Role of the canonical and non-canonical Wnt signaling pathway in the beta cell function and proliferation during experimental prediabetes

• Grant number: 15/25442-1
• Support Opportunities: Regular Research Grants
• Duration: April 01, 2016 - March 31, 2018
• Field of knowledge: Biological Sciences - Morphology - Histology
• Principal Investigator: Carla Beatriz Collares Buzato
• Grantee: Carla Beatriz Collares Buzato
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

There has been an increasing interest in studying intracellular pathways involved in pancreatic beta cell proliferation in order to apply this knowledge in molecular and cellular therapies of diabetes. In particular, the canonical Wnt signaling pathway, as well known as the Wnt/beta-catenin pathway, has been investigated as inductor of cell proliferation and differentiation in several tissues/organs. It was recently discovered in humans a relationship between type 2 diabetes (T2DM) and mutation in the gene encoding the transcription factor TCF7L2 related to the canonical Wnt pathway. Nevertheless, no study has directly investigated the involvement of this signaling pathway in the process of compensatory hyperplasia of beta cell mass observed in the initial phase of type 2 diabetes, known as prediabetes. Studies of our research group have recently shown a possible activation of this pathway, revealed by an increase in islet expression of active beta-catenin and cyclin D in prediabetic animals fed a high-fat diet (HFD) for 60 days. These preliminary data suggest that the canonical Wnt pathway is activated during prediabetes and may play a role in the induction of the compensatory beta cell hyperplasia observed in this phase of diabetes development. Yet, the noncanonical Wnt pathway has not been investigated in the context of the beta cell biology. In this research project, we aim at carrying on this study having as general objectives: 1) to assess the translocation of beta-catenin to the nucleus, the cell distribution and content/expression of proteins associated with the activation of the canonical pathway, such as beta-catenin and TCF7L2 (co-activators), cyclins D1/2 and c-Myc (target genes of the pathway activation), GSK-3beta and axins 1/2 (inhibitors) in pancreatic islets of mice fed a HFD for 30 and 60d; 2) to analyze the activation of the canonical Wnt transcription factors TCF/LEF using the TOPflash kit in hyperplastic islets (obtained from animals fed with HFD for 60 days) and non-hyperplastic ones (obtained from animals exposed to HFD only for 30 days); 3) to determine, by RT-PCR, qPCR and in situ hybridization, which subtypes of Wnts, from canonical and noncanonical pathways, are expressed by cells of exocrine pancreas/islets and whether their expression changes in the pancreas and/or pancreatic islets under normal conditions and during prediabetes after 30 and 60d HFD exposure. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MASCHIO, DANIELA A.; MATHEUS, VALQUIRIA A.; COLLARES-BUZATO, CARLA B.. Islet cells are the source of Wnts that can induce beta-cell proliferation in vitro. Journal of Cellular Physiology, v. 234, n. 11, p. 19852-19865, NOV 2019. (15/25442-1)

MASCHIO, D. A.; OLIVEIRA, R. B.; SANTOS, M. R.; CARVALHO, C. P. F.; BARBOSA-SAMPAIO, H. C. L.; COLLARES-BUZATO, C. B.. Activation of the Wnt/beta-catenin pathway in pancreatic beta cells during the compensatory islet hyperplasia in prediabetic mice. Biochemical and Biophysical Research Communications, v. 478, n. 4, p. 1534-1540, SEP 30 2016. (15/25442-1)