期刊
NATURE GENETICS
卷 51, 期 11, 页码 1596-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-019-0513-9
关键词
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资金
- Welcome Trust [203141]
- University of Helsinki
- Folkhalsan Research Foundation
- Sigrid Juselius Foundation
- Academy of Finland [263401, 267882, 312063, 312072, 317599]
- EU (EXGENESIS) [EUFP7-MOSAIC FP7-600914]
- Ollqvist Foundation
- Swedish Cultural Foundation in Finland
- Finnish Diabetes Research Foundation
- Foundation for Life and Health in Finland
- Signe and Ane Gyllenberg Foundation
- Finnish Medical Society
- Paavo Nurmi Foundation
- Helsinki University Central Hospital Research Foundation
- Perklen Foundation
- Narpes Health Care Foundation
- Ministry of Education in Finland, Municipal Heath Care Center and Hospital in Jakobstad
- Pfizer Inc.
- Regeneron Genetics Center LLC
- Hjelt Foundation
- Rhapsody
- Vinnova (Sweden's Innovation Agency) [2015-01549]
- Swedish Diabetes Foundation
- Albert Pahlsson Foundation
- Crafoord Foundation
- Royal Physiographic Society in Lund
- Swedish Foundation for Strategic Research [IRC15-0067]
- Swedish Research Council [2009-1039, Dnr: 2017-02688]
- Pahlsson Foundation
- Diabetes Research Foundation
- Italian Ministry of University and Research [PRIN 2015373Z39_004]
- University of Parma Research Funds
- Wellcome Trust Senior Investigator Award [WT098424AIA]
- MRC Programme grants [MR/R022259/1, MR/J0003042/1, MR/L020149/1]
- Experimental Challenge Grant (DIVA) [MR/L02036X/1]
- MRC [MR/N00275X/1]
- Diabetes UK [BDA/11/0004210, BDA/15/0005275, BDA 16/0005485]
- Imperial Confidence in Concept grants
- Royal Society Wolfson Research Merit Award
- Wellcome Trust [203141, 095101, 200837, 098381, 106130, 090531]
- Medical Research Council [MR/L020149/1]
- European Union Horizon 2020 Programme (T2D Systems)
- NIH [U01-DK105535, U01-DK085545]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
- Biocenter Finland
- Ahokas Foundation
- Hjelt Foundations
- Ministry of Education in Finland, Health Care Center in Vasa
- Ministry of Education in Finland, Health Care Centers in Narpes
- Ministry of Education in Finland, Health Care Centers in Korsholm
- Nordic Center of Excellence in Disease Genetics
- Vinnova [2015-01549] Funding Source: Vinnova
- Medical Research Council [MR/N00275X/1] Funding Source: researchfish
- Academy of Finland (AKA) [317599, 317599] Funding Source: Academy of Finland (AKA)
- BBSRC [BB/J015873/1] Funding Source: UKRI
- MRC [MR/N020472/1, MR/L02036X/1, MR/R022259/1, G0801995, MR/N00275X/1, MR/R010676/1, MR/M012646/1, MR/L020149/1, MR/K001981/1] Funding Source: UKRI
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 K-ATP 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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