The cytokine is over-expressed in adipose tissue of different models of obesity and known to inhibit insulin signalling. Moreover, immuno-neutralization of TNFa in Zucker fa/fa rats has been shown to increase insulin receptor autophosphorylation and phosphorylation of insulin receptor substrate- 1 in muscle and adipose tissue and to reduce glucose, insulin and FFA plasma levels. In our study, we now demonstrate, for the first time, a very strong increase in TNFa expression in pancreatic b-cells from fa/fa rats. That such an increase could interfere in b-cell function cannot be excluded; its importance should nevertheless be dampened by the drastic decrease in TNFR2 receptor expression and its delocalization; the receptor seems much less co-localized with insulin granules. The increased expression of TNFa could however be partly responsible for the marked increase in IL-6 expression we found in pancreatic b-cells; indeed, TNFa has been reported to up-regulate IL-6 in murine pancreatic islets. No consistent in vitro data are available regarding insulin secretion in human and rodent islets. However, the marked increase in IL-6 expression together with a clear delocalization to insulin granules questions the possible involvement of IL-6 in the hyperinsulinemia of fa/fa rats, which deserves to be reassessed in vivo in this model of prediabetic state. Concerning b-cell survival, IL-6 has been shown to stimulate human islet cell proliferation and to afford protection against IL-1b, TNFa and IFNc-induced cell death. Such an effect could occur in pancreatic islets and account for the marked decrease in active caspase-3 expression; indeed, chronic exposure of neurons to IL-6 prevents the enhancement of the cleaved caspase-3 levels induced by NMDA. Finally, from our abArray study, it appears that up- and down regulation of Vorinostat HDAC inhibitor factors involved in the regulation of cell proliferation/ survival, Perifosine clinical trial contributes to control islet hyperplasia known to occur in fa/fa rats. We may conclude that pancreatic islets from hyperphagic, obese insulin-resistant Zucker fa/fa rats undergo a clear and possibly selfperpetuating inflammatory process. The complexity of cytokines effects and of their interactions makes it difficult to evaluate their pathogenic role in b-cell hyperactivity that compensates for insulin resistance. In Zucker rats, compensation will keep going, but in the presence of an additional b-cell defect, as in ZDF rats, inflammation will be exacerbated and diabetes will ensue. Prion diseases, known as transmissible spongiform encephalopathies , are fatal progressive neurodegenerative diseases characterized with spongiosis and neuronal loss in the central nervous system. PrP is a glycosylphosphatidylinositol -anchored membrane protein expressed mainly in CNS, whose normal function is still enigmatic.