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

Abstract

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 a large panel of antioxidant genes as well as pro/antiapoptotic genes. We demonstrate that such combination confers resistance to cytotoxic H2O2exposure in vitro, raising the possibility that at least some of the activated stress/defense genes have protective effects against H2O2-triggered β-cell death. We also present some evidence that the GK/Par β-cell resistance to H2O2is at least partly cAMP dependent. Finally, we show that such a phenotype is not innate but is spontaneously acquired after diabetes onset as the result of an adaptive response to the diabetic environment.