Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention

Ernesto S. Nakayasu, Farooq Syed, Sarah A. Tersey, Marina A. Gritsenko, Hugh D. Mitchell, Chi Yuet Chan, Ercument Dirice, Jean Valery Turatsinze, Yi Cui, Rohit N. Kulkarni, Decio L. Eizirik, Wei Jun Qian, Bobbie Jo M. Webb-Robertson, Carmella Evans-Molina, Raghavendra G. Mirmira., Thomas O. Metz

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Type 1 diabetes (T1D) results from the progressive loss of β 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-1β and interferon-γ, 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-1β+interferon-γ-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.

Original languageEnglish (US)
Pages (from-to)363-374.e6
JournalCell Metabolism
Volume31
Issue number2
DOIs
StatePublished - Feb 4 2020

Keywords

  • apoptosis
  • cytokine
  • GDF15
  • human islets
  • islet protective factor
  • proteomics
  • type 1 diabetes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Nakayasu, E. S., Syed, F., Tersey, S. A., Gritsenko, M. A., Mitchell, H. D., Chan, C. Y., Dirice, E., Turatsinze, J. V., Cui, Y., Kulkarni, R. N., Eizirik, D. L., Qian, W. J., Webb-Robertson, B. J. M., Evans-Molina, C., Mirmira., R. G., & Metz, T. O. (2020). Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention. Cell Metabolism, 31(2), 363-374.e6. https://doi.org/10.1016/j.cmet.2019.12.005