Fas-associated death receptor signaling evoked by human amylin in islet beta-cells

Diabetes. 2008 Feb;57(2):348-56. doi: 10.2337/db07-0849. Epub 2007 Oct 31.


Objective: Aggregation of human amylin (hA) into beta-sheet-containing oligomers is linked to islet beta-cell dysfunction and the pathogenesis of type 2 diabetes. Here, we investigated possible contributions of Fas-associated death-receptor signaling to the mechanism of hA-evoked beta-cell apoptosis.

Research design and methods: We measured responses to hA in isolated mouse islets and two insulinoma cell lines, wherein we measured Fas/Fas ligand (FasL) and Fas-associated death domain (FADD) expression by quantitative RT-PCR, Western blotting, and immunofluorescence staining. We used two anti-Fas/FasL blocking antibodies and the Fas/FasL antagonist Kp7-6 to probe roles of Fas interactions in the regulation of apoptosis in hA-treated beta-cells and measured Kp7-6-mediated effects on beta-sheet formation and aggregation using circular dichroism and thioflavin-T binding.

Results: hA treatment stimulated Fas and FADD expression in beta-cells. Both blocking antibodies suppressed hA-evoked apoptosis but did not modify its aggregation. Therefore, Fas receptor interactions played a critical role in induction of this pathway. Interestingly, hA-evoked beta-cell apoptosis was suppressed and rescued by Kp7-6, which also impaired hA beta-sheet formation.

Conclusions: This is the first report linking hA-evoked induction and activation of Fas and FADD to beta-cell apoptosis. We have identified a Fas/FasL antagonist, Kp7-6, as a potent inhibitor of hA aggregation and related beta-cell death. These results also support an interaction between hA and Fas on the surface of apoptotic beta-cells. Increased expression and activation of Fas in beta-cells could constitute a molecular event common to the pathogenesis of both type 1 and type 2 diabetes, although the mode of pathway activation may differ between these common forms of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / pharmacology*
  • Animals
  • Cell Line, Tumor
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / physiology*
  • Humans
  • Insulinoma
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / physiology
  • Male
  • Mice
  • Mice, Inbred Strains
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Amyloid
  • Fas-Associated Death Domain Protein
  • Islet Amyloid Polypeptide