Expression of the NH2-Terminal Fragment of RasGAP in Pancreatic β-Cells Increases Their Resistance to Stresses and Protects Mice From Diabetes
- Jiang-Yan Yang1,2,
- Jöel Walicki1,2,
- Evrim Jaccard1,2,
- Gilles Dubuis1,2,
- Natasa Bulat1,2,
- Jean-Pierre Hornung2,
- Bernard Thorens1,3 and
- Christian Widmann1,2
- 1Department of Physiology, University of Lausanne, Lausanne, Switzerland;
- 2Department of Cell Biology and Morphology, University of Lausanne, Lausanne, Switzerland;
- 3Center for Integrative Genomics, Genopode Building, University of Lausanne, Lausanne, Switzerland.
- Corresponding author: Christian Widmann, christian.widmann{at}unil.ch.
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J.-Y.Y., J.W., and E.J. contributed equally to this article.
Abstract
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 β-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 β-cells of RIP-N mice express fragment N, activate Akt, and block nuclear factor κB 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 β-cell apoptosis.
CONCLUSIONS Fragment N efficiently increases the overall resistance of β-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.
Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received January 22, 2009.
- Accepted August 2, 2009.
- © 2009 American Diabetes Association
