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Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets
Kim Cheng, … , C. Ronald Kahn, Jenny E. Gunton
Kim Cheng, … , C. Ronald Kahn, Jenny E. Gunton
Published May 3, 2010
Citation Information: J Clin Invest. 2010;120(6):2171-2183. https://doi.org/10.1172/JCI35846.
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Research Article Metabolism

Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets

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Abstract

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.

Authors

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

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Figure 1

HIF-1α is present in normoxic β cells, associates with ARNT, and is decreased in T2D.

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HIF-1α is present in normoxic β cells, associates with ARNT, and is decr...
(A) HIF1A mRNA was decreased in islets of people with T2D (n = 6) compared with people with normal glucose tolerance (n = 12). ***P < 0.001. (B) HIF-1α protein was present in β cells in floxed control mice (horizontal arrows) but was decreased in β-Hif1a-null mice. In both genotypes, HIF-1α was present in blood vessels (vertical arrows). Scale bar: 20 μm. (C) HIF-1α protein was higher than background in people with normal glucose tolerance (top panels) but was decreased in T2D pancreata (bottom panels). Scale bar: 50 μm. (D) HIF-1α protein (arrow) was associated with ARNT by affinity purification. Cyto, cytoplasm; Nuc, nucleus; Prot, protein. (E) HIF-1α protein associated with ARNT in the basal state in Min6 cells, and nuclear HIF-1α increased with DFO. (F) ARNT protein associated with HIF-1α by coimmunoprecipitation. (G) HIF-1α protein was increased by DFO treatment of isolated mouse islets and was decreased in islets from a β-Hif1a-null mouse (Cre+).

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