Zhang, ShaopingLiu, HongYu, HCooper, Garth2012-03-112008Diabetes 57(2):348-356 Feb 20080012-1797http://hdl.handle.net/2292/13752OBJECTIVE--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.Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from http://www.sherpa.ac.uk/romeo/issn/0012-1797/https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htmJournal Article10.2337/db07-0849Copyright: American Diabetes Association17977957http://purl.org/eprint/accessRights/RestrictedAccess1939-327X