Objective Preventing β-cell loss is a major purpose of T2DM treatment. Recently, ER stress has been emerged as a major factor that causes β-cell loss. Our group and others have shown that β-cell loss in Wfs1-/- mice is related to apoptosis due to ER stress and β-cells from these mice are susceptible to ER stress. In earlier studies, we showed that Adrenomedullin (AM) is up-regulated in Wfs1-/- mice islets and thapsigargin treated Min6 cells. In this study, we investigated the AM signaling in β-cells to respond ER stress. Methods We studied the gene expression of RAMP2, RAMP3 and CRLR, which compose AM receptor, in Wfs1-/- mice islets and thapsigargin treated Min6 cells. In addition, we transfected AM into Min6 cells and evaluated apoptosis using DNA ladder assay after thapsigargin treatment in these cells. Simultaneously we measured cAMP using ELISA kit. Results The expressions of RAMP2, RAMP3 and CRLR genes were 1.5-2.3 fold increased in Wfs1-/- mice islets and thapsigargin treated Min6 cells compared to controls. AM transfected Min6 cells were resistant to apoptsis caused by thapsigargin treatment. Intracellular cAMP in AM-transfected cells tended to increase compared to control cells. Conclusion The expression of AM receptor is up-regulated in β-cells exposed to ER stress, as well as AM itself. AM has the cytoprotective effect in various tissues. Therefore we speculate that AM signaling in β-cells is upregulated by ER stress in an autocrine manner and important to handle ER stress. Increased intracellular cAMP is compatible with this mechanism.