In this study, we examined: (1) whether the tPA/plasmin system is upregulated in vitro in amyloid-laden mouse islets and in islets isolated from donors with type 2 diabetes; (2) the islet cell types expressing tPA; and (3) whether plasmin can limit hIAPP aggregation in a cell-free system and reduce hIAPP-induced beta cell toxicity. Here, PLAT is linked to type 2 diabetes mellitus.