Abstract

Objective - Our laboratory has previously established in vitro that a caspase-generated RasGAP N-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 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 NFκB 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 injection-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 anti-diabetic tools.