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

Abstract

IntroductionCongenital 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 (KATP) are limited to primary islets from patients and theSur1-/-mouse model. Zebrafish exhibit potential as a novel KATPHI 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 methodsWe evaluated zebrafish as a model for KATPHI using a genetically encoded Ca2+sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of anabcc8-/-zebrafish line.ResultsWe observed significantly higher islet cytosolic Ca2+in vivo inabcc8-/-compared withabcc8+/+zebrafish larvae. Additionally,abcc8-/-larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared withabcc8+/+controls. However, adultabcc8-/-zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared withabcc8+/+zebrafish.ConclusionsOur results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.