Inhibition of human IAPP fibril formation does not prevent beta-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP.
Type 2 diabetes mellitus (T2DM) is characterized by an approximately 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 overexpression of hIAPP in cells induces 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 overexpression of hIAPP (transgenic rats and adenovirus-transduced beta-cells). We report that rifampicin (Acocella G. Clin Pharmacokinet 3: 108-127, 1978) prevents hIAPP fibril formation, but not formation of toxic hIAPP oligomers (Bates G. Lancet 361: 1642-1644, 2003), and does not protect beta-cells from apoptosis induced by either overexpression 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 to be useful as candidates for prevention of T2DM.
Meier
Juris J
JJ
Larry Hillblom Islet Research Center, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA 90095-7073, USA.
Kayed
Rakez
R
Lin
Chia-Yu
CY
Gurlo
Tatyana
T
Haataja
Leena
L
Jayasinghe
Sajith
S
Langen
Ralf
R
Glabe
Charles G
CG
Butler
Peter C
PC
D000256:Adenoviridae / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D052160:Benzothiazoles; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D004396:Coloring Agents; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005456:Fluorescent Dyes; D006801:Humans; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000502:physiology*; D007515:Islets of Langerhans / Q000737:chemistry* / Q000502:physiology*; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000494:pharmacology; D013778:Tetrazolium Salts; D013844:Thiazoles
D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D004396:Coloring Agents; D018076:DNA, Complementary; D005456:Fluorescent Dyes; D013778:Tetrazolium Salts; D013844:Thiazoles; C009462:thioflavin T; D011419:Propidium; C022616:thiazolyl blue; D012293:Rifampin