Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1α protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1α is required for normal β cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1α protein is present at low levels in mouse and human normoxic β cells and islets. Decreased levels of HIF-1α impaired glucose-stimulated ATP generation and β cell function. C57BL/6 mice with β cell–specific Hif1a disruption (referred to herein as β-Hif1a-null mice) exhibited glucose intolerance, β cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1α levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in β-Hif1a-null mice. Increasing HIF-1α levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1α was bound to the Arnt promoter in a mouse β cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1α in β cell reserve and regulation of ARNT expression and demonstrate that HIF-1α is a potential therapeutic target for the β cell dysfunction of T2D.
Kim Cheng, Kenneth Ho, Rebecca Stokes, Christopher Scott, Sue Mei Lau, Wayne J. Hawthorne, Philip J. O’Connell, Thomas Loudovaris, Thomas W. Kay, Rohit N. Kulkarni, Terumasa Okada, Xiaohui L. Wang, Sun Hee Yim, Yatrik Shah, Shane T. Grey, Andrew V. Biankin, James G. Kench, D. Ross Laybutt, Frank J. Gonzalez, C. Ronald Kahn, Jenny E. Gunton
HIF-1α is present in normoxic β cells, associates with ARNT, and is decreased in T2D.