Key Laboratory of Glycoscience & Glycotechnology of Shandong Province, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Molecules. 2020 Mar 13;25(6):1314. doi: 10.3390/molecules25061314.
The deposition of aggregated human islet amyloid polypeptide (hIAPP) in the pancreas, that has been associated with β-cell dysfunction, is one of the common pathological features of patients with type 2 diabetes (T2D). Therefore, hIAPP aggregation inhibitors hold a promising therapeutic schedule for T2D. Chitosan oligosaccharides (COS) have been reported to exhibit a potential antidiabetic effect, but the function of COS on hIAPP amyloid formation remains elusive. Here, we show that COS inhibited the aggregation of hIAPP and disassembled preformed hIAPP fibrils in a dose-dependent manner by thioflavin T fluorescence assay, circular dichroism spectroscopy, and transmission electron microscope. Furthermore, COS protected mouse β-cells from cytotoxicity of amyloidogenic hIAPP, as well as apoptosis and cycle arrest. There was no direct binding of COS and hIAPP, as revealed by surface plasmon resonance analysis. In addition, both chitin-oligosaccharide and the acetylated monosaccharide of COS and glucosamine had no inhibition effect on hIAPP amyloid formation. It is presumed that, mechanistically, COS regulate hIAPP amyloid formation relating to the positive charge and degree of polymerization. These findings highlight the potential role of COS as inhibitors of hIAPP amyloid formation and provide a new insight into the mechanism of COS against diabetes.
人胰岛淀粉样多肽（hIAPP）在胰腺中的沉积与β细胞功能障碍有关，是 2 型糖尿病（T2D）患者的常见病理特征之一。因此，hIAPP 聚集抑制剂为 T2D 提供了一种有前途的治疗方案。壳寡糖（COS）已被报道具有潜在的抗糖尿病作用，但 COS 对 hIAPP 淀粉样形成的功能仍不清楚。在这里，我们通过硫代黄素 T 荧光法、圆二色光谱法和透射电子显微镜显示，COS 以剂量依赖的方式抑制 hIAPP 的聚集和解聚原有的 hIAPP 纤维。此外，COS 还能保护小鼠β细胞免受淀粉样 hIAPP 的细胞毒性、凋亡和细胞周期停滞的影响。表面等离子体共振分析显示，COS 与 hIAPP 之间没有直接结合。此外，壳聚糖寡糖和 COS 及葡萄糖胺的乙酰化单糖都没有抑制 hIAPP 淀粉样形成的作用。据推测，从机制上讲，COS 通过正电荷和聚合度来调节 hIAPP 淀粉样形成。这些发现强调了 COS 作为 hIAPP 淀粉样形成抑制剂的潜在作用，并为 COS 防治糖尿病的机制提供了新的见解。
