Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, Missouri, USA.
Center for the Investigation of Membrane Excitability Diseases, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.
Islets. 2022 Dec 31;14(1):200-209. doi: 10.1080/19382014.2022.2149206.
ATP-sensitive potassium channel (K)gain- (GOF) and loss-of-function (LOF) mutations underlie human neonatal diabetes mellitus (NDM) and hyperinsulinism (HI), respectively. While transgenic mice expressing incomplete K LOF do reiterate mild hyperinsulinism, K knockout animals do not exhibit persistent hyperinsulinism. We have shown that islet excitability and glucose homeostasis are regulated by identical K channels in zebrafish. SUR1 truncation mutation (K499X) was introduced into gene to explore the possibility of using zebrafish for modeling human HI. Patch-clamp analysis confirmed the complete absence of channel activity in β-cells from K499X (SUR1) fish. No difference in random blood glucose was detected in heterozygous SUR1+/- fish nor in homozygous SUR1 fish, mimicking findings in SUR1 knockout mice. Mutant fish did, however, demonstrate impaired glucose tolerance, similar to partial LOF mouse models. In paralleling features of mammalian diabetes and hyperinsulinism resulting from equivalent LOF mutations, these gene-edited animals provide valid zebrafish models of K -dependent pancreatic diseases.
三磷酸腺苷敏感性钾通道（K）功能获得（GOF）和功能丧失（LOF）突变分别是导致人类新生儿糖尿病（NDM）和胰岛素过多症（HI）的原因。尽管表达不完全 K LOF 的转基因小鼠会再次出现轻度胰岛素过多症，但 K 敲除动物不会出现持续的胰岛素过多症。我们已经证明，在斑马鱼中，胰岛兴奋性和葡萄糖稳态受相同的 K 通道调节。我们将 SUR1 截断突变（K499X）引入 基因，以探索使用斑马鱼进行人类 HI 建模的可能性。膜片钳分析证实，来自 K499X（SUR1）鱼的β细胞中完全没有通道活性。杂合 SUR1+/-鱼和纯合 SUR1 鱼的随机血糖没有差异，这与 SUR1 敲除小鼠的发现相似。然而，突变鱼表现出葡萄糖耐量受损，类似于部分 LOF 小鼠模型。这些基因编辑动物与由于等效 LOF 突变导致的哺乳动物糖尿病和胰岛素过多症的特征平行，为 K 依赖性胰腺疾病提供了有效的斑马鱼模型。
