胰岛淀粉样多肽的分子结构、毒性及其抑制因素

Molecular Structure,Cytotoxicity and Inhibitive Factors of Human Amylin

人胰岛淀粉样多肽(human amylin,hAmylin)是2型糖尿病患者胰岛中淀粉样蛋白沉积的主要成分,是由37个氨基酸组成的多肽。生理状态下,hAmylin与胰岛素共同产生并储存于胰岛β细胞,按1∶100的比例共同分泌,且促进胰岛素分泌的因素亦均可促进hAmylin分泌。hAmylin的单体结构未折叠,呈不稳定状态。与β淀粉样蛋白(amyloidβpeptide,Aβ)一样,hAmylin的细胞毒性与其单体状态不稳定,易发生聚集,形成寡聚物及纤维结构的特性有关。hAmylin的聚集会对细胞造成不可逆的损伤。该文重点综述了hAmylin的结构、聚集与脂质膜的相互作用、毒性及其毒性抑制剂的最新研究进展。

Human amylin （hAmylin） is the major component of amyloid deposits in the pancreatic islets of patients with diabetes mellitus 2 （DM2）. Physiologically,mature hAmylin,a 37 amino acid peptide,is co-produced and co-secreted with insulin in a ratio of 1∶100 in islet β-cells. hAmylin is released in response to the stimuli that lead to insulin secretion. The monomeric hAmylin is an unstable and unfolded peptide which tends to accumulate and form oligomer or fibril. The unstable state of hAmylin monomer is closely related to hAmylin cytotoxicity. Accumulating evidences suggest that hAmylin amyloid accumulation that accompany DM2 is not just an insignificant phenomenon derived from the disease progression but that hAmylin aggregation induces processes that impair the functionality and the viability of β-cells. In this review,we particularly focus on hAmylin structure,hIAPP aggregation and hAmylin-membrane interactions. We will discuss recent findings on the mechanism of hAmylin-membrane damage and hIAPP-induced cell death. Finally,the development of successful anti-amyloidogenic agents that prevent hAmylin fibril formation have been discussed.