Abstract
Type 2 diabetes (T2D) is a disease characterized by impaired insulin secretion. The Wnt signaling transcription factor Tcf7l2 is to date the T2D-associated gene with the largest effect on disease susceptibility. However, the mechanisms by which TCF7L2 variants affect insulin release from β-cells are not yet fully understood. By taking advantage of a tcf7l2 zebrafish mutant line, we first show that these animals are characterized by hyperglycemia and impaired islet development. Moreover, we demonstrate that the zebrafish tcf7l2 gene is highly expressed in the exocrine pancreas, suggesting potential bystander effects on β-cell growth, differentiation and regeneration. Finally, we describe a peculiar vascular phenotype in tcf7l2 mutant larvae, characterized by significant reduction in the average number and diameter of pancreatic islet capillaries. Overall, the zebrafish Tcf7l2 mutant, characterized by hyperglycemia, pancreatic and vascular defects, and reduced regeneration proves to be a suitable model to study the mechanism of action and the pleiotropic effects of Tcf7l2, the most relevant T2D GWAS hit in human populations.
Highlights
The world prevalence of diabetes is estimated to be 9% among the adult population
Functional studies on Tcf7l2 in murine models and humans have indicated that individuals with TCF7L2 polymorphisms exhibit impaired insulin secretion and enhanced rate of hepatic glucose production[4,5,6,7]
Given the existing controversy in the literature over the relative importance of Tcf7l2 for proper development of β cells, liver and/or other tissues, as well as the contributions of extra-pancreatic tissues to risk variants activity on diabetes susceptibility[17], the present study has been designed to investigate the general effects of Tcf7l2 in a simple model: the zebrafish (Danio rerio)
Summary
The world prevalence of diabetes is estimated to be 9% among the adult population (aged 20–79 years). Given the existing controversy in the literature over the relative importance of Tcf7l2 for proper development of β cells, liver and/or other tissues, as well as the contributions of extra-pancreatic tissues to risk variants activity on diabetes susceptibility[17], the present study has been designed to investigate the general effects of Tcf7l2 in a simple model: the zebrafish (Danio rerio). This vertebrate organism offers numerous advantages that have been exploited in this study. In both species the pancreas consists of an exocrine compartment (formed by acinar cells), producing digestive enzymes secreted into a ductal system and transported to the digestive tract, and an endocrine compartment, represented by islets embedded in a dense capillary network, playing a critical role in blood sugar homeostasis[18]
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