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


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.
Yang
Jiang-Yan
JY
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Walicki
Jöel
J
Jaccard
Evrim
E
Dubuis
Gilles
G
Bulat
Natasa
N
Hornung
Jean-Pierre
JP
Thorens
Bernard
B
Widmann
Christian
C
D000818:Animals; D017209:Apoptosis; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000502:physiology / Q000503:physiopathology; D002455:Cell Division / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000517:prevention & control*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D020703:ras GTPase-Activating Proteins / Q000235:genetics*
D001786:Blood Glucose; D018076:DNA, Complementary; D007328:Insulin; D010446:Peptide Fragments; D020703:ras GTPase-Activating Proteins
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