During advancement of diabetes type 2, pancreatic |β cells are exposed to sustained metabolic overload. We postulated this condition mediates a hypoxic phenotype driven by hypoxia-inducible factor-1|¨¢ (HIF-1|¨¢) which treatment using the HIF-1|¨¢ inhibitor PX-478 would improve |β cell function. Our studies demonstrated the HIF-1|¨¢ protein was contained in pancreatic |β cells of diabetic mouse models. In mouse islets rich in glucose metabolic process, the emergence of intracellular Ca2 oscillations at low glucose concentration and also the abnormally high basal discharge of insulin were covered up by treatment using the HIF-1|¨¢ inhibitor PX-478, indicating improvement of |β cell function. Management of db/db rodents with PX-478 avoided an upswing of glycemia and diabetes progression by upkeep of elevated plasma insulin concentration. In streptozotocin-caused diabetic rodents, PX-478 improved the recovery of glucose homeostasis. Islets isolated from all of these rodents demonstrated hallmarks of improved |? cell function including elevation of insulin content, elevated expression of genes involved with |β cell function and maturity, inhibition of dedifferentiation markers, and formation of mature insulin granules. As a result of PX-478 treatment, human islet organoids chronically uncovered to high glucose presented improved stimulation index of glucose-caused insulin secretion. These results claim that the HIF-1|¨¢ inhibitor PX-478 can behave as an antidiabetic therapeutic agent that preserves |β cell function under metabolic overload.