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.

Geniposide Prevents Hypoxia/Reoxygenation-Induced Apoptosis in H9c2 Cells: Improvement of Mitochondrial Dysfunction and Activation of GLP-1R and the PI3K/AKT Signaling Pathway

“…GLP-1, a gut hormone, and GLP-1 analogs have beneficial effects on cardiovascular system by inhibiting cardiomyocyte apoptosis during I/R [23,[40][41][42][43]. It has been reported that geniposide, as a novel GLP-1R agonist, exerts different protective effects by activating GLP-1R in various tissues [15][16][17][18][19]. GLP-1R is expressed in various tissues and organs, including the pancreas, gastrointestinal tract, nervous system, blood vessels, and heart [44,45]..…”

“…Geniposide, an extract of Gardenia jasminoides J. Ellis and a novel agonist for glucagon-like peptide-1 receptor (GLP-1R), has been shown to exert antinociception effects [15], promote β-cell regeneration, attenuate β-cell apoptosis [16,17], regulate insulin secretion in INS-1 cells [18], and prevent oxidative stress of PC12 cell [19]. Accumulating evidences has revealed that glucagon-like peptide 1 (GLP-1) and GLP-1 analogues exert anti-apoptotic effects by activating GLP-1R via the phosphatidylinositol 3 kinase (PI3K)/ AKT signaling pathway [3,[20][21][22].…”

Wnt4 antagonises Wnt3a mediated increases in growth and glucose stimulated insulin secretion in the pancreatic beta-cell line, INS-1

“…Subsequent studies implicated β-cell dysfunction as the underlying cause of diabetes in patients with the TCF7L2 risk variant [2][3][4][5] and have suggested that Wnt signalling plays an important role in both pancreatic development and in the function of mature pancreatic islets [6]. The activation of the canonical Wnt pathway, by ligands such as Wnt3a, has been of particular interest as it can increase β-cell proliferation, decrease apoptosis and improve glucose stimulated insulin secretion [6][7][8][9][10][11][12]. However there is now increasing evidence that non-canonical Wnt ligands such as Wnt4 can antagonise the signalling mediated by Wnt3a and may play an equally important role in β-cell function [13][14][15].…”

Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus

“…TCF7L2 influences b-cell functions by affecting b-cell survival in pancreatic islets. Yao et al [29] identified a novel role of geniposide in promoting b-cell survival and regeneration by mechanisms involving the activation of b-catenin/TCF7L2 signaling. The carriers of an at-risk allele in TCF7L2 are thought to be more susceptible to T2DM, since active TCF7L2 might be essential for pancreatic b-cells proliferation.…”

“…The African Americans Y Sale et al [13] b-cell apoptosis increased with the decrease of active TCF7L2, which influenced the insulin secretion eventually. Finding a way to prevent the apoptosis of b-cells may be a possible treatment for T2DM, like the use of geniposide [29]. The prohormone precursor to insulin, proinsulin, is produced in the b-cells of the islets, specialized regions of the pancreas.…”