TCF7L2 promotes beta cell regeneration in human and mouse pancreas

Abstract

Aims/hypothesis Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration. Methods Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells. Results TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/ STAT3 pathway. Conclusions/interpretation The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.

Association of the rs7903146 single nucleotide polymorphism at the Transcription Factor 7-like 2 (TCF7L2) locus with type 2 diabetes in Brazilian subjects

“…More recently, TCF7L2 expression in the endocrine pancreas was correlated not only with beta cell proliferation, but also with beta cell regeneration in different murine models of diabetes (35). In the same study, it was shown that in human exocrine pancreatic tissue, TCF7L2 overexpression induced beta cell phenotype and insulin production in ductal epithelial cells (35).…”

“…In addition, it has been shown to be involved in the expression of glucagon-like peptide 1, and gastric inhibitory peptide receptors in beta cells, which mediate the effects of the correspondent incretin hormones to promote beta cell proliferation, neogenesis, and survival in rodent models (34). More recently, TCF7L2 expression in the endocrine pancreas was correlated not only with beta cell proliferation, but also with beta cell regeneration in different murine models of diabetes (35). In the same study, it was shown that in human exocrine pancreatic tissue, TCF7L2 overexpression induced beta cell phenotype and insulin production in ductal epithelial cells (35).…”

Design of an allele-specific PCR assay to genotype the rs12255372 SNP in a pilot study of association between common TCF7L2 polymorphisms and type 2 diabetes in Venezuelans

“…The TCF7L2 gene spans 215.9 kb on chromosome 10q25.3, and its product is a high-mobility box-containing transcription factor involved in the Wnt signaling pathway (10). Wnt pathway activity plays an important role for lipid and glucose metabolism, pancreatic islets proliferation, regeneration and function, and for production of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) (11)(12)(13). Therefore, alteration in this pathway could cause the reduction of GLP-1 secretion, then affecting insulin secretion, and subsequently, among other effects, impairing blood glucose homeostasis.…”

Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis

“…Following pivotal studies indicating that the transcription factor 7-like 2 (TCF7L2) is an important risk gene for the development of type 2 diabetes (T2D) (1), great efforts have been made to explore its role as a Wnt signaling molecule in pancreatic b-cells and other tissues including liver (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Although several investigations suggested that TCF7L2 negatively regulates hepatic gluconeogenesis (8,10,11,17), one recent study (7) reported that liver-specific knockout of TCF7L2 reduced hepatic glucose production (HGP), while hepatic overexpression of TCF7L2 increased HGP.…”

“…Although several investigations suggested that TCF7L2 negatively regulates hepatic gluconeogenesis (8,10,11,17), one recent study (7) reported that liver-specific knockout of TCF7L2 reduced hepatic glucose production (HGP), while hepatic overexpression of TCF7L2 increased HGP. As a result, the controversial issues surrounding the metabolic function of TCF7L2 have been extended from pancreatic b-cells to liver and hepatocytes specifically (4)(5)(6)9,13,(18)(19)(20). TCF7L2 or other transcription factor (TCF) members can interact with b-catenin (b-cat), forming the bipartite transcription factor b-cat/TCF, which serves as the important effector of the Wnt signaling pathway.…”