期刊
CELL METABOLISM
卷 31, 期 2, 页码 363-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.12.005
关键词
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资金
- NIDDK
- National Institutes of Health (NIH), United States, National Institute of Diabetes and Digestive and Kidney Diseases [UC4 DK104166, UC4 DK104167, UC4 DK108101, R01 DK60581, R01 DK093954]
- United States Department of Veterans Affairs, VA Merit Award [I01BX001733]
- Fonds National de la Recherche Scientifique (FNRS), Welbio, Belgium [CR-2015A-06]
- JDRF (United States) Strategic Research Agreement
- JDRF [3-PDF-2016-199-A-N]
- Innovative Medicines Initiative 2 Joint Undertaking - Union's Horizon 2020 research and innovation program [115797]
- EFPIA (Belgium)
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust (United States)
- NIH [P30 DK097512, P30 DK020595]
- DOE [DE-AC05-76RLO01830]
Type 1 diabetes (T1D) results from the progressive loss of beta cells, a process propagated by pro-inflammatory cytokine signaling that disrupts the balance between pro- and anti-apoptotic proteins. To identify proteins involved in this process, we performed comprehensive proteomics of human pancreatic islets treated with interleukin-1 beta and interferon-gamma, leading to the identification of 11,324 proteins, of which 387 were significantly regulated by treatment. We then tested the function of growth/differentiation factor 15 (GDF15), which was repressed by the treatment. We found that GDF15 translation was blocked during inflammation, and it was depleted in islets from individuals with T1D. The addition of exogenous GDF15 inhibited interleukin-1 beta+interferon-gamma-induced apoptosis of human islets. Administration of GDF15 reduced by 53% the incidence of diabetes in NOD mice. Our approach provides a unique resource for the identification of the human islet proteins regulated by cytokines and was effective in discovering a potential target for T1D therapy.
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