Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
BMJ Open Diabetes Res Care. 2024 Apr 4;12(2):e003735. doi: 10.1136/bmjdrc-2023-003735.
Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Current models to study the most common and severe form of HI resulting from inactivating mutations in the ATP-sensitive potassium channel (K) are limited to primary islets from patients and the mouse model. Zebrafish exhibit potential as a novel KHI model since they express canonical insulin secretion pathway genes and those with identified causative HI mutations. Moreover, zebrafish larvae transparency provides a unique opportunity for in vivo visualization of pancreatic islets.
We evaluated zebrafish as a model for KHI using a genetically encoded Ca sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of an zebrafish line.
We observed significantly higher islet cytosolic Ca in vivo in compared with zebrafish larvae. Additionally, larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared with controls. However, adult zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared with zebrafish.
Our results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.
先天性高胰岛素血症（HI）是婴儿持续性低血糖的主要原因。目前用于研究最常见和最严重的由三磷酸腺苷（ATP）敏感性钾通道（K）失活突变引起的 HI 的模型仅限于患者和小鼠模型的原代胰岛。斑马鱼作为一种新型 KHI 模型具有一定的潜力，因为它们表达了经典的胰岛素分泌途径基因和已鉴定出的致 HI 突变基因。此外，斑马鱼幼虫的透明性为胰腺胰岛的体内可视化提供了独特的机会。
我们使用在β细胞中受胰岛素启动子控制表达的遗传编码 Ca 传感器（ins:gCaMP6s），评估了斑马鱼作为 KHI 模型的适用性。
与野生型斑马鱼相比，我们观察到经基因改造的斑马鱼幼虫的胰岛细胞内 Ca2+ 水平显著升高。此外，与野生型对照相比，经基因改造的斑马鱼幼虫的全身血糖水平显著降低，而全身胰岛素水平显著升高。然而，与野生型斑马鱼相比，成年经基因改造的斑马鱼的血浆葡萄糖、血浆胰岛素或葡萄糖耐量没有差异。
我们的研究结果表明，斑马鱼幼虫而非成年鱼是 HI 研究的一种新型模型。
