부산대학교 도서관

Hypoxia affects the function of pancreatic β cells, and the molecular mechanism underlying hypoxia-related β 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. CoCl 2 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 β cell-disallowed genes was upregulated by CoCl 2 , including progenitor cell marker NGN3, β cell differentiation marker ALDH1A3, and genes that are typically inhibited in mature β cells, namely, GLUT1 and LDHA , indicating that CoCl 2 -mimicked hypoxia induced β cell dedifferentiation of human islets. This finding in human islets was confirmed in mouse β cell line NIT-1. By using Dimethyloxalylglycine (DMOG) to activate hypoxia-inducible factor-1α (HIF-1α) or siRNAs to knockdown HIF-1α, we found that HIF-1α was a key regulator of hypoxia-induced dedifferentiation of β cells by upregulating mature β cell-disallowed genes. Our findings suggested that HIF-1α activation might be an important contributor to β cell dedifferentiation in human T2DM islets, and HIF-1α-targeted therapies may have the potential to reverse β cell dedifferentiation of human T2DM islets. • HIF-1α signaling was activated in human T2DM islets compared with human ND islets. • CoCl 2 -mimicked hypoxia induced β cell dedifferentiation in both human islets and β cell line NIT-1 cells. • HIF-1α mediates the expression mature β cell-disallowed genes in hypoxia induced β cell dedifferentiation. [ABSTRACT FROM AUTHOR]