The endoplasmic reticulum (ER) unfolded protein response (UPRer) pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPRer gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPRer gene expression and subsequent β cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic β cells and correlates with UPRer gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive β cell function during metabolic stress by controlling UPRer and represents a promising target for T2D prevention and treatment. Display omitted •The expression of UPR markers is altered in diabetic islets•Loss of Kat2b contributes to defective insulin secretion and β cell compensation•KAT2B regulates an UPR gene program in pancreatic β cells•KAT2B expression is reduced in mouse and human diabetic β cells Rabhi et al. reveal a role for Kat2b in the control of insulin secretion and pancreatic β cell adaptation to metabolic stress through cell-autonomous regulation of the unfolded protein response (UPR). These data collected demonstrate that Kat2b expression is decreased in diabetic islets and suggest molecular links among KAT2B, the UPR, and diabetes.