Amyloid inhibitors enhance survival of cultured human islets.

Abstract

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.

GENERAL SIGNIFICANCE:

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.

• Authors: Kathryn J Potter, Louise A Scrocchi, Garth L Warnock, Ziliang Ao, Marika A Younker, Lawrence Rosenberg, Mark Lipsett, C Bruce Verchere, Paul E Fraser
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1790 Issue 6 Pg. 566-74 (Jun 2009) ISSN: 0006-3002 [Print] Netherlands
• PMID: 19264107 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid
• Islet Amyloid Polypeptide

Topics

• Amino Acid Sequence
• Amyloid (antagonists & inhibitors, metabolism)
• Animals
• Apoptosis (physiology)
• Cell Survival (physiology)
• Cells, Cultured
• Humans
• Islet Amyloid Polypeptide
• Islets of Langerhans (physiology, ultrastructure)
• Molecular Sequence Data