The effect of curcumin on human islet amyloid polypeptide misfolding and toxicity.
Type 2 diabetes involves aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and resultant pancreatic amyloid deposits. Curcumin, a biphenolic small molecule, has offered potential benefits in other protein misfolding diseases, such as Alzheimer's disease. Our aim was to investigate whether curcumin alters h-IAPP misfolding and protects from cellular toxicity at physiologically relevant concentrations. The effect of curcumin on h-IAPP misfolding in vitro was investigated by electron paramagnetic resonance spectroscopy, ThT fluorescence and electron microscopy. Our in vitro studies revealed that curcumin significantly reduces h-IAPP fibril formation and aggregates formed in the presence of curcumin display alternative morphology and structure. We then tested a potential protective effect of curcumin against h-IAPP toxicity on β-cells. Micromolar concentrations of curcumin partially protect INS cells from exogenous IAPP toxicity. This protective effect, however, is limited to a narrow concentration range, as curcumin becomes cytotoxic at micromolar concentrations. In different models of endogenous over-expression of h-IAPP (INS cells and h-IAPP transgenic rat islets), curcumin failed to protect β-cells from h-IAPP-induced apoptosis. While curcumin has the ability to inhibit amyloid formation, the present data suggest that, without further modification, it is unlikely to be therapeutically useful in protection of β-cells in type 2 diabetes.
Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Marie
M
Daval
Sahar
S
Bedrood
Tatyana
T
Gurlo
Chang-Jiang
CJ
Huang
Safia
S
Costes
Peter C
PC
Butler
Ralf
R
Langen
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide / Q000378:metabolism* / Q000633:toxicity; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008854:Microscopy, Electron; D051381:Rats; D055647:Rats, Transgenic
D058228:Islet Amyloid Polypeptide; D003474:Curcumin