciences.org/articles/06990)
  9. Marroqui L, Santos RSD, Op de Beeck A, Brachene AC, Marselli L, Marchetti P, Eizirik DL Interferon-alpha mediates human beta cell HLA class I overexpression, endoplasmic reticulum stress and apoptosis, three hallmarks of early human type 1 diabetes. Diabetologia, 60:656-667, 2017 (https://link.springer.com/article/10.1007%2Fs00125-016-4201-3)
  10. Juan-Mateu J, Alvelos MI, Turatsinze JV, Villate O, Lizarraga-Mollinedo E, Grieco FA, Marroquí L, Bugliani M, Marchetti P, Eizirik DL A SRp55-regulated alternative splicing network controls pancreatic beta cell survival and function. Diabetes, 67: 423-436, 2018 (http://diabetes.diabetesjournals.org/content/67/3/423.long)
  11. Colli M, Hill JLE, Marroqui L, Chaffey J, Dos Santos R, Leete P, Brachene AC, Paula FMM, Op de Beeck, Castela A, Marselli L, Krogvold L, Dahl-Jorgensen K, Marcheti P, Morgan NG*, Richardson SJ*, Eizirik DL*. PDL1 is expressed in the islets of people with type 1 diabetes and is up-regulated by interferons-α and –β via IRF1 induction. EBioMedicine, 36: 367-375, 2018; *equal contribution.
  12.  Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze J-V, Nigi L, Lalanne AI, Sebastiani G, Carre A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buus S, You S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Dotta F, Scharfmann R, Eizirik DL*, Verdier Y*, Vinh J*, Mallone R. Conventional and neo-antigenic peptides presented by cells are targeted by circulating naïve CD8+ T cells in type 1 diabetic and healthy donors. Cell Metab, 28: 946-960, 2018 (*equal contribution).
  13. Ramos-Rodriguez M, Raurell-Vila H, Colli ML, Alvelos MI, Subirana M, Juan-Mateu J, Norris R, Turatsinze JV, Nakayasu ES, Webb-Robertson BJ, Marchetti P, Piemonti L, Esteller M, Todd JA, Metz TO, Eizirik DL, Pasquali L The impact of pro-inflammatory cytokines on the β-cell regulatory landscape provides new insights into the genetics of type 1 diabetes. Nature Genet, 51:1588-1595, 2019
  14. Demine S, Schiavo AA, Marin-Canas S, Marchetti P, Cnop M, Eizirik DL Pro-inflammatory cytokines induce cell death, inflammatory responses and endoplasmic reticulum stress in human iPSC-derived beta cells. Stem Cells Res Therap, 11: 7 (pp 1-15), 2020
  15. Eizirik DL, Pasquali L, Cnop M Pancreatic β-cells in type 1 and type 2 diabetes: different pathways to failure. Nature Rev Endocrinol, 16:349-362, 2020
  16. Colli M, Ramos-Rodriguez M, Nakayasu E, Alvelos MI, Lopes M, Hill JL, Turatsinze J-V, Coomans de Brachène A, Russel MA, Raurell-Villa H, Castela A, Juan-Mateu J, Webb-Robertson B-J, Krogvold L, Dahl-Jorgensen K, Marselli L, Marchetti P, Richardson SJ, Morgan NG, Metz TO, Pasquali L, Eizirik DL. An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells. Nature Commun, 11: 2584-2601, 2020
  17. Szymczak F, Colli ML, Mamula M, Evans-Mollina C, Eizirik DL. Gene expression signatures of target tissues in type 1 diabetes, lupus erythematosus, multiple sclerosis and rheumatoid arthritis. Sci. Adv. 7, eabd7600, 2021 (Commented in Nature at “Highlights from research” – https://www.nature.com/articles/d41586-021-01834-x)
  18. Eizirik DL, Szymczak F, Alvelos MI, Martin F. From pancreatic beta-cell gene networks to novel therapies for type 1 diabetes. Diabetes, 70: 1915-25, 2021
  19. Szymczak F, Alvelos MI, Marin-Canas S, Castela A, Demine S, Colli ML, Op de Beeck A, Thomaidou S, Marselli L, Zaldumbide A, Marchetti P, Eizirik DL. Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic beta-cells. Science Adv, 8, eabn5732, 2022
  20. Eizirik DL, Szymczak F, Mallone R Why does the immune system destroy pancreatic beta-cells but not a-cells in type 1 diabetes? Nat Rev Endocrinol. 2023 Apr 18. doi: 10.1038/s41574-023-00826-3. Online ahead of print; PMID 37072614

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