Expression of the NH(2)-terminal fragment of RasGAP in pancreatic beta-cells increases their resistance to stresses and protects mice from diabetes.

Détails

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Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_9B124E90768D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Expression of the NH(2)-terminal fragment of RasGAP in pancreatic beta-cells increases their resistance to stresses and protects mice from diabetes.
Périodique
Diabetes
Auteur(s)
Yang J.Y., Walicki J., Jaccard E., Dubuis G., Bulat N., Hornung J.P., Thorens B., Widmann C.
ISSN
1939-327X[electronic], 0012-1797[linking]
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
58
Numéro
11
Pages
2596-2606
Langue
anglais
Résumé
OBJECTIVE: Our laboratory has previously established in vitro that a caspase-generated RasGAP NH(2)-terminal moiety, called fragment N, potently protects cells, including insulinomas, from apoptotic stress. We aimed to determine whether fragment N can increase the resistance of pancreatic beta-cells in a physiological setting. RESEARCH DESIGN AND METHODS: A mouse line, called rat insulin promoter (RIP)-N, was generated that bears a transgene containing the rat insulin promoter followed by the cDNA-encoding fragment N. The histology, functionality, and resistance to stress of RIP-N islets were then assessed. RESULTS: Pancreatic beta-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor kappaB activity without affecting islet cell proliferation or the morphology and cellular composition of islets. Intraperitoneal glucose tolerance tests revealed that RIP-N mice control their glycemia similarly as wild-type mice throughout their lifespan. Moreover, islets isolated from RIP-N mice showed normal glucose-induced insulin secretory capacities. They, however, displayed increased resistance to apoptosis induced by a series of stresses including inflammatory cytokines, fatty acids, and hyperglycemia. RIP-N mice were also protected from multiple low-dose streptozotocin-induced diabetes, and this was associated with reduced in vivo beta-cell apoptosis. CONCLUSIONS: Fragment N efficiently increases the overall resistance of beta-cells to noxious stimuli without interfering with the physiological functions of the cells. Fragment N and the pathway it regulates represent, therefore, a potential target for the development of antidiabetes tools.
Mots-clé
Animals, Apoptosis, Blood Glucose/metabolism, Brain/physiology, Brain/physiopathology, Cell Division/genetics, DNA, Complementary/genetics, Diabetes Mellitus, Experimental/physiopathology, Diabetes Mellitus, Experimental/prevention &amp, control, Glucose Tolerance Test, Insulin/genetics, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/drug effects, Mice, Mice, Transgenic, Peptide Fragments/genetics, Peptide Fragments/pharmacology, Promoter Regions, Genetic, Rats, ras GTPase-Activating Proteins/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
15/09/2009 7:30
Dernière modification de la notice
20/08/2019 15:02
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