The aggregation potential of human amylin determines its cytotoxicity towards islet beta-cells

FEBS J. 2006 Aug;273(15):3614-24. doi: 10.1111/j.1742-4658.2006.05367.x.


Human amylin is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type 2 diabetes. There is evidence that it can elicit in vitro apoptosis in islet beta-cells, but the physical properties that underpin its cytotoxicity have not been clearly elucidated. Here we employed electron microscopy, thioflavin T fluorescence and CD spectroscopy to analyze amylin preparations whose cytotoxic potential was established by live-dead assay in cultured beta-cells. Highly toxic amylin contained few preformed fibrils and initially showed little beta-sheet content, but underwent marked time-dependent aggregation and beta-conformer formation following dissolution. By contrast, low-toxicity amylin contained abundant preformed fibrils, and demonstrated high initial beta-sheet content but little propensity to aggregate further once dissolved. Thus, mature amylin fibrils are not toxic to beta-cells, and aggregates of fibrils such as occur in pancreatic islet amyloid in vivo are unlikely to contribute to beta-cell loss. Rather, the toxic molecular species is likely to comprise soluble oligomers with significant beta-sheet content. Attempts to find ways of protecting beta-cells from amylin-mediated death might profitably focus on preventing the conformational change from random coil to beta-sheet.

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry
  • Amyloid / pharmacology*
  • Amyloid / toxicity
  • Cell Line
  • Circular Dichroism
  • Humans
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / cytology
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / ultrastructure
  • Microscopy, Electron, Transmission
  • Molecular Sequence Data
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Amyloid
  • Islet Amyloid Polypeptide