PDF(Pubmed)
Abstract：
Aggregation of the human islet amyloid polypeptide (hIAPP) contributes to the development and progression of Type 2 Diabetes (T2D). hIAPP aggregates within a few hours at few micromolar concentration in vitro but exists at millimolar concentrations in vivo. Natively occurring inhibitors of hIAPP aggregation might therefore provide a model for drug design against amyloid formation associated with T2D. Here, we describe the combined ability of low pH, zinc, and insulin to inhibit hIAPP fibrillation. Insulin dose-dependently slows hIAPP aggregation near neutral pH but had less effect on the aggregation kinetics at acidic pH. We determine that insulin alters hIAPP aggregation in two manners. First, insulin diverts the aggregation pathway to large nonfibrillar aggregates with ThT-positive molecular structure, rather than to amyloid fibrils. Second, soluble insulin suppresses hIAPP dimer formation, which is an important early aggregation event. Further, we observe that zinc significantly modulates the inhibition of hIAPP aggregation by insulin. We hypothesize that this effect arose from controlling the oligomeric state of insulin and show that hIAPP interacts more strongly with monomeric than oligomeric insulin.
摘要：
人胰岛淀粉样多肽(hIAPP)的聚集有助于2型糖尿病(T2D)的发展和进展。hIAPP在体外以数微摩尔浓度在数小时内聚集,但在体内以毫摩尔浓度存在。因此,天然存在的hIAPP聚集抑制剂可提供针对与T2D相关的淀粉样蛋白形成的药物设计模型。这里,我们描述了低pH的综合能力，锌，和胰岛素抑制hIAPP纤颤。胰岛素剂量依赖性地减缓在中性pH附近的hIAPP聚集，但在酸性pH下对聚集动力学的影响较小。我们确定胰岛素以两种方式改变hIAPP聚集。首先,胰岛素将聚集途径转向具有ThT阳性分子结构的大型非纤维状聚集体，而不是淀粉样纤维。第二,可溶性胰岛素抑制hIAPP二聚体形成，这是一个重要的早期聚集事件。Further,我们观察到锌显著调节胰岛素对hIAPP聚集的抑制作用。我们假设这种作用是由控制胰岛素的寡聚状态引起的，并且表明hIAPP与单体胰岛素的相互作用比寡聚胰岛素更强。
