The Wnt/beta-catenin signaling pathway, also known as the canonical Wnt pathway, plays a role in cell proliferation and differentiation in several tissues/organs. It has been recently described in humans a relationship between type 2 diabetes (T2DM) and mutation in the gene encoding the transcription factor TCF7L2 associated to the Wnt/beta-catenin pathway. In the present study, we demonstrated that hyper plastic pancreatic islets from prediabetic mice fed a high-fat diet (HFD) for 60 d displayed nuclear translocation of active p-catenin associated with significant increases in protein content and gene expression of beta-catenin as well as of cyclins Dl, D2 and c-Myc (target genes of the Wnt pathway) but not of Tcf7I2 (the transcription factor). Meanwhile, these alterations were not observed in pancreatic islets from 30 d HFD-fed mice, that do not display significant beta cell hyperplasia. These data suggest that the Wnt/beta-catenin pathway is activated in pancreatic islets during prediabetes and may play a role in the induction of the compensatory beta cell hyperplasia observed at early phase of T2DM. (C) 2016 Published by Elsevier Inc.