Evolution of Membrane Leakage by Pre-Amyloidogenic Oligomers of Islet Amyloid Polypeptide

Abstract

Islet amyloid polypeptide (IAPP) is the primary amyloid component found in patients suffering from type II diabetes. IAPP has been implicated in the death of pancreatic beta-cells, resulting in a greater strain on the remaining insulin producing cells and contributing to further progression of the disease. While fibers are the most obvious characteristic of any amyloid disease, it has been found that smaller soluble oligomers are the most likely source of cytotoxicity. Previous research has shown that IAPP oligomers are capable of permeabilizing lipid bilayers under physiological conditions. Permeabilization of cellular membranes resulting in ionic imbalance and subsequent apoptosis is a leading theory for the cause of beta-cell death in type II diabetes. In order to better understand the mechanism by which IAPP causes cell death we have examined the evolution of membrane-bound leakage states over time. Using a combination of bulk and single molecule techniques we have uncovered a multi-phasic leakage mechanism in which we observe two clear time regimes of leakage behavior induced by soluble pre-amyloidogenic oligomers. Our results give us further insight into the mechanism by which IAPP is capable of inducing membrane leakage.