Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1alpha 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 beta-Hif1a-null mice. Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1alpha is a potential therapeutic target for the beta cell dysfunction of T2D.
Cheng
Kim
K
Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, New South Wales, Australia.
Ho
Kenneth
K
Stokes
Rebecca
R
Scott
Christopher
C
Lau
Sue Mei
SM
Hawthorne
Wayne J
WJ
O'Connell
Philip J
PJ
Loudovaris
Thomas
T
Kay
Thomas W
TW
Kulkarni
Rohit N
RN
Okada
Terumasa
T
Wang
Xiaohui L
XL
Yim
Sun Hee
SH
Shah
Yatrik
Y
Grey
Shane T
ST
Biankin
Andrew V
AV
Kench
James G
JG
Laybutt
D Ross
DR
Gonzalez
Frank J
FJ
Kahn
C Ronald
CR
Gunton
Jenny E
JE
D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D014157:Transcription Factors; D005947:Glucose