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J Proteome Res. 2019 Mar 1;18(3):814-825. doi: 10.1021/acs.jproteome.8b00875. Epub 2019 Jan 3.

Identification of Hybrid Insulin Peptides (HIPs) in Mouse and Human Islets by Mass Spectrometry.

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Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, United States
Barbara Davis Center for Childhood Diabetes , Aurora , Colorado 80045 , United States.
Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045, United States


We recently discovered hybrid insulin peptides (HIPs) as a novel class of post-translationally modified peptides in murine-derived beta cell tumors, and we demonstrated that these molecules are autoantigens in type 1 diabetes (T1D). A HIP consists of an insulin fragment linked to another secretory granule peptide via a peptide bond. We verified that autoreactive CD4 T cells in both mouse and human autoimmune diabetes recognize these modified peptides. Here, we use mass spectrometric analyses to confirm the presence of HIPs in both mouse and human pancreatic islets. We also present criteria for the confident identification of these peptides. This work supports the hypothesis that HIPs are autoantigens in human T1D and provides a foundation for future efforts to interrogate this previously unknown component of the beta cell proteome.


beta cell proteome; hybrid insulin peptide (HIP); mass spectrometry; pancreatic islets; type 1 diabetes (T1D)

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