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Fas-associated Death Receptor Signaling Evoked by Human Amylin in Islet ß-cells

¹The School of Biological Sciences, Faculty of Science, and
²the Maurice Wilkins Centre for Molecular BioDiscovery, the University of Auckland, Private Bag 92019, Auckland, New Zealand; and
³the MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, United Kingdom

Objective: Aggregation of human amylin (hA) into ß-sheet-containing oligomers is linked to islet ß-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 ß-cell apoptosis.

Research Design and Methods: We measured responses to hA in isolated mouse islets and two insulinoma cell lines, wherein we measured Fas/FasL and FADD expression by qRT-PCR, western-blotting and immunofluorescence staining. We employed 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 ß-cells and measured Kp7-6-mediated effects on ß-sheet formation and aggregation using circular dichroism and thioflavin-T binding.

Results: Human amylin treatment stimulated Fas and FADD expression in ß-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 ß-cell apoptosis was suppressed and rescued by Kp7-6, which also impaired hA ß-sheet formation.

Conclusions: This is the first report linking hA-evoked induction and activation of Fas and FADD to ß-cell apoptosis. We have identified a Fas/FasL antagonist, Kp7-6, as a potent inhibitor of hA aggregation and related ß-cell death. These results also support an interaction between hA and Fas on the surface of apoptotic ß-cells. Increased expression and activation of Fas in ß-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.

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