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1 Larry Hillblom Islet Research Center, UCLA David Geffen School of Medicine, Los Angeles, California, United States
2 Molecular biology and biochemistry, UCI, Irvine, California, United States
3 Larry Hillblom Islet Research Center, UCLA, Los Angeles, California, United States
4 Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, United States
5 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, California, United States
* To whom correspondence should be addressed. E-mail: pbutler{at}mednet.ucla.edu.
Type 2 diabetes mellitus (T2DM) is characterized by an ~ 60% deficit in beta-cell mass, increased beta-cell apoptosis and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers leading to either amyloid fibrils or toxic oligomers in an aqueous solution in vitro. Either application of hIAPP on, or over-expression of hIAPP in cells both induce apoptosis. It remains controversial whether the fibrils or smaller toxic oligomers induce beta-cell apoptosis. Rifampicin prevents hIAPP amyloid fibril formation and has been proposed as a potential target for prevention of T2DM. We examined the actions of rifampicin on hIAPP amyloid fibril and toxic oligomer formation as well as its ability to protect beta-cells from either application of hIAPP or endogenous over expression of hIAPP (transgenic rats and adenovirus-transduced beta-cells). We report that rifampicin (1) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers, (2) does not protect beta-cells from apoptosis induced by either over expression or application of hIAPP. These data emphasize that toxic hIAPP oligomers rather than hIAPP fibrils initiate beta-cell apoptosis, and that screening tools to identify inhibitors of amyloid fibril formation are likely to be less useful than those that identify inhibitors of toxic oligomer formation. Finally, rifampicin and related molecules do not appear useful as candidates for prevention of T2DM.
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