Old astrocyte specifically induced substance (OASIS) has previously been shown to be a putative endoplasmic reticulum (ER) stress sensor in astrocytes with a mechanism of activation that is similar to ATF6. In this study we investigated the expression and activation of endogenous and overexpressed OASIS in pancreatic beta-cells. OASIS mRNA expression was detected in pancreatic beta-cell lines and rodent islets, and the expression level was up-regulated by ER stress-inducing compounds. Endogenous OASIS protein, however, is expressed at low levels in pancreatic beta-cell lines and rodent islets, possibly due to abundant levels of the micro-RNA miR-140 present in these cells. In contrast, expression of both full-length and cleaved (active) OASIS was readily detectable in the developing mouse pancreas (embryonic d 15.5). Microarray analysis after expression of an active nuclear-localized version of OASIS in an inducible INS-1 beta-cell line resulted in the up-regulation of many genes implicated in extracellular matrix production and protein transport but not classical ER stress response genes. Consistent with this, expression of active OASIS failed to induce glucose-regulated protein 78 kDa promoter activity in pancreatic beta-cells. These results suggest that the repertoire of genes induced by OASIS is cell type-dependent and that the OASIS protein may have a role in pancreas development.