TCF7L2 transcription factor and Type 2 Diabetes: we WNT to know

Most studies on TCF7L2 SNP variants in the pathogenesis of type 2 diabetes (T2D) focus on a role of the Wnt signaling transcription factor Tcf7l2 in beta cells. Diabetes is characterized by loss or dysfunction of beta cells. A major goal of diabetes therapy is to promote the formation of new beta cells. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. First, the results that the zebrafish Tcf7l2 gene is expressed in intestinal endocrine cells but also in pancreas suggest a possible effects on beta cell growth, differentiation or regeneration from the precursor/stem cells. We observe a phenotypic defect in Tcf7l2 mutant larvae with transgenic backgrounds fli1:eGFP/ins:dsRED, when analyzed at 3 weeks post-fertilization. Confocal microscopy of transgenic ins:dsRED/Tcf7l2 mutants demonstrate a reduction in the number of beta cells, and the analysis of transgenic fli1:eGFP/ins:dsRED/Tcf7l2 mutants show morphological changes with a reduction in the number and diameter of pancreatic islet capillaries observed under confocal microscope and measured quantitatively. Furthermore, Tcf7l2 mutants show a loss of proliferation in endothelial and beta cells, when examined with an H2B-RFP fusion protein. We show that the Tcf7l2 mutant is a suitable model for the study of T2D in zebrafish, in applications such as: a) measurement of blood glucose level, a commonly used method for assessing beta cell function; b) regeneration of tail fin and beta cells. The extensive evaluation of Tcf7l2 function and Wnt signaling effects in beta cells have resulted in contradictory findings. Indeed, the transgenic biosensor generated by Moro et al. shows a Wnt signaling activity in a wide range of tissues but not in beta cells. Our results show no alteration in the number of beta cells in transgenic embryos ins:dsRED when treated with BIO (an activator of Wnt signaling) and Xav (an inhibitor of Wnt signaling) compared to untreated control. Here, we describe the generation, validation and applications of a transgenic reporter line for Wnt/β-catenin signaling in beta cells, and show that it is a reliable and sensitive Wnt biosensor for in vivo studies in the pancreas. The responsiveness of the reporter to Wnt signaling and the resulting increased number of beta cells was tested by treating embryos with BIO and XAV and observing the reporter activity, which is respectively increased or decreased compared to untreated controls. In conclusion, these data highlight the Tcf7l2 mutant as a novel model organism to analyze diabetic complications. Therefore, the model presented here will allow exploring molecular mechanisms by which Tcf7l2, as a component of the Wnt signaling pathway, exerts its physiological functions in diabetic pathology.