The Molecular Physiopathogenesis of Islet Amyloidosis.
The Molecular Physiopathogenesis of Islet Amyloidosis.
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DOI：
10.1007/164_2017_62
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发表时间：
2018
影响因子：
--
通讯作者：
Jeremic AM
中科院分区：
文献类型：
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作者：
Bhowmick DC;Singh S;Trikha S;Jeremic AM
人胰岛淀粉样多肽或胰岛淀粉样多肽 (hA) 是一种由 37 个氨基酸组成的肽激素，由胰腺 β 细胞产生并与胰岛素共同分泌。在生理条件下，hA 调节广泛的生物过程，包括胰岛素释放和胃排空减慢，从而维持葡萄糖稳态。然而，在与2型糖尿病（T2DM）相关的病理条件下，hA经历从可溶性无规卷曲单体到α-螺旋寡聚体和不溶性β-片状淀粉样原纤维或淀粉样斑块的构象转变。 hA寡聚/聚集、hA毒性与糖尿病进展之间存在正相关。由于糖尿病患者失去了 hA 合成、释放和摄取之间的稳态平衡，并且 hA 聚集是 T2DM 的标志，因此本章重点关注生物物理和细胞生物学研究，研究胰腺细胞中 hA 摄取、运输和降解的分子机制及其与 hA 毒性的相关性。我们还将讨论内吞作用和蛋白水解途径在清除有毒 hA 物质中的调节作用。最后，我们将讨论特异性靶向 hA 运输途径和胰岛 β 细胞毒性的潜在药理学方法，作为治疗 T2DM 患者的潜在新途径。
Human islet amyloid polypeptide or amylin (hA) is a 37- amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological conditions hA regulates a broad range of biological processes including insulin release and slowing of gastric emptying, thereby maintaining glucose homeostasis. However, under the pathological conditions associated with type-2 diabetes mellitus (T2DM), hA undergoes a conformational transition from soluble random coil monomers to alpha-helical oligomers and insoluble β-sheet amyloid fibrils or amyloid plaques. There is positive correlation between hA oligomerization/aggregation, hA toxicity and diabetes progression. Because the homeostatic balance between hA synthesis, release and uptake is lost in diabetics, and hA aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies investigating molecular mechanisms of hA uptake, trafficking and degradation in pancreatic cells and its relevance to h’s toxicity. We will also discuss the regulatory role of endocytosis and proteolytic pathways in clearance of toxic hA species. Finally, we will discuss potential pharmacological approaches for specific targeting of hA trafficking pathways and toxicity in islet β-cells as potential new avenues toward treatments of T2DM patients.