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ZnT8蛋白失活可增强胰岛素分泌
作者:小柯机器人 发布时间:2019/11/2 23:46:07

芬兰赫尔辛基大学Leif Groop研究团队发现,ZnT8蛋白的功能丧失可通过增强胰岛素分泌来预防糖尿病。2019年11月1日,国际学术期刊《自然—遗传学》在线发表了这一研究成果。

据研究人员介绍,SLC30A8基因(编码锌转运蛋白8,ZnT8)中的一种罕见的功能丧失等位基因p.Arg138*,在芬兰西部人群中富集,其可预防2型糖尿病(T2D)。

研究人员招募了已鉴定携带者的亲属,结果表明,由于葡萄糖反应性和胰岛素原转化增强,这种保护与更好的胰岛素分泌相关,特别是与具有常见T2D风险等位基因SLC30A8(p.Arg325)基因型的个体相比。在基因组编辑的人类诱导的多能干细胞(iPSC)衍生的β样细胞中,研究人员确定p.Arg138 *等位基因由于单拷贝功能不足而导致SLC30A8表达降低。在人β细胞中,与从T2D保护性等位基因p.Trp325人群分离的胰岛细胞相似,SLC30A8的缺失导致葡萄糖反应性增强和KATP通道功能降低。这些数据表明,ZnT8可作为旨在维持T2D中胰岛素分泌能力的治疗靶标。

附:英文原文
 
Title:Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
 
Author:Om Prakash Dwivedi, Mikko Lehtovirta, Benoit Hastoy, Vikash Chandra, Nicole A. J. Krentz, Sandra Kleiner, Deepak Jain, Ann-Marie Richard, Fernando Abaitua, Nicola L. Beer, Antje Grotz, Rashmi B. Prasad, Ola Hansson, Emma Ahlqvist, Ulrika Krus, Isabella Artner, Anu Suoranta, Daniel Gomez, Aris Baras, Benoite Champon, Anthony J. Payne, Daniela Moralli, Soren K. Thomsen, Philipp Kramer, Ioannis Spiliotis, Reshma Ramracheya, Pauline Chabosseau, Andria Theodoulou, Rebecca Cheung, Martijn van de Bunt, Jason Flannick, Maddalena Trombetta, Enzo Bonora, Claes B. Wolheim, Leena Sarelin, Riccardo C. Bonadonna, Patrik Rorsman, Benjamin Davies, Julia Brosnan, Mark I. McCarthy, Timo Otonkoski, Jens O. Lagerstedt, Guy A. Rutter, Jesper Gromada, Anna L. Gloyn, Tiinamaija Tuomi & Leif Groop 
 
Issue&Volume:01 November 2019
 
Abstract: A rare loss-of-function allele p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8), which is enriched in Western Finland, protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, particularly when compared with individuals matched for the genotype of a common T2D-risk allele in SLC30A8, p.Arg325. In genome-edited human induced pluripotent stem cell (iPSC)-derived β-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human β cells, loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function similar to isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aimed at maintaining insulin secretion capacity in T2D.
 
DOI:10.1038/s41588-019-0513-9
 
Source: https://www.nature.com/articles/s41588-019-0513-9

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex