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Publication : Loss of ZnT8 function protects against diabetes by enhanced insulin secretion.

First Author  Dwivedi OP Year  2019
Journal  Nat Genet Volume  51
Issue  11 Pages  1596-1606
PubMed ID  31676859 Mgi Jnum  J:291279
Mgi Id  MGI:6446557 Doi  10.1038/s41588-019-0513-9
Citation  Dwivedi OP, et al. (2019) Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nat Genet 51(11):1596-1606
abstractText  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 beta-like cells, we establish that the p.Arg138* allele results in reduced SLC30A8 expression due to haploinsufficiency. In human beta 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.
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