Data Availability Individual level data for the human study can only be obtained via the Biobank of The Institute of Health and Welfare in Finland (https://thl.fi/en/web/thl-biobank). Next-generation sequencing data have been deposited in the SRA data base (PRJNA563975) and its processed counts data could be found in the Supplementary Dataset 1. The individual processed data from cell lines (Fig. 4 and 5), mice studies (Fig. 6) and human islet work (Fig. 7) are available in the Source Data files. Additional data supporting the findings of this study are available on request from the corresponding author.
69A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) 70 enriched in Western Finland protects against type 2 diabetes (T2D). We recruited relatives of the 71 identified carriers and showed that protection was associated with better insulin secretion due to 72 enhanced glucose responsiveness and proinsulin conversion, especially compared with individuals 73 matched for the genotype of a common T2D risk variant in SLC30A8, p.Arg325. In genome-edited 74 human IPS-derived β-like cells, we establish that the p.Arg138* variant results in reduced SLC30A8 75 expression due to haploinsufficiency. In human β-cells loss of SLC30A8 leads to increased glucose 76 responsiveness and reduced K ATP channel function, which was also seen in isolated islets from 77 carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for 78 treatment aiming at maintaining insulin secretion capacity in T2D. 79 80 106 Results 107
Recruitment by genotype 108Given the enrichment of the p.Arg138*-SLC30A8 variant in Western Finland, we genotyped
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