Hybrid Insulin Peptides in Type 1 Diabetes: How They Form and Why They Matter

Type 1 diabetes is a T cell-mediated autoimmune disease that leads to the destruction of the insulin-producing beta cells of the pancreas, yet the antigens that drive this response have been difficult to define. 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-2.5 clone in the nonobese diabetic (NOD) mouse, we show that its natural ligand is a hybrid of an insulin C-peptide fragment and a peptide derived from chromogranin A, and that subsequent mass spectrometry analyses defined a set of disease-relevant 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-trigger model linking a species difference in HIP formation to the focal, episodic islet pathology of human type 1 diabetes.