Amyloid inhibitors enhance survival of cultured human islets.
BACKGROUND
Amyloid fibrils created by misfolding and aggregation of proteins are a major pathological feature in a variety of degenerative diseases. Therapeutic approaches including amyloid vaccines and anti-aggregation compounds in models of amyloidosis point to an important role for amyloid in disease pathogenesis. Amyloid deposits derived from the beta-cell peptide islet amyloid polypeptide (IAPP or amylin) are a characteristic of type 2 diabetes and may contribute to loss of beta-cells in this disease.


METHODS
We developed a cellular model of rapid amyloid deposition using cultured human islets and observed a correlation between fibril accumulation and beta-cell death. A series of overlapping peptides derived from IAPP was generated.


RESULTS
A potent inhibitor (ANFLVH) of human IAPP aggregation was identified. This inhibitory peptide prevented IAPP fibril formation in vitro and in human islet cultures leading to a striking increase in islet cell viability.


CONCLUSIONS
These findings indicate an important contribution of IAPP aggregation to beta-cell death in situ and point to therapeutic applications for inhibitors of IAPP aggregation in enhancing beta-cell survival.


CONCLUSIONS
Anti-amyloid compounds could potentially reduce the loss of beta-cell mass in type 2 diabetes and maintain healthy human islet cultures for beta-cell replacement therapies.
Potter
Kathryn J
KJ
Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Scrocchi
Louise A
LA
Warnock
Garth L
GL
Ao
Ziliang
Z
Younker
Marika A
MA
Rosenberg
Lawrence
L
Lipsett
Mark
M
Verchere
C Bruce
CB
Fraser
Paul E
PE
D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000502:physiology / Q000648:ultrastructure; D008969:Molecular Sequence Data
D000682:Amyloid; D058228:Islet Amyloid Polypeptide