Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2019-11-01
Date Acceptance
2019-09-13
Citation
Nature Genetics, 2019, 51, pp.1596-1606
ISSN
1061-4036
Publisher
Nature Research
Start Page
1596
End Page
1606
Journal / Book Title
Nature Genetics
Volume
51
Copyright Statement
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2019. The final publication is available at Springer via https://doi.org/10.1038/s41588-019-0513-9
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/31676859
PII: 10.1038/s41588-019-0513-9
Subjects
11 Medical and Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2019-11-01