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This review traces the identification of hybrid insulin peptides (HIPs), posttranslationally modified autoantigens formed when a fragment of insulin is joined through a peptide bond to a fragment of a second beta cell granule protein, creating a sequence not encoded by any single gene. Beginning with the search for the antigen of the diabetogenic BDC\u20102.5 clone in the nonobese diabetic (NOD) mouse, we show that its natural ligand is a hybrid of an insulin C\u2010peptide fragment and a peptide derived from chromogranin A, and that subsequent mass spectrometry analyses defined a set of disease\u2010relevant HIPs supported by both T cell reactivity and detection of the endogenous peptide. We summarize the recognition of HIPs by CD4 T cells across several HLA class II alleles in human disease, the enzymatic and nonenzymatic routes of HIP formation within acidic secretory and crinophagic compartments, and genetic evidence that reducing HIP formation delays diabetes. Finally, we propose a multi\u2010trigger model linking a species difference in HIP formation to the focal, episodic islet pathology of human type 1 diabetes.<\/jats:p>","DOI":"10.1111\/imr.70185","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T05:41:56Z","timestamp":1792474916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hybrid Insulin Peptides in Type 1 Diabetes: How They Form and Why They Matter"],"prefix":"10.1111","volume":"343","author":[{"given":"Kelly","family":"Douglas","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus  Aurora Colorado 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