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Abstract
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.
| Abbreviations | ||
| EM | = | electron microscopy |
| EPR | = | electron paramagnetic resonance |
| HBSS | = | Hank's buffered salt solution |
| HFIP | = | hexafluoroisopropanol |
| h-IAPP | = | human islet amyloid polypeptide |
| IAPP | = | islet amyloid polypeptide |
| INS | = | insulinoma cell line |
| MTSL | = | 1-oxyl-2,2,5,5-tetramethyl-Δ3-pyrroline-3-methyl methanethiosulfonate |
| T2DM | = | type 2 diabetes mellitus |
| ThT | = | Thioflavin T |
| Abbreviations | ||
| EM | = | electron microscopy |
| EPR | = | electron paramagnetic resonance |
| HBSS | = | Hank's buffered salt solution |
| HFIP | = | hexafluoroisopropanol |
| h-IAPP | = | human islet amyloid polypeptide |
| IAPP | = | islet amyloid polypeptide |
| INS | = | insulinoma cell line |
| MTSL | = | 1-oxyl-2,2,5,5-tetramethyl-Δ3-pyrroline-3-methyl methanethiosulfonate |
| T2DM | = | type 2 diabetes mellitus |
| ThT | = | Thioflavin T |
Acknowledgements
This work was supported by a grant from the National Institutes of Health (AG027936) to RL and PCB (DK59579), The Larry Hillblom Foundation (RL, PCB) and from Fondation pour la Recherche Médicale (FRM) to MD. We are grateful to Matthew Schibler (Brain Research Institute, Advanced Microscopy/Spectroscopy Core Facility, UCLA) for his help with confocal microscopy experiments.