The Mechanism of Islet Amyloid Polypeptide Toxicity Is Membrane Disruption by Intermediate-Sized Toxic Amyloid Particles

摘要

NIDDM is characterized by islet amyloid deposits and decreased β-cell mass. Islet amyloid is derived from the locally expressed protein islet amyloid polypeptide (IAPP). While it is now widely accepted that abnormal aggregation of IAPP ahs a role in β-cell death in NIDDM, the mechanism remains unknown. We hypothe- Sized that small IAPP aggregates, rather than mature Large amyloid deposits, are cytotoxic, Consistent with This hypothesis, freshly dissolved human (h)-IAPP was Cytotoxic when added to dispersed mouse and human Islet cells, provoking the formation of abnormal vesicle- Like membrane structures in association with vac- Uolization and cell death.