Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus.
Causative factors for formation of toxic islet amyloid polypeptide oligomer in type 2 diabetes mellitus.
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DOI：
10.2147/cia.s95297
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发表时间：
2015
影响因子：
3.6
通讯作者：
An SS
中科院分区：
文献类型：
--
作者：
Jeong HR;An SS
人胰岛淀粉样多肽（Human islet amyloid polypeptide，h-IAPP）是由胰岛β细胞合成并与胰岛素共同分泌的一种肽类激素。最近，h-IAPP被认为是2型糖尿病（T2 DM）患者细胞毒性胰腺淀粉样蛋白沉积的主要成分。由于IAPP（或胰淀素）寡聚体聚集的致病因素还不完全清楚，本文将讨论各种形式的h-IAPP聚集。并非所有形式的IAPP聚集体都会引发β细胞功能的破坏和β细胞质量的损失;然而，毒性寡聚体确实会引发这些事件。一旦在T2 DM的异常代谢条件下形成这些毒性寡聚体，它们可通过诱导细胞膜不稳定而导致细胞破坏。在这篇综述中，已被证明是诱导有毒的IAPP寡聚体形成的各种因素，以及从pro-IAPP寡聚体和原纤维形成的潜在机制。最初，pro-IAPP经历酶促反应以产生IAPP单体，其然后可以发展成低聚物和原纤维。通过这种机制，有毒低聚物可以由不同的途径组分产生。因此，将介绍影响淀粉样蛋白聚集的因素之间的相互联系（例如，缺乏PC 2酶、脱酰胺、二硫键还原、细胞中的环境因素、基因突变、铜金属离子和肝素）。因此，这篇综述将有助于了解IAPP寡聚体形成的基本致病因素，并支持研究新型T2 DM治疗方法，如开发抑制剂以预防糖尿病病理早期阶段的寡聚化。
Human islet amyloid polypeptide (h-IAPP) is a peptide hormone that is synthesized and cosecreted with insulin from insulin-secreting pancreatic β-cells. Recently, h-IAPP was proposed to be the main component responsible for the cytotoxic pancreatic amyloid deposits in patients with type 2 diabetes mellitus (T2DM). Since the causative factors of IAPP (or amylin) oligomer aggregation are not fully understood, this review will discuss the various forms of h-IAPP aggregation. Not all forms of IAPP aggregates trigger the destruction of β-cell function and loss of β-cell mass; however, toxic oligomers do trigger these events. Once these toxic oligomers form under abnormal metabolic conditions in T2DM, they can lead to cell disruption by inducing cell membrane destabilization. In this review, the various factors that have been shown to induce toxic IAPP oligomer formation will be presented, as well as the potential mechanism of oligomer and fibril formation from pro-IAPPs. Initially, pro-IAPPs undergo enzymatic reactions to produce the IAPP monomers, which can then develop into oligomers and fibrils. By this mechanism, toxic oligomers could be generated by diverse pathway components. Thus, the interconnections between factors that influence amyloid aggregation (eg, absence of PC2 enzyme, deamidation, reduction of disulfide bonds, environmental factors in the cell, genetic mutations, copper metal ions, and heparin) will be presented. Hence, this review will aid in understanding the fundamental causative factors contributing to IAPP oligomer formation and support studies for investigating novel T2DM therapeutic approaches, such as the development of inhibitory agents for preventing oligomerization at the early stages of diabetic pathology.