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Cited by 465Diabetes and associated disordersPancreatic function and diabetesEndoplasmic Reticulum Stress and Disease

The Human Pancreatic Islet Transcriptome: Expression of Candidate Genes for Type 1 Diabetes and the Impact of Pro-Inflammatory Cytokines

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Eizirik, Décio L., Sammeth, Michael, Bouckenooghe, Thomas, Bottu, Guy, Sisino, Giorgia, Igoillo-Esteve, Mariana, Ortis, Fernanda, Santin, Izortze +10 more·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1002552PMC PMC3297576
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Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic beta cells are killed by infiltrating immune cells and by cytokines released by these cells. Signaling events occurring in the pancreatic beta cells are decisive for their survival or death in diabetes. We have used RNA sequencing (RNA-seq) to identify transcripts, including splice variants, expressed in human islets of Langerhans under control conditions or following exposure to the pro-inflammatory cytokines interleukin-1β (IL-1β) and interferon-γ (IFN-γ). Based on this unique dataset, we examined whether putative candidate genes for T1D, previously identified by GWAS, are expressed in human islets. A total of 29,776 transcripts were identified as expressed in human islets. Expression of around 20% of these transcripts was modified by pro-inflammatory cytokines, including apoptosis- and inflammation-related genes. Chemokines were among the transcripts most modified by cytokines, a finding confirmed at the protein level by ELISA. Interestingly, 35% of the genes expressed in human islets undergo alternative splicing as annotated in RefSeq, and cytokines caused substantial changes in spliced transcripts. Nova1, previously considered a brain-specific regulator of mRNA splicing, is expressed in islets and its knockdown modified splicing. 25/41 of the candidate genes for T1D are expressed in islets, and cytokines modified expression of several of these transcripts. The present study doubles the number of known genes expressed in human islets and shows that cytokines modify alternative splicing in human islet cells. Importantly, it indicates that more than half of the known T1D candidate genes are expressed in human islets. This, and the production of a large number of chemokines and cytokines by cytokine-exposed islets, reinforces the concept of a dialog between pancreatic islets and the immune system in T1D. This dialog is modulated by candidate genes for the disease at both the immune system and beta cell level.

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  • Over 40% of genes associated with type 1 diabetes are expressed in the islet or beta cell.

    “More recently, there has been increased focus on whether many of these variants may influence beta cell interactions with the immune system, with over 40% of genes associated with type 1 diabetes being expressed in the islet or beta cell.”

    From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [57]

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Authors
Eizirik, D. L., Sammeth, M., Bouckenooghe, T., Bottu, G., Sisino, G., Igoillo-Esteve, M., Ortis, F., Santin, I., Colli, M. L., Barthson, J., Bouwens, L., Hughes, L., Gregory, L., Lunter, G., Marselli, L., Marchetti, P., McCarthy, M. I., & Cnop, M.
Affiliations
  • Centro Nacional de Análisis Genómico (ES)
  • Université Libre de Bruxelles (BE)
  • Vrije Universiteit Brussel (BE)
  • Churchill Hospital (GB)
  • University of Pisa (IT)
  • Centre for Human Genetics (GB)
Corresponding author
Cnop, Miriam
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2012-03-08
Volume
8
Issue
3
Pages
e1002552
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002552
PMC
PMC3297576
OpenAlex
W2093090129
Cited by
465
References
9
Citations by year
2026: 11 · 2025: 20 · 2024: 25 · 2023: 33 · 2022: 36 · 2021: 43 · 2020: 40 · 2019: 28 · 2018: 36 · 2017: 37 · 2016: 36 · 2015: 34 · 2014: 44 · 2013: 26 · 2012: 12
FWCI
22.36
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Juvenile Diabetes Research Foundation International
  • Wellcome Trust (090532)
  • University of Oxford
  • European Commission
  • European Foundation for the Study of Diabetes
  • Fonds De La Recherche Scientifique - FNRS
  • Novo Nordisk
  • Université de Genève
  • Biotechnology and Biological Sciences Research Council (BB/I02593X/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
type 1 diabetes, pancreatic islets, islet transcriptome, IL-1β, interferon-gamma, inflammatory cytokines, alternative splicing, NOVA1, chemokines, beta-cell death, gene expression
MeSH terms
Insulin Secretion, Adult, Aged, Aged, 80 and over, Animals, Cell Line, Diabetes Mellitus, Type 1, Female, Gene Expression Regulation, Humans, Immune System, Insulin, Interferon-gamma, Islets of Langerhans, Male, Middle Aged, Signal Transduction, Rats, Wistar, Apoptosis, Alternative Splicing, Sequence Analysis, RNA, Insulin-Secreting Cells, Mice, Rats, Interleukin-1beta, Genetic Association Studies, Transcriptome

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