Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland.
Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK.
Nat Genet. 2019 Nov;51(11):1596-1606. doi: 10.1038/s41588-019-0513-9. Epub 2019 Nov 1.
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 K 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.
一种罕见的锌转运蛋白 8（ZnT8）编码基因 SLC30A8 中的功能丧失性等位基因 p.Arg138*，在富含西方芬兰人群中存在，可预防 2 型糖尿病（T2D）。我们招募了已确定的携带者的亲属，并表明这种保护与更好的胰岛素分泌有关，这是由于增强了葡萄糖反应性和胰岛素原转化，特别是与携带 SLC30A8 中常见的 T2D 风险等位基因 p.Arg325 的个体相比。在经过基因组编辑的人诱导多能干细胞（iPSC）衍生的β样细胞中，我们证实 p.Arg138*等位基因由于杂合不足导致 SLC30A8 表达减少。在人类β细胞中，SLC30A8 的缺失导致葡萄糖反应性增加和 K 通道功能降低，类似于 T2D 保护性等位基因 p.Trp325 携带者的分离胰岛。这些数据将 ZnT8 定位为治疗 2 型糖尿病以维持胰岛素分泌能力的有吸引力的靶标。
