Dataset Information

Characterization of cytokine treatment on human pancreatic islets by top-down proteomics

ABSTRACT: Top-down proteomic data from 6 human islet donors; islets were treated with interferon gamma (IFN-gamma) and interleukin-1 beta (IL-1 beta). Time points include t=0 (control) and t=24 hours for each donor. Samples were reduced and alkylated, then analyzed by LC-MS/MS. Data was searched with TopPIC using PNNL's DMS processing pipeline and post-processed with TopPICR.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Wei-Jun Qian

PROVIDER: MSV000097810 | MassIVE | Tue May 06 11:29:00 BST 2025

REPOSITORIES: MassIVE

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Publications

Characterization of Cytokine Treatment on Human Pancreatic Islets by Top-Down Proteomics.

Ives Ashley N AN Sagendorf Tyler J TJ Nierves Lorenz L Lin Tai-Tu TT Dirice Ercument E Kulkarni Rohit N RN Paša-Tolić Ljiljana L Qian Wei-Jun WJ Fulcher James M JM

Proteomics 20250921

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin-producing β cells in the pancreatic islet. This process is modulated by pro-inflammatory cytokine signaling, which has been previously shown to alter protein expression in ex vivo islets. Herein, we applied top-down proteomics to globally evaluate proteoforms from human islets treated with proinflammatory cytokines (interferon-γ and interleukin-1β). We measured 1636 unique proteoforms across six donors and two time poi ...[more]

PMID: 40977091

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Project description:Immune-mediated beta cell destruction and lack of alpha cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects as well as its beta cell protective effects shown in rodent islets. Here, we examined the functional and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1β ± interferon (IFN)-γ in human EndoC-βH5 beta cells and isolated human islets, respectively. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-βH5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10, but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.