PERK is a pancreatic endoplasmic reticulum (ER) kinase. Its complete deletion in pancreatic β cells induces insulin deficiency; however, the effects of partial Perk suppression are unclear. We investigated the effect of partial PERK suppression using the specific PERK inhibitors GSK2606414 and GSK2656157. Low-dose GSK2606414 treatment for 24 h enhanced glucose-stimulated insulin secretion (GSIS), islet insulin content and calcium transit in mouse (at 40 nM) and human (at 50-100 nM) pancreatic islets. GSK2606414 also induced the expression of the ER chaperone BiP and the release of calcium from the ER. When Bip expression was inhibited using a Bip siRNA, the GSK2606414-induced augmentation of the ER calcium level, islet insulin contents, glucose-stimulated cytosolic calcium transit and GSIS were abrogated. In both wild-type and insulin-deficient Atg7-knockout mice, 8 weeks of GSK2656157 treatment enhanced GSIS and improved hyperglycemia without affecting body weight. In conclusion, partial PERK inhibition induced BiP expression in islets, increased glucose-stimulated calcium transit and islet insulin contents and enhanced GSIS, suggesting that low-dose PERK inhibitors could potentially be used to treat insulin deficiency.