Geniposide promotes beta-cell regeneration and survival through regulating β-catenin/TCF7L2 pathway

T-cell factor 7-like 2 (TCF7L2) is an important transcription factor of Wnt/beta-catenin signaling, which has critical roles in beta-cell survival and regeneration. In preliminary screening assay, we found geniposide, a naturally occurring compound, was able to increase TCF7L2 mRNA level in Min6 cells. Here we aimed to investigate the role of geniposide in beta-cell and underlying mechanism involved. Geniposide was found to promote beta-cell survival by increasing beta-cell proliferation and decreasing beta-cell apoptosis in cultured mouse islets after challenge with diabetic stimuli. Geniposide protected beta-cell through activating Wnt signaling, enhanced expressions of TCF7L2 and GLP-1R, activated AKT, inhibited GSK3 beta activity, and promoted beta-catenin nuclear translocation. The protective effect of geniposide was remarkably suppressed by siRNAs against beta-catenin, or by ICG001 (beta-catenin/TCF-mediated transcription inhibitor). Moreover, geniposide promoted beta-cell regeneration in vivo to normalize blood glucose in high-fat diet and db/db mice. Increased beta-cell proliferation was observed in pancreatic sections of geniposide-treated diabetic mice. Most importantly, geniposide triggered small islet-like cell clusters formation as a result of beta-cell neogenesis from ductal epithelium, which was well correlated with the increase in TCF7L2 expression. In exocrine cells isolated from mouse pancreas, geniposide could induce duct cell differentiation through upregulating TCF7L2 expression and activating JAK2/STAT3 pathway. Taken together, we identified a novel role of geniposide in promoting beta-cell survival and regeneration by mechanisms involving the activation of beta-catenin/TCF7L2 signaling. Our finding highlights the potential value of geniposide as a possible treatment for type 2 diabetes.