title: Activation of the transcription factor carbohydrate-responsive element-binding protein by glucose leads to increased pancreatic beta cell differentiation in rats.
abstract: OBJECTIVE
  Pancreatic cell development is a tightly controlled process. Although information is available regarding the mesodermal signals that control pancreatic development, little is known about the role of environmental factors such as nutrients, including glucose, on pancreatic development. We previously showed that glucose and its metabolism through the hexosamine biosynthesis pathway (HBP) promote pancreatic endocrine cell differentiation. Here, we analysed the role of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) in this process. This transcription factor is activated by glucose, and has been recently described as a target of the HBP.
  
  
  METHODS
  We used an in vitro bioassay in which pancreatic endocrine and exocrine cells develop from rat embryonic pancreas in a way that mimics in vivo pancreatic development. Using this model, gain-of-function and loss-of-function experiments were undertaken.
  
  
  RESULTS
  ChREBP was produced in the endocrine lineage during pancreatic development, its abundance increasing with differentiation. When rat embryonic pancreases were cultured in the presence of glucose or xylitol, the production of ChREBP targets was induced. Concomitantly, beta cell differentiation was enhanced. On the other hand, when embryonic pancreases were cultured with inhibitors decreasing ChREBP activity or an adenovirus producing a dominant-negative ChREBP, beta cell differentiation was reduced, indicating that ChREBP activity was necessary for proper beta cell differentiation. Interestingly, adenovirus producing a dominant-negative ChREBP also reduced the positive effect of N-acetylglucosamine, a substrate of the HBP acting on beta cell differentiation.
  
  
  CONCLUSIONS
  Our work supports the idea that glucose, through the transcription factor ChREBP, controls beta cell differentiation from pancreatic progenitors.
authors: INSERM U845, Research Center Growth and Signalling, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Hôpital Necker, Paris, France.
authors: A
authors: A
authors: Soggia
authors: INSERM U845, Research Center Growth and Signalling, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Hôpital Necker, Paris, France.
authors: K
authors: K
authors: Flosseau
authors: CNRS - UMR 7225, CNRS - UMR 7225 Hôpital Pitié Salpêtrière, Paris, France.
authors: P
authors: P
authors: Ravassard
authors: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors: G
authors: G
authors: Szinnai
authors: INSERM U845, Research Center Growth and Signalling, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Hôpital Necker, Paris, France.
authors: R
authors: R
authors: Scharfmann
authors: INSERM U845, Research Center Growth and Signalling, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Hôpital Necker, Paris, France. ghislaine.guillemain@inserm.fr.
authors: G
authors: G
authors: Guillemain
mesh_terms: D000117:Acetylglucosamine / Q000494:pharmacology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects* / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology*; D023421:Models, Animal; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000502:physiology; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014993:Xylitol / Q000494:pharmacology
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C442825:Mlxipl protein, rat; D005947:Glucose; D000117:Acetylglucosamine; D014993:Xylitol