Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, Maharashtra, India.
Department of Biotechnology, Savitribai Phule Pune University (Formerly University of Pune), Ganeshkhind, Pune, 411007, Maharashtra, India.
Biol Chem. 2020 Sep 4;402(2):133-153. doi: 10.1515/hsz-2020-0174. Print 2021 Jan 27.
The human islet amyloid polypeptide (hIAPP) or amylin, a neuroendocrine peptide hormone, is known to misfold and form amyloidogenic aggregates that have been observed in the pancreas of 90% subjects with Type 2 Diabetes Mellitus (T2DM). Under normal physiological conditions, hIAPP is co-stored and co-secreted with insulin; however, under chronic hyperglycemic conditions associated with T2DM, the overexpression of hIAPP occurs that has been associated with the formation of amyloid deposits; as well as the death and dysfunction of pancreatic β-islets in T2DM. Hitherto, various biophysical and structural studies have shown that during this process of aggregation, the peptide conformation changes from random structure to helix, then to β-sheet, subsequently to cross β-sheets, which finally form left-handed helical aggregates. The intermediates, formed during this process, have been shown to induce higher cytotoxicity in the β-cells by inducing cell membrane disruption, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, islet inflammation, and DNA damage. As a result, several research groups have attempted to target both hIAPP aggregation phenomenon and the destabilization of preformed fibrils as a therapeutic intervention for T2DM management. In this review, we have summarized structural aspects of various forms of hIAPP viz. monomer, oligomers, proto-filaments, and fibrils of hIAPP. Subsequently, cellular toxicity caused by toxic conformations of hIAPP has been elaborated upon. Finally, the need for performing structural and toxicity studies to fill in the gap between the structural and cellular aspects has been discussed.
人胰岛淀粉样多肽（hIAPP）或胰岛淀粉样肽，是一种神经内分泌肽激素，已知错误折叠并形成淀粉样原纤维聚集物，这些聚集物已在 90%的 2 型糖尿病（T2DM）患者的胰腺中观察到。在正常生理条件下，hIAPP 与胰岛素共同储存和共同分泌；然而，在与 T2DM 相关的慢性高血糖条件下，hIAPP 的过度表达与淀粉样沉积物的形成有关；以及 T2DM 中胰岛β细胞的死亡和功能障碍。迄今为止，各种生物物理和结构研究表明，在聚集过程中，肽构象从无规结构变为螺旋，然后变为β-折叠，随后变为交叉β-折叠，最终形成左手螺旋聚集物。在此过程中形成的中间体已被证明通过诱导细胞膜破裂、内质网应激、线粒体功能障碍、氧化应激、胰岛炎症和 DNA 损伤，在β细胞中诱导更高的细胞毒性。因此，一些研究小组试图针对 hIAPP 聚集现象和预形成原纤维的不稳定性作为 T2DM 管理的治疗干预措施。在这篇综述中，我们总结了 hIAPP 各种形式的结构方面，即单体、寡聚物、原纤维和 hIAPP 纤维。随后，详细阐述了 hIAPP 毒性构象引起的细胞毒性。最后，讨论了进行结构和毒性研究以填补结构和细胞方面之间差距的必要性。
