Journal
DIABETES
Volume 58, Issue 11, Pages 2596-2606Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-0104
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Funding
- Juvenile Diabetes Research Foundation
- Swiss National Science Foundation
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OBJECTIVE-Our laboratory has previously established in vitro that a caspase-generated RasGAP NH2-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 kappa B 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. Diabetes 58:2596-2606, 2009
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