The islet tissue plasminogen activator/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation‑induced toxicity – published online 09/09/2024

Nathalie Esser, Meghan F. Hogan, Andrew T. Templin, Rehana Akter, Brendy S. Fountaine, Joseph J. Castillo, Assam El‑Osta, Lakshan Manathunga, Alexander Zhyvoloup, Daniel P. Raleigh, Sakeneh Zraika, Rebecca L. Hull, Steven E. Kahn

Islet amyloid deposition and reduced beta cell mass are pathological hallmarks of type 2 diabetes. Aggregation of human islet amyloid polypeptide (hIAPP), the main peptide component of islet amyloid deposits in humans, is toxic to beta cells. In this issue, Esser et al (https://doi.org/10.1007/s00125-024-06161-0) delineate a new role for the fibrinolytic system in modulating islet amyloidogenesis. The authors identify that a local tissue plasminogen activator (tPA)/plasmin system is specifically upregulated in vitro in amyloid-laden hIAPP transgenic mouse islets and islets from human donors with type 2 diabetes. The authors also demonstrate that plasmin is an hIAPP-degrading enzyme that protects beta cells from hIAPP-induced toxicity. Together, these findings suggest that the tPA/plasmin system serves a protective function to limit islet amyloid deposition and its cytotoxic effects. The authors conclude that interventions aimed at increasing the islet tPA/plasmin system activity may reduce or limit hIAPP aggregation, and thereby, improve beta cell survival in type 2 diabetes.