Characterization of the zebrafish as a model of ATP-sensitive potassium channel hyperinsulinism

Introduction 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 ATP ) are limited to primary islets from patients and the Sur1 -/- mouse model. Zebrafish exhibit potential as a novel K ATP HI 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. Research design and methods We evaluated zebrafish as a model for K ATP HI using a genetically encoded Ca 2+ sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of an abcc8 -/- zebrafish line. Results We observed significantly higher islet cytosolic Ca 2+ in vivo in abcc8 -/- compared with abcc8 +/+ zebrafish larvae. Additionally, abcc8 -/- larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared with abcc8 +/+ controls. However, adult abcc8 -/- zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared with abcc8 +/+ zebrafish. Conclusions Our results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.