Indeed, Ire1, which is one of the effector branches of the UPR, when continuously activated has been shown to cause suppression of insulin gene expression (Lipson et al., 2006), possibly explaining why prolonged hyperglycemia in T2D patients leads to diminished insulin production also in the absence of apoptosis (Shimizu and Hendershot, 2009). The gene discussed is INS; the disease is type 2 diabetes mellitus.