Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Amyloid. 2010 Sep;17(3-4):118-28. doi: 10.3109/13506129.2010.530008. Epub 2010 Nov 10.
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.
2 型糖尿病涉及人胰岛淀粉样多肽（h-IAPP）的异常错误折叠和由此产生的胰腺淀粉样沉积物。姜黄素是一种双酚小分子，在阿尔茨海默病等其他蛋白质错误折叠疾病中具有潜在的益处。我们的目的是研究姜黄素是否能改变 h-IAPP 的错误折叠并在生理相关浓度下保护细胞免受毒性。通过电子顺磁共振波谱、ThT 荧光和电子显微镜研究了姜黄素对 h-IAPP 在体外错误折叠的影响。我们的体外研究表明，姜黄素可显著减少 h-IAPP 纤维形成，并且在姜黄素存在下形成的聚集体显示出替代形态和结构。然后，我们测试了姜黄素对β细胞中 h-IAPP 毒性的潜在保护作用。姜黄素的毫摩尔浓度部分保护 INS 细胞免受外源性 IAPP 毒性。然而，这种保护作用仅限于狭窄的浓度范围，因为姜黄素在毫摩尔浓度下会产生细胞毒性。在 h-IAPP 内源性过表达的不同模型（INS 细胞和 h-IAPP 转基因大鼠胰岛）中，姜黄素未能保护β细胞免受 h-IAPP 诱导的细胞凋亡。虽然姜黄素具有抑制淀粉样形成的能力，但目前的数据表明，在没有进一步修饰的情况下，它不太可能在 2 型糖尿病中对β细胞的保护具有治疗作用。
