Hybrid insulin peptides (HIPs) form if peptide fragments of (pro)insulin bind through peptide bonds to fragments of other proteins. We previously demonstrated that HIPs can be detected in human and murine islets by mass spectrometry, are targeted by diabetes-triggering CD4 T cell clones from non-obese diabetic mice, and are recognized by CD4 T cells isolated from the residual islets of pancreatic organ donors with type 1 diabetes (T1D). HIPs may be key antigens in the development of T1D as they contain non-genomically encoded amino acid sequences. Since the initial discovery of HIPs, we have established a set of rigorous criteria that allow us to identify various new HIPs in pancreatic islets with high confidence. The formation of HIPs involves the chemical activation of the C-terminal carboxylic acid groups of (pro)insulin peptides. These activated peptides can react with N-terminal amines of other peptides, leading to the formation of HIPs. The identification of such activated peptides is of great interest as it will help us understand which peptides contribute to hybrid peptide formation. We developed a new technique, which allows us to identify such chemically activated peptides by mass spectrometry. This technique may lead to the identification of activated peptides that are not derived from (pro)insulin and could provide valuable information needed for the identification of new hybrid peptides that may play a role in the development of type 1 diabetes and other autoimmune diseases.


T. Delong: None.


American Diabetes Association (1-15-ACE-14); National Institutes of Health; JDRF

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