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Islet amyloid polypeptide demonstrates a persistent capacity to disrupt membrane integrity

Nicholas B Last1, Elizabeth Rhoades, Andrew D Miranker

  • 1Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 25, 2011
PubMed

Insights

Small oligomers of islet amyloid polypeptide form on cell membranes, disrupting them and causing cell death. This discovery reveals a new pathway for amyloid-related diseases like type II diabetes.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Medicine

Background:

  • Amyloid fiber formation is linked to diseases such as Alzheimer's, Parkinson's, and type II diabetes.
  • While fibrillar deposits characterize these disorders, smaller oligomeric species are increasingly implicated in cellular dysfunction and death.
  • The exact mechanism of cell damage by oligomers, likely involving membrane interactions, remains unclear.

Purpose of the Study:

  • To investigate the role of islet amyloid polypeptide (IAPP) in the loss of insulin-secreting cells in type II diabetes.
  • To identify and characterize oligomeric species of IAPP formed on biological membranes.
  • To elucidate the mechanism by which these oligomers disrupt cell membrane integrity.

Main Methods:

  • Utilized a combination of ensemble and single-particle evaluation techniques.
  • Investigated the stochastic nucleation and assembly of IAPP oligomers on membranes.
  • Characterized the stability, leakage properties, and kinetic pathway of IAPP oligomer formation.

Main Results:

  • Discovered novel oligomeric IAPP species that form via stochastic nucleation on membranes.
  • Demonstrated that these oligomers disrupt the lipid bilayer, causing "all-or-none" leakage.
  • Identified a three-state kinetic framework for IAPP assembly, suggesting a non-amyloid intermediate.

Conclusions:

  • Oligomeric IAPP species are directly involved in disrupting cell membranes, contributing to cell loss in type II diabetes.
  • The identified three-state kinetic model provides a more comprehensive understanding of IAPP assembly on membranes.
  • A previously identified non-amyloid intermediate in the IAPP pathway may represent a viable therapeutic target for type II diabetes.

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