Deciphering\nthe Molecular Dance: Exploring the Dynamic\nInterplay Between Mouse Insulin B9–23 Peptides and their Variants

Type 1 diabetes results from the autoimmune destruction\nof pancreatic\ninsulin-producing β-cells, primarily targeted by autoreactive\nT cells that recognize insulin B9–23 peptides as antigens.\nUsing drift tube ion mobility spectrometry-mass spectrometry, transmission\nelectron microscopy, and two-dimensional infrared spectroscopy, we\ncharacterized mouse insulin 1 B9–23 (Ins1 B9–23), insulin\n2 B9–23 (Ins2 B9–23), along with two of their mutants,\nIns2 B9–23 Y16A and Ins2 B9–23 C19S. Our findings indicate\nthat Ins1 B9–23 and the Ins2 Y16A mutant exhibit rapid fibril\nformation, whereas Ins2 B9–23 and the Ins2 C19S mutant show\nslower fibrillization and a structural rearrangement from globular\nprotofibrils to fibrillar aggregates. These differences in aggregation\nbehaviors also manifest in interactions with (−)epigallocatechin\ngallate (EGCG), a canonical amyloid inhibitor. EGCG effectively disrupts\nthe fibrils formed by Ins1 B9–23 and the Y16A mutant. However,\nit proves ineffective in preventing fibril formation of Ins2 B9–23\nand the C19S mutant. These results establish a strong correlation\nbetween the aggregation behaviors of these peptides and their divergent\neffects on anti-islet autoimmunity.