Hypoxia affects the function of pancreatic beta cells, and the molecular mechanism underlying hypoxiarelated beta cell dysfunction in human type 2 diabetes mellitus (T2DM) remains to be elucidated. In this study, by comparing the gene expression profiles of islets from nondiabetic and T2D subjects using gene chip array, we aimed to elucidate that hypoxia signaling pathways are activated in human T2DM islets. CoCl2 treatment, which was employed to mimic hypoxic stimulation in human islets, decreased insulin secretion, insulin content, and the functional gene expression of human islets. In parallel, the expression of mature beta cell-disallowed genes was upregulated by CoCl2, including progenitor cell marker NGN3, beta cell differentiation marker ALDH1A3, and genes that are typically inhibited in mature beta cells, namely, GLUT1 and LDHA, indicating that CoCl2-mimicked hypoxia induced beta cell dedifferentiation of human islets. This finding in human islets was confirmed in mouse beta cell line NIT-1. By using Dimethyloxalylglycine (DMOG) to activate hypoxia-inducible factor-1 alpha (HIF-1 alpha) or siRNAs to knockdown HIF-1 alpha, we found that HIF-1 alpha was a key regulator of hypoxia-induced dedifferentiation of beta cells by upregulating mature beta cell-disallowed genes. Our findings suggested that HIF-1 alpha activation might be an important contributor to beta cell dedifferentiation in human T2DM islets, and HIF-1 alpha-targeted therapies may have the potential to reverse beta cell dedifferentiation of human T2DM islets. (C) 2019 Elsevier Inc. All rights reserved.