title: TCF7L2 promotes beta cell regeneration in human and mouse pancreas.
abstract: OBJECTIVE
  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
  The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
authors.affiliation: Centre for Biomolecular Interactions Bremen, University of Bremen, Leobener Strasse NW2, Bremen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Shu
authors.forename: K
authors.initials: K
authors.lastname: Zien
authors.forename: G
authors.initials: G
authors.lastname: Gutjahr
authors.forename: J
authors.initials: J
authors.lastname: Oberholzer
authors.forename: F
authors.initials: F
authors.lastname: Pattou
authors.forename: J
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: K
authors.initials: K
authors.lastname: Maedler
mesh_terms: D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D012038:Regeneration; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism*
chemical_list: C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein