Hypoxia-inducible factor-1? regulates ? cell function in mouse and human islets
Hypoxia-inducible factor-1? (HIF-1?) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1? protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1? is required for normal ? cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1? protein is present at low levels in mouse and human normoxic ? cells and islets. Decreased levels of HIF-1? impaired glucose-stimulated ATP generation and ? cell function. C57BL/6 mice with ? cell?specific Hif1a disruption (referred to herein as ?-Hif1a-null mice) exhibited glucose intolerance, ? cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1? 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 ?-Hif1a-null mice. Increasing HIF-1? levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1? was bound to the Arnt promoter in a mouse ? cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1? in ? cell reserve and regulation of ARNT expression and demonstrate that HIF-1? is a potential therapeutic target for the ? cell dysfunction of T2D.
|Authors||Cheng, K.; Ho, K.; Stokes, R.; Scott, C.; Lau, S.M., Hawthorne, W.J.; O'Connell, P.J.; Loudovaris, T.; Kay, T.W.; Kulkarni, R.N.; Okada, K.; Wang, X.; Yim, S.H.; Shah, Y.; Grey, S.T.; Biankin, A.V.; Kench, J.; Laybutt, R.; Gonzalez, F.J.; Kahn, C.R.; Gunton, J.E.:|
|Publisher Name||JOURNAL OF CLINICAL INVESTIGATION|
|URL link to publisher's version||http://www.jci.org/articles/view/35846|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/10282|