title: Geniposide promotes beta-cell regeneration and survival through regulating β-catenin/TCF7L2 pathway.
abstract: T-cell factor 7-like 2 (TCF7L2) is an important transcription factor of Wnt/β-catenin signaling, which has critical roles in β-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 β-cell and underlying mechanism involved. Geniposide was found to promote β-cell survival by increasing β-cell proliferation and decreasing β-cell apoptosis in cultured mouse islets after challenge with diabetic stimuli. Geniposide protected β-cell through activating Wnt signaling, enhanced expressions of TCF7L2 and GLP-1R, activated AKT, inhibited GSK3β activity, and promoted β-catenin nuclear translocation. The protective effect of geniposide was remarkably suppressed by siRNAs against β-catenin, or by ICG001 (β-catenin/TCF-mediated transcription inhibitor). Moreover, geniposide promoted β-cell regeneration in vivo to normalize blood glucose in high-fat diet and db/db mice. Increased β-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 β-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 β-cell survival and regeneration by mechanisms involving the activation of β-catenin/TCF7L2 signaling. Our finding highlights the potential value of geniposide as a possible treatment for type 2 diabetes.
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, China.
authors.forename: D D
authors.initials: DD
authors.lastname: Yao
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, China.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Wei
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, China.
authors.forename: X B
authors.initials: XB
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: W
authors.initials: W
authors.lastname: Yin
authors.affiliation: Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Province Academy of Chinese Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Shu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects*; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D039823:Iridoids; D012333:RNA, Messenger; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; C007835:geniposide