A hallmark of diabetes is reduced functional β cell mass (Donath and Halban, 2004; Pipeleers et al., 2008). This can be caused by upregulation of genes inducing cell death or by downregulation of genes promoting cell survival in β cells. Cell death-promoting genes that are upregulated in β cells during the progression of diabetes are promising targets for the development of diabetes therapeutics.In patients with type 1 diabetes, destruction of β cells by inflammatory cytokines including interleukin-1β (IL-1β) leads to an absolute deficiency of insulin (Atkinson et al., 2011; Bluestone et al., 2010). In contrast, type 2 diabetes is a state of relative insulin deficiency as a result of β cell dysfunction and death caused by a combination of increased circulating glucose and saturated fatty acids and development of inflammation (Butler et al., 2003; Donath and Halban, 2004). Recent evidence suggests that endoplasmic reticulum (ER) stress also plays a role in the loss of β cells during the progression of type 1 and type 2 diabetes and Wolfram syndrome, a genetic form of diabetes and neurodegeneration (Eizirik et al., 2008; Oslowski and Urano, 2011).The crosstalk between inflammation and ER stress has been suggested to play a significant role in β cell dysfunction and death (Zhang and Kaufman, 2008). However, a key molecule that links ER stress to inflammation has not been identified. Here we report that thioredoxin-interacting protein (TXNIP), also known as thioredoxin binding protein-2 (TBP-2) and vitamin-D3 upregulated protein-1 (VDUP1) (Chen and DeLuca, 1994; Nishiyama et al., 1999), is a critical link between ER stress, inflammation and cell death.