Abstract
Diabetes mellitus is characterized by disrupted glucose homeostasis due to loss or dysfunction of insulin-producing beta cells. In this work, we characterize pancreatic islet development and function in zebrafish mutant for pdx1, a gene which in humans is linked to genetic forms of diabetes and is associated with increased susceptibility to Type 2 diabetes. Pdx1 mutant zebrafish have the key diabetic features of reduced beta cells, decreased insulin and elevated glucose. The hyperglycemia responds to pharmacologic anti-diabetic treatment and, as often seen in mammalian diabetes models, beta cells of pdx1 mutants show sensitivity to nutrient overload. This unique genetic model of diabetes provides a new tool for elucidating the mechanisms behind hyperglycemic pathologies and will allow the testing of novel therapeutic interventions in a model organism that is amenable to high-throughput approaches.
Highlights
Described zebrafish embryos depleted for pancreas-related factors include examples of beta cell deficiency[5,7], but these approaches are limited by the transient and incomplete effectiveness of morpholino knock-downs or early-lethal developmental effects on other organ systems
Insulin deficiency is associated with decreased fetal growth, a feature commonly seen in neonatal diabetes[4]
In this work we demonstrate that the pdx[1] mutant zebrafish is a new vertebrate model of diabetes, as fish show the key features of decreased beta cells and insulin, and persistently elevated glucose levels
Summary
Described zebrafish embryos depleted for pancreas-related factors (using antisense morpholinos) include examples of beta cell deficiency[5,7], but these approaches are limited by the transient and incomplete effectiveness of morpholino knock-downs or early-lethal developmental effects on other organ systems. Alternative methods for generating hyperglycemic zebrafish have relied on incubation in high-glucose solutions[8,9,10], and surgical or toxin-mediated ablation[11,12,13,14,15] With such interventions there is often variability in the responses of the animals, and the regenerative response of pancreatic beta cells following ablation precludes long-term studies[12,13,14,15]. Using a high fat diet feeding protocol, we show that beta cells of pdx[1] mutants are nutrient sensitive and undergo increased apoptosis Overall, this new vertebrate genetic model of diabetes will allow the testing of new therapeutic interventions and provides a novel tool to elucidate biological mechanisms behind the toxic effects of sustained high glucose
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