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JCI:自噬作用可保护胰腺β细胞免于毒性蛋白质的损伤

来源:生物谷 2014-07-29 09:18

2014年7月29日 讯 /生物谷BIOON/ --II型糖尿病个体中往往存在一种过量的名为胰岛淀粉样多肽的蛋白质(IAPP),该蛋白质的积累往往和产生胰岛素的胰腺β细胞的缺失直接相关,引发糖尿病患者机体中IAPP的积累的原因至今仍是个谜;近日,来自加州大学洛杉矶分校的研究人员通过研究揭开了谜底,研究者发现了一种自体吞噬现象,即从细胞中清除损伤或者有毒的蛋白质,相关研究刊登于国际杂志Journal of Clinical Investigation上。

研究者发现,在未患II型糖尿病的个体机体中,细胞的自噬作用会抑制毒性的IAPP的积累,而在II型糖尿病个体中,自噬过程并不会正常工作,引发胰腺β细胞的破坏,而是随着机体胰岛素的分泌,胰腺β细胞在维持机体血糖水平上扮演着越来越重要作用。

研究者Safia Costes表示,此前有一些研究报道,自噬过程对于β细胞的生存和功能的发挥至关重要,而本项研究并未研究自噬过程在调节淀粉样蛋白过程中的作用;文章中研究者利用三种实验模型证实了,自噬过程可以清除胰腺β细胞的IAPP,这三种实验模型分别为胰腺β细胞、可以表达人类IAPP的离体胰岛、人类的胰岛。

与此同时研究人员还开发了一种新型的小鼠模型,这种小鼠模型的胰腺β细胞缺失自噬过程,研究者发现这种小鼠机体中往往存在较高水平的有毒IAPP,从而引发胰腺β细胞死亡,最终使得小鼠患上糖尿病。本文中研究者的目的就是揭示胰腺β细胞破坏背后的细胞分子机制,以便研究者可以早日找到保护胰腺β细胞的靶点,研究者希望通过他们的研究可以开发出新一代的结合疗法来治疗II型糖尿病。(生物谷Bioon.com)

Autophagy defends pancreatic β cells from human islet amyloid polypeptide-induced toxicity

Jacqueline F. Rivera1, Safia Costes1, Tatyana Gurlo1, Charles G. Glabe2 and Peter C. Butler1

Type 2 diabetes (T2D) is characterized by a deficiency in β cell mass, increased β cell apoptosis, and extracellular accumulation of islet amyloid derived from islet amyloid polypeptide (IAPP), which β cells coexpress with insulin. IAPP expression is increased in the context of insulin resistance, the major risk factor for developing T2D. Human IAPP is potentially toxic, especially as membrane-permeant oligomers, which have been observed to accumulate within β cells of patients with T2D and rodents expressing human IAPP. Here, we determined that β cell IAPP content is regulated by autophagy through p62-dependent lysosomal degradation. Induction of high levels of human IAPP in mouse β cells resulted in accumulation of this amyloidogenic protein as relatively inert fibrils within cytosolic p62-positive inclusions, which temporarily averts formation of toxic oligomers. Mice hemizygous for transgenic expression of human IAPP did not develop diabetes; however, loss of β cell–specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of β cell mass. In human IAPP–expressing mice that lack β cell autophagy, increased oxidative damage and loss of an antioxidant-protective pathway appeared to contribute to increased β cell apoptosis. These findings indicate that autophagy/lysosomal degradation defends β cells against proteotoxicity induced by oligomerization-prone human IAPP.

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