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Purpose: Signal transducer and activator of transcription 1 (STAT-1) plays a crucial role in cytokine-induced beta-cell destruction. However, its precise downstream pathways have not been completely clarified. We performed a proteome analysis of cytokine-exposed C57Bl/6 and STAT-1(-/-) mouse islets and prioritized proteins for their potential in relation to type 1 diabetes (T1D)., Experimental Design: Differential proteins were identified using a combination of 2D-DIGE and MALDI-TOF/TOF analysis and were subjected to ingenuity pathway analysis (IPA). Protein-protein interaction networks were created and a phenome-interactome ranking of the differential proteins based on their assignment to T1D was performed., Results: Numerous STAT-1-regulated proteins were identified and divided in different groups according to their biological function. The largest group of proteins was the one involved in protein synthesis and processing. Network analysis revealed a complex interaction between proteins from different functional groups and IPA analysis confirmed the protective effect of STAT-1 deletion on cytokine-induced beta-cell death. Finally, a central role in this STAT-1-regulated mechanism was assigned to small ubiquitin-related modifier 4 (SUMO4)., Conclusions and Clinical Relevance: These findings confirm a central role for STAT-1 in pancreatic islet inflammation induced destruction and most importantly elucidate the underlying proteomic pathways involved., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pancreatic beta-cells have a crucial role in the regulation of blood glucose homeostasis by the production and secretion of insulin. In type 1 diabetes (T1D), an autoimmune reaction against the beta-cells together with the presence of inflammatory cytokines and ROS in the islets leads to beta-cell dysfunction and death. This review gives an overview of proteomic studies that lead to better understanding of beta-cell functioning in T1D. Protein profiling of isolated islets and beta-cell lines in health and T1D contributed to the unraveling of pathways involved in cytokine-induced cell death. In addition, by studying the serological proteome of T1D patients, new biomarkers and beta-cell autoantigens were discovered, which may improve screening tests and follow-up of T1D development. Interestingly, an important role for PTMs was demonstrated in the generation of beta-cell autoantigens. To conclude, proteomic techniques are of indispensable value to improve the knowledge on beta-cell function in T1D and the search toward therapeutic targets., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)