Type 1 diabetes may depend on cytokine-induced beta-cell death and therefore the current investigation was performed in order to elucidate this response in Shb-deficient islets. A combination of interleukin-1 beta and interferon-gamma caused a diminished beta-cell death response in SO null islets. Furthermore, the induction of an unfolded protein response (UPR) by adding cyclopiazonic acid did not increase cell death in Shb-deficient islets, despite simultaneous expression of UPR markets. The heat-hock protein Hsp70 was more efficiently induced in Shb knockout islets, providing an explanation for the decreased Susceptibility of Shb-deficient islets to cytokines. It is concluded that islets deficient in the Shb protein are less Susceptible to cytotoxic conditions, and that this partly depends on their increased ability to induce Hsp70 under Such Circumstances. Interference with Shb signaling may provide means to improve beta-cell viability under conditions of beta-cell stress. (C) 2009 Elsevier Inc. All rights reserved.