Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress.
Amyloid formation in human IAPP transgenic mouse islets and pancreas, and human pancreas, is not associated with endoplasmic reticulum stress.
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DOI：
10.1007/s00125-009-1329-4
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发表时间：
2009-06
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：
Hull, R. L.;Zraika, S.;Udayasankar, J.;Aston-Mourney, K.;Subramanian, S. L.;Kahn, S. E.
人胰岛淀粉样多肽（hIAPP）的超生理水平与β细胞内质网（ER）应激有关。然而，在人类2型糖尿病患者中，hIAPP水平与对照组相当或降低。因此，我们试图研究在hIAPP的生理水平上，内质网应激是否在淀粉样变性过程中被诱导。产生淀粉样蛋白的hIAPP转基因小鼠和不产生淀粉样蛋白的非转基因小鼠的胰岛在11.1、16.7和33.3 mmol/l葡萄糖中培养7天。对hIAPP转基因和非转基因小鼠以及患有或不患有2型糖尿病的人类受试者的胰腺进行了评估。组织学上确定淀粉样蛋白的形成。胰岛内质网应激通过定量测定BiP、Atf4和Chop mRNA水平，XBP-1 mRNA交替剪接或胰岛内质网应激通过免疫染色测定BiP、Chop和XBP-1。hIAPP转基因胰岛中淀粉样蛋白的形成以葡萄糖和时间依赖的方式与β细胞面积的减少有关。然而，在任何培养条件下，淀粉样蛋白的形成与内质网应激标志物表达的显著增加无关。作为阳性对照，Thapsigargin治疗确实导致了显著的内质网应激。hIAPP转基因小鼠或人类胰腺样品体内淀粉样蛋白的形成与内质网应激标志物的上调无关。我们的数据表明，内质网应激并不是hIAPP生理水平上介导淀粉样蛋白形成毒性作用的必经途径。
Supraphysiological levels of the amyloidogenic peptide human islet amyloid polypeptide (hIAPP) have been associated with beta cell endoplasmic reticulum (ER) stress. However, in human type 2 diabetes, levels of hIAPP are equivalent or decreased relative to matched controls. Thus, we sought to investigate whether ER stress is induced during amyloidogenesis at physiological levels of hIAPP. Islets from hIAPP transgenic mice that develop amyloid, and non-transgenic mice that do not, were cultured for up to seven days in 11.1, 16.7 and 33.3 mmol/l glucose. Pancreata from hIAPP transgenic and non-transgenic mice and human subjects with or without type 2 diabetes were also evaluated. Amyloid formation was determined histologically. ER stress was determined in islets by quantifying mRNA levels of BiP, Atf4 and Chop, and alternate splicing of XBP-1 mRNA or in pancreata by immunostaining for BiP, CHOP and XBP-1. Amyloid formation in hIAPP transgenic islets was associated with reduced beta-cell area in a glucose- and time-dependent manner. However, amyloid formation was not associated with significant increases in expression of ER stress markers under any culture condition. Thapsigargin treatment, a positive control, did result in significant ER stress. Amyloid formation in vivo in pancreas samples from hIAPP transgenic mice or humans was not associated with upregulation of ER stress markers. Our data suggest that ER stress is not an obligatory pathway mediating the toxic effects of amyloid formation at physiological levels of hIAPP.
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影响因子：
8.2
作者：
Marchetti, P.;Bugliani, M.;Cnop, M.
通讯作者：
Cnop, M.
影响因子：
7.7
作者：
Huang, Chang-jiang;Lin, Chia-yu;Butler, Peter C.
通讯作者：
Butler, Peter C.
影响因子：
7.7
作者：
Kahn, SE;Verchere, CB;Fujimoto, WY
通讯作者：
Fujimoto, WY
影响因子：
15.9
作者：
Horwich, A
通讯作者：
Horwich, A
影响因子：
7.7
作者：
Hull, RL;Shen, ZP;Kahn, SE
通讯作者：
Kahn, SE