Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?
Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?
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DOI：
10.1007/s00125-010-1671-6
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发表时间：
2010-06
期刊：
影响因子：
8.2
通讯作者：
Kahn, S. E.
中科院分区：
文献类型：
--
作者：
Zraika, S.;Hull, R. L.;Verchere, C. B.;Clark, A.;Potter, K. J.;Fraser, P. E.;Raleigh, D. P.;Kahn, S. E.
2型糖尿病是一种进行性疾病，大多数患者的特点是胰岛淀粉样物沉积。淀粉样蛋白的形成被认为是胰岛功能恶化和β细胞质量减少的一个重要因素，它涉及正常溶解的β细胞肽、人胰岛淀粉样多肽(HIAPP)的单体聚集成低聚物、纤维，最终形成成熟的淀粉样沉积。尽管在体外进行了广泛的研究，但对hIAPP在体内聚集的过程知之甚少，尽管它被广泛报道为促进细胞毒性。最近，研究表明，只有纤维组装的早期阶段，特别是小的hIAPP寡聚体，才是导致β细胞细胞毒性的原因。这挑战了先前的概念，即新形成的纤维和/或成熟的纤维淀粉样蛋白具有细胞毒性。在这里，提出了支持和反对毒性hIAPP寡聚体假说的证据；由此，很明显，当hIAPP聚集时究竟是什么导致β细胞死亡仍然存在争议。此外，与目前可用的更具体的试剂和技术相比，需要更多的工作才能最终确定hIAPP聚集造成的有毒物种。对细胞毒性侮辱的性质保持开放的态度对2型糖尿病的治疗发展和临床护理具有重要意义。
Type 2 diabetes is a progressive disease characterised by islet amyloid deposits in the majority of patients. Amyloid formation is considered a significant factor in deterioration of islet function and reduction in beta cell mass, and involves aggregation of monomers of the normally soluble beta cell peptide, human islet amyloid polypeptide (hIAPP) into oligomers, fibrils and, ultimately, mature amyloid deposits. Despite extensive in vitro studies, the process of hIAPP aggregation in vivo is poorly understood, though it is widely reported to promote cytotoxicity. Recently, studies have suggested that only the early stages of fibril assembly, and in particular small hIAPP oligomers, are responsible for beta cell cytotoxicity. This challenges the prior concept that newly formed fibrils and/or mature fibrillar amyloid are cytotoxic. Herein, evidence both for and against the toxic hIAPP oligomer hypothesis is presented; from this, it is apparent that what exactly causes beta cell death when hIAPP aggregates remains debatable. Moreover, substantially more work with more specific reagents and techniques than are currently available will be required to identify conclusively the toxic species resulting from hIAPP aggregation. Keeping an open mind on the nature of the cytotoxic insult has implications for therapeutic developments and clinical care in type 2 diabetes.
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影响因子：
7.7
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2007.03.016
发表时间：
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