PMID- 16849627
OWN - NLM
STAT- MEDLINE
DCOM- 20061212
LR  - 20220317
IS  - 0193-1849 (Print)
IS  - 0193-1849 (Linking)
VI  - 291
IP  - 6
DP  - 2006 Dec
TI  - Inhibition of human IAPP fibril formation does not prevent beta-cell death: 
      evidence for distinct actions of oligomers and fibrils of human IAPP.
PG  - E1317-24
AB  - 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.
FAU - Meier, Juris J
AU  - Meier JJ
AD  - Larry Hillblom Islet Research Center, University of California Los Angeles David 
      Geffen School of Medicine, Los Angeles, CA 90095-7073, USA.
FAU - Kayed, Rakez
AU  - Kayed R
FAU - Lin, Chia-Yu
AU  - Lin CY
FAU - Gurlo, Tatyana
AU  - Gurlo T
FAU - Haataja, Leena
AU  - Haataja L
FAU - Jayasinghe, Sajith
AU  - Jayasinghe S
FAU - Langen, Ralf
AU  - Langen R
FAU - Glabe, Charles G
AU  - Glabe CG
FAU - Butler, Peter C
AU  - Butler PC
LA  - eng
GR  - DK-59579/DK/NIDDK NIH HHS/United States
GR  - NS-31230/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060718
PL  - United States
TA  - Am J Physiol Endocrinol Metab
JT  - American journal of physiology. Endocrinology and metabolism
JID - 100901226
RN  - 0 (Amyloid beta-Protein Precursor)
RN  - 0 (Benzothiazoles)
RN  - 0 (Coloring Agents)
RN  - 0 (DNA, Complementary)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Tetrazolium Salts)
RN  - 0 (Thiazoles)
RN  - 2390-54-7 (thioflavin T)
RN  - 36015-30-2 (Propidium)
RN  - EUY85H477I (thiazolyl blue)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - Adenoviridae/genetics
MH  - Amyloid beta-Protein Precursor/*chemistry/*physiology
MH  - Animals
MH  - Apoptosis/physiology
MH  - Benzothiazoles
MH  - Blotting, Western
MH  - Cell Death/physiology
MH  - Coloring Agents
MH  - DNA, Complementary/biosynthesis/genetics
MH  - Fluorescent Dyes
MH  - Humans
MH  - In Situ Nick-End Labeling
MH  - Insulin-Secreting Cells/*physiology
MH  - Islets of Langerhans/*chemistry/*physiology
MH  - Propidium
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Rifampin/pharmacology
MH  - Tetrazolium Salts
MH  - Thiazoles
EDAT- 2006/07/20 09:00
MHDA- 2006/12/13 09:00
CRDT- 2006/07/20 09:00
PHST- 2006/07/20 09:00 [pubmed]
PHST- 2006/12/13 09:00 [medline]
PHST- 2006/07/20 09:00 [entrez]
AID - 00082.2006 [pii]
AID - 10.1152/ajpendo.00082.2006 [doi]
PST - ppublish
SO  - Am J Physiol Endocrinol Metab. 2006 Dec;291(6):E1317-24. doi: 
      10.1152/ajpendo.00082.2006. Epub 2006 Jul 18.