학술논문
Loss of ZnT8 function protects against diabetes by enhanced insulin secretion
Document Type
Article
Author
Dwivedi, Om Prakash; Lehtovirta, Mikko; Hastoy, Benoit; Chandra, Vikash; Krentz, Nicole A. J.; Kleiner, Sandra; Jain, Deepak; Richard, Ann-Marie; Abaitua, Fernando; Beer, Nicola L.; Grotz, Antje; Prasad, Rashmi B.; Hansson, Ola; Ahlqvist, Emma; Krus, Ulrika; Artner, Isabella; Suoranta, Anu; Gomez, Daniel; Baras, Aris; Champon, Benoite; Payne, Anthony J.; Moralli, Daniela; Thomsen, Soren K.; Kramer, Philipp; Spiliotis, Ioannis; Ramracheya, Reshma; Chabosseau, Pauline; Theodoulou, Andria; Cheung, Rebecca; van de Bunt, Martijn; Flannick, Jason; Trombetta, Maddalena; Bonora, Enzo; Wolheim, Claes B.; Sarelin, Leena; Bonadonna, Riccardo C.; Rorsman, Patrik; Davies, Benjamin; Brosnan, Julia; McCarthy, Mark I.; Otonkoski, Timo; Lagerstedt, Jens O.; Rutter, Guy A.; Gromada, Jesper; Gloyn, Anna L.; Tuomi, Tiinamaija; Groop, Leif
Source
Nature Genetics; November 2019, Vol. 51 Issue: 11 p1596-1606, 11p
Subject
Language
ISSN
10614036; 15461718
Abstract
A rare loss-of-function allele p.Arg138* in SLC30A8encoding 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 SLC30A8expression due to haploinsufficiency. In human β cells, loss of SLC30A8leads to increased glucose responsiveness and reduced KATPchannel 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.