IAPP25 in Beta Cells and DNSP11 in Alpha Cells Inhibit IAPP37 Fibrillation

Amyloidosis due to aggregation of mature islet amyloid polypeptide (IAPP37) in human islets causes β-cell dysfunction and there is a need to develop anti-amyloid therapeutics to protect β-cells. We used a bioinformatic approach to uncover novel human IAPP isoforms and we developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their translated peptide levels in human pancreatic islets. We used the Thioflavin T amyloid reporter assay to monitor the isoform-derived peptides for fibrillation propensity and for anti-amyloid potential to prevent aggregation of IAPP37. We uncovered hominid specific IAPP isoforms that are encoded by 4 exons instead of the conventional 3 exons: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is a frameshifted prepropeptide that is processed to mature IAPP25 instead of IAPP37. We found IAPP25 peptide levels to be significantly reduced in the islets of T2DM postmortem samples. We also found IAPP25, Cα-peptide (a novel short C-peptide of 19 AAs), and GDNF-derived DNSP11 present in α cells, to be nonaggregating peptides that inhibited the aggregation of IAPP37 in vitro. These novel peptides have potential to be developed as peptide based anti-amyloid therapies (This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging). Disclosure Q.Liu: None. M.Zhu: None. J.M.Egan: None. Funding National Institute on Aging