For most in vitro studies, lipopolysaccharide is used to provide signal-1 whereas substances such as minimally modified LDL and free fatty acids could possibly serve this role in vivo. Signal-2 causes activation of the NLRP3-inflammasome resulting in generation of active caspase-1. Caspase-1 cleaves pro-IL-1b to IL-1b that can then be secreted by the cell. Substances such as cholesterol crystals, nigericin, alum and uric acid crystals have been shown to activate the inflammasome. Some substances can provide both signal-1 and 2. These include glucose, ER stress-inducing drugs such as thapsigargin and tunicamycin, and the mitochondrial oxidative stress-inducing drug rotenone. It has been suggested that increased reactive oxygen species accumulation inside the cell causes dissociation of the thioredoxin-interacting protein from the antioxidant protein thioredoxin resulting in its activation. TXNIP then binds to NLRP3 to stimulate its activation. In addition to IL-1b mediated apoptosis, inflammasome activation can lead to caspase-1-dependent death of the IL-1b-producing cell called pyroptosis. Pyroptosis is characterised by DNA fragmentation, cellular swelling and formation of pores in the plasma membrane. Activation of ER stress molecules IRE1a and PERK, as well as high concentrations of glucose can also activate the inflammasome via TXNIP upregulation. However, the involvement of TXNIP in inflammasome activation is controversial. While suppression of TXNIP in the INS-1 beta cell line reduced thapsigargin NSC-718781 toxicity, mouse islets lacking TXNIP were not protected across a range of concentrations tested. Macrophages express inflammasome components including NLRP3, ASC and caspase-1, and show inflammasome activation, in response to pathogens. However, while their expression in pancreatic islets has been demonstrated, it is at much lower levels when compared with bone marrow derived macrophages. In addition, although the expression of TLR4 and IL-1b has been reported previously in human and mouse islets and MIN6 beta cells, inflammasome activation has not convincingly been demonstrated in beta cells. In addition, a recent study reported absence of TLR4 in rat beta cells, making the understanding of the role for these factors in beta cells more complicated. Therefore, we decided to directly examine whether deletion of inflammasome components in islets results in protection from cell death. Our results show that deletion of inflammasome components does not affect the apoptosis of islet cells in response to glucose or chemicals that induce oxidative or ER stress, and that activation of NLRP3 in beta cells does not contribute to IL-1b production and islet cell death. In this study, we have investigated whether exposure of islets to stress could cause inflammasome mediated islet cell death. We did not find a significant role for the NLRP3 inflammasome or IL-1b in islet cell killing in response to high glucose concentrations or chemicals that induce ER or oxidative stress. Previous studies showed that exposure of human islets to 33.3 mM glucose for 5 days resulted in a very low level of IL-1b secretion. Similarly in mouse islets, high glucose concentrations that was abrogated in islets lacking NLRP3 or TXNIP.