2039-P: Plasmin-Mediated Cleavage of Human Islet Amyloid Polypeptide (hIAPP) Protects ß-Cells from Amyloid-Induced Toxicity

Islet amyloid deposition and reduced s-cell mass are pathologic hallmarks of type 2 diabetes. Amyloid deposits contain the 37 amino acid hIAPP, aggregation of which is toxic to s cells. The 20-29 amino acid region of the peptide is known to confer its amyloidogenic potential. We previously reported that plasmin, a fibrinolytic protease, cleaves hIAPP thereby inhibiting fibril formation. We now sought to determine whether hIAPP fragments arising from plasmin-mediated cleavage retain the potential to aggregate and induce cytotoxicity. The s-cell line INS-1 was treated for 24 h with full-length hIAPP (20 µM) alone or in the presence of plasmin (0.4 µM); plasmin alone or buffer were used as controls. Exposure to hIAPP alone decreased cell viability (53±1.4% of buffer, p In summary, plasmin protects s cells from hIAPP-induced toxicity by cleaving hIAPP between amino acids 11 and 12. Thus, increasing islet plasmin activity might be a strategy to limit s-cell loss in type 2 diabetes. Disclosure N. Esser: None. M.F. Hogan: None. A.T. Templin: None. J.J. Castillo: None. D. Raleigh: None. J.S. Edgar: None. S. Zraika: Research Support; Self; Novartis Pharmaceuticals Corporation. R.L. Hull: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc. Funding U.S. Department of Veterans Affairs (I01BX001060)