Activation of the transcription factor carbohydrate-responsive element-binding protein by glucose leads to increased pancreatic beta cell differentiation in ratsReport as inadecuate




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Diabetologia

, Volume 55, Issue 10, pp 2713–2722

First Online: 05 July 2012Received: 10 January 2012Accepted: 17 May 2012

Abstract

Aims-hypothesisPancreatic 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.

MethodsWe 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.

ResultsChREBP 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-interpretationOur work supports the idea that glucose, through the transcription factor ChREBP, controls beta cell differentiation from pancreatic progenitors.

KeywordsCarbohydrate-responsive element-binding protein Glucose metabolism Insulin Pancreatic beta cell differentiation Pancreatic development Pentose phosphate pathway AbbreviationsACCaseAcetyl-CoA carboxylase

ChREBPCarbohydrate-responsive element-binding protein

dnChREBPDominant-negative carbohydrate-responsive element-binding protein

FASFatty acid synthase

GFPGreen fluorescent protein

GlcNAcN-Acetylglucosamine

HBPHexosamine biosynthetic pathway

L-PKLiver-type pyruvate kinase

NEUROG3Neurogenin3

PC1-3Proconvertase 1-3

PDX1Pancreatic and duodenum homeobox 1

PP2AProtein phosphatase 2A

Electronic supplementary materialThe online version of this article doi:10.1007-s00125-012-2623-0 contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Author: A. Soggia - K. Flosseau - P. Ravassard - G. Szinnai - R. Scharfmann - G. Guillemain

Source: https://link.springer.com/







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