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

Content Provider	PubMed Central
Author	Cheng, Kim Ho, Kenneth Stokes, Rebecca Scott, Christopher Lau, Sue Mei Hawthorne, Wayne J. O’connell, Philip J. Thomas, Loudovaris Kay, Thomas W. Kulkarni, Rohit N. Okada, Terumasa Wang, Xiaohui L. Yim, Sun Hee Shah, Yatrik Grey, Shane T. Biankin, Andrew V. Kench, James G. Laybutt, D. Ross Gonzalez, Frank J. Kahn, C. Ronald Gunton, Jenny E.
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.
Related Links	http://dx.doi.org/10.1172/jci35846
Ending Page	2183
Page Count	13
Starting Page	2171
File Format	PDF
ISSN	00219738
e-ISSN	15588238
Journal	The Journal of Clinical Investigation
Issue Number	6
Volume Number	120
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2010-06-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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