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RESEARCH ARTICLE

Diabetic GK/Par rat β-cells are spontaneously protected against H₂O₂-induced apoptosis. A cAMP-dependent adaptive response

¹Unite BFA ²University Paris Diderot

Submitted 27 October 2008 ; revised 25 September 2009 ; accepted in final form 8 October 2009

The alteration of the β-cell population in the Goto-Kakizaki rat (GK/Par line), a model of spontaneous type 2 diabetes, has been ascribed to significantly decreased β-cell replication and neogenesis, while β-cell apoptosis is surprisingly not enhanced and remains in the normal range. To gain insight into the mechanisms by which those β-cells are protected from death, we studied ex vivo the apoptotic activity and the expression of a large set of pro/antiapoptotic and pro/antioxidant genes in GK/Par islet cells. This was done in vitro in freshly isolated islets as well as in response to culture conditions and calibrated reactive oxygen species (ROS) exposure (i.e., H₂O₂). We also investigated the intracellular mechanisms of the diabetic β-cell response to ROS, the role if any of the intracellular cAMP metabolism, and finally the kinetic of ROS response, taking advantage of the GK/Par rat normoglycemia until weaning. Our results show that the peculiar GK/Par β-cell phenotype was correlated with an increased expression of many stress genes as well as pro/antiapoptotic genes. We demonstrate that such combination confers resistance to cytotoxic H₂O₂ exposure in vitro, raising the possibility that at least some of the activated stress/defense genes have protective effects against β-cell death. We also present some evidence that the GK/Par β-cell resistance to H₂O₂ is at least partly cAMP dependant. Finally, we show that such a phenotype is not innate but it is spontaneously acquired after diabetes onset, as the result of an adaptive response to the diabetic environment.

beta-cell; apoptosis; reactive oxygen species; cAMP