ULB Center for Diabetes Research

Pathogenesis of Type 1 Diabetes

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

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The “Pathogenesis of type 1 diabetes Laboratory” focus on the role of endoplasmic reticulum (ER) stress and alternative splicing in β-cell dysfunction and death. Dr Eizirik was the first to show that ER stress induces direct degradation of insulin mRNA, which has a major impact on β-cell function, and his group clarified the crosstalk between ER stress and mitochondria that regulates β-cell apoptosis in models of type 1 diabetes (T1D).

 

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

Decio L. Eizirik, M.D., Ph.D., is Full Professor and Director of the ULB Center for Diabetes Research, Medical Faculty, Universite Libre de Bruxells (ULB), Belgium. He has published >330 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 74. Dr Eizirik has served as Honorary (Scientific) Secretary of the EASD and as Deputy Editor of Diabetologia.

Research Interests

The “Pathogenesis of type 1 diabetes Laboratory” focuses on the role of endoplasmic reticulum stress and alternative splicing in β cell dysfunction and death. Dr Eizirik was the first to show that endoplasmic reticulum stress induces direct degradation of insulin mRNA, which has a major impact on β cell function, and his group clarified the crosstalk between endoplasmic reticulum stress and mitochondria that regulates β-cell apoptosis in models of type 1 diabetes. Eizirik has shown that endoplasmic reticulum stress markers are present in pancreatic islets from individuals affected by type 1 diabetes and in diabetes-prone NOD mice and that endoplasmic reticulum stress amplifies inflammation in β cells via activation of the IRE-1α-XBP-1 pathway. Alternative splicing affects more than 90% of human genes and generates enormous proteome diversity. The Eizirik group has recently shown, using advanced functional genomics and bioinformatics tools, that pancreatic β-cell exposure to the pro-inflammatory cytokines modifies alternative splicing of >2000 genes, leading to well-defined “alternative splicing signatures” in response to specific stresses. His group identified a role for Bim splicing in β cell death and discovered that this is regulated by the diabetes candidate gene Glis3, suggesting a crosstalk between alternative splicing and type 1 diabetes candidate genes. These functional genomics studies also provide the background for the identification of novel β cell biomarkers, useful for β cell imaging. Future work on these research lines will focus on endoplasmic reticulum stress, alternative splicing, the role for candidate genes for type 1 diabetes at the beta cell level and beta cell imaging.

 

 
 
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Honours & Awards

  • "Paulo Brossard Prize" for the best Medical Curriculum among the 1978 medical graduates from the state of Rio Grande do Sul, Brazil."Postdoctoral Fellowship Award" from the Juvenile Diabetes Foundation International, USA, 07/89-07/91.Opening plenary conference for the 8th Congress  of the Latin American Diabetes Association, Mar del Plata, Argentina, 1992, entitled "Cytokines and beta-cell destruction in IDDM".
  • "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"; one such award is presented every year), 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). This award is given annually for "innovative research in the field of physiopathology of human diseases". The award was given for our work on "The search for new beta-cell gene products of potential relevance for diabetes mellitus", Brussels, 1998."Diabetes Care Research Award", awarded by Juvenile Diabetes Foundation International/Roche Diagnostics. This international award is given annually to one or two scientists for "outstanding research in the way diabetes is prevented, detected, treated or cured", 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
  • “Dusseldorf Diabetes Lecture”, of the German Diabetes Center, Leibniz Center for Diabetes Research and the Heinrich Heine University, entitled “Alternative splicing as a key regulating mechanism of beta cell function, dysfunction and apoptosis”, Dusseldorf, 2016.

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 (cited 275 times) (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 (cited 213 times) (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 (cited 152 times) (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 (cited 649 times) (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 (cited 92 times) (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”) (cited 162 times) (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 (cited 50 times) (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 (cited 8 times) (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 (cited 7 times) (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)