Plesner, A.; Cao, P.; Raleigh, D.; Abedini, A.

Aggregation of islet amyloid polypeptide (IAPP) contributes to pancreatic {beta}-cell dysfunction in diabetes, yet the identity and temporal persistence of the toxic species remain unresolved. Because amyloid formation proceeds through distinct kinetic phases, relating cytotoxicity to these phases provides a direct strategy to test competing mechanistic models. Here, we combine time-resolved {beta}-cell functional assays with concurrent biophysical measurements to quantitatively link IAPP aggregation kinetics to cellular dysfunction across multiple perturbations and sequence variants. We demonstrate that maximal toxicity occurs during the lag phase and establish aggregation kinetics as a predictive framework for the onset and duration of IAPP proteotoxicity. Across 22 independent experiments spanning more than a 450-fold range in lag times, the duration of {beta}-cell dysfunction scales linearly with lag phase length. Perturbations that alter aggregation kinetics, including changes in concentration, temperature, and sequence, predictably shift both the onset and duration of toxicity. Early lag-phase intermediates of the diabetes-associated S20G-IAPP mutant are more toxic than corresponding species formed by wild-type h-IAPP. Together, these results show that aggregation kinetics quantitatively define the temporal window of IAPP proteotoxicity and support a model in which transient pre-fibrillar intermediates, rather than mature fibrils, dominate {beta}-cell dysfunction.