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Item Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention(Elsevier, 2020-02-04) Nakayasu, Ernesto S.; Syed, Farooq; Tersey, Sarah A.; Gritsenko, Marina A.; Mitchell, Hugh D.; Chan, Chi Yuet; Dirice, Ercument; Turatsinze, Jean-Valery; Cui, Yi; Kulkarni, Rohit N.; Eizirik, Decio L.; Qian, Wei-Jun; Webb-Robertson, Bobbie-Jo M.; Evans-Molina, Carmella; Mirmira., Raghavendra G.; Metz, Thomas O.; Pediatrics, School of MedicineType 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.Item Distinct gene expression pathways in islets from individuals with short‐ and long‐duration type 1 diabetes(Wiley, 2018) Mastracci, Teresa L.; Turatsinze, Jean-Valery; Book, Benita K.; Restrepo, Ivan A.; Pugia, Michael J.; Weibke, Eric A.; Pescovitz, Mark D.; Eizirik, Decio L.; Mirmira, Raghavendra G.; Biochemistry and Molecular Biology, School of MedicineAims Our current understanding of the pathogenesis of type 1 diabetes (T1D) arose, in large part, from studies using the non‐obese diabetic (NOD) mouse model. In the present study, we chose a human‐focused method to investigate T1D disease mechanisms and potential targets for therapeutic intervention by directly analysing human donor pancreatic islets from individuals with T1D. Materials and Methods We obtained islets from a young individual with T1D for 3 years and from an older individual with T1D for 27 years and performed unbiased functional genomic analysis by high‐depth RNA sequencing; the T1D islets were compared with islets isolated from 3 non‐diabetic donors. Results The islets procured from these T1D donors represent a unique opportunity to identify gene expression changes in islets after significantly different disease duration. Data analysis identified several inflammatory pathways up‐regulated in short‐duration disease, which notably included many components of innate immunity. As proof of concept for translation, one of the pathways, governed by IL‐23(p19), was selected for further study in NOD mice because of ongoing human trials of biologics against this target for different indications. A mouse monoclonal antibody directed against IL‐23(p19) when administered to NOD mice resulted in a significant reduction in incidence of diabetes. Conclusion While the sample size for this study is small, our data demonstrate that the direct analysis of human islets provides a greater understanding of human disease. These data, together with the analysis of an expanded cohort to be obtained by future collaborative efforts, might result in the identification of promising novel targets for translation into effective therapeutic interventions for human T1D, with the added benefit of repurposing known biologicals for use in different indications.