As described in this review, hypoxia makes β-cells susceptible to dysfunction and failure, and the inhibition of HIF-1α activity and the suppression of BHLHE40 expression improve insulin secretion and hyperglycemia in animal models of diabetes, suggesting that hypoxia might be a novel target for the treatment of type 2 diabetes and that improving hypoxia might be beneficial for preventing progressive β-cell dysfunction in type 2 diabetes. This evidence concerns the gene BHLHE40 and type 2 diabetes mellitus.