title: Pancreatic β-Cell Membrane Fluidity and Toxicity Induced by Human Islet Amyloid Polypeptide Species.
abstract: Aggregation of human islet amyloid polypeptide (hIAPP) into fibrils and plaques is associated with pancreatic β-cell loss in type 2 diabetes (T2D). However, due to the rapidness of hIAPP conversion in aqueous phase, exactly which hIAPP species is responsible for the observed toxicity and through what mechanisms remains ambiguous. In light of the importance of understanding hIAPP toxicity for T2D here we show a biophysical scheme based on the use of a lipophilic Laurdan dye for examining MIN6 cell membranes upon exposure to fresh and oligomeric hIAPP as well as mature amyloid. It has been found that all three hIAPP species, especially fresh hIAPP, enhanced membrane fluidity and caused losses in cell viability. The cell generation of reactive oxygen species (ROS), however, was the most pronounced with mature amyloid hIAPP. The correlation between changes in membrane fluidity and cell viability and their lack of correlation with ROS production suggest hIAPP toxicity is elicited through both physical and biochemical means. This study offers a new insight into β-cell toxicity induced by controlled hIAPP species, as well as new biophysical methodologies that may prove beneficial for the studies of T2D as well as neurological disorders.
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Pilkington
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Kakinen
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Litwak
authors.affiliation: St Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, VIC 3065, Australia.|Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Stanley
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.|Department of Chemistry, University of Warwick, Gibbet Hill, Coventry, CV4 7AL, United Kingdom.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
authors.affiliation: ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
authors.forename: Pu Chun
authors.initials: PC
authors.lastname: Ke
mesh_terms: D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species