In pancreatic β cells, which produce and secrete insulin, calcium (Ca2+) signals are contribute to insulin production and secretion. Bisphenol A (BPA) and octylphenol (OP) were known to increase plasma insulin levels and insulin transcription factors, but regulation of plasma glucose levels did not decrease proportionally to the insulin increase. We hypothesized that BPA and OP disrupt calcium homeostasis results in insulin resistance, by inducing ER stress. BPA and OP treatment leads to survival of pancreatic β cells against streptozotocin, but despite of increased insulin level, serum glucose regulation does not properly regulated. The expression of genes involved in transporting calcium ions to the cytosol and ER were decreased while the expression of those affecting the removal of calcium from the cytosol and ER were increased. Depletion of calcium from the ER leads to ER stress and can induce insulin resistance. Insulin resistance is also confirmed with insulin responsive gene such as glucose transporter 4 (glut4) and Irs2 expression. Taken together, these results imply that the disruption of calcium homeostasis by BPA and OP induces ER-stress and leads to insulin resistance especially in streptozotocin (STZ) -induced type 1 diabetes mellitus model.