title: Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets.
abstract: 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.
authors.affiliation: Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, New South Wales, Australia.
authors.forename: Kim
authors.initials: K
authors.lastname: Cheng
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ho
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stokes
authors.forename: Christopher
authors.initials: C
authors.lastname: Scott
authors.forename: Sue Mei
authors.initials: SM
authors.lastname: Lau
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Thomas
authors.initials: T
authors.lastname: Loudovaris
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.forename: Terumasa
authors.initials: T
authors.lastname: Okada
authors.forename: Xiaohui L
authors.initials: XL
authors.lastname: Wang
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Yim
authors.forename: Yatrik
authors.initials: Y
authors.lastname: Shah
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: D Ross
authors.initials: DR
authors.lastname: Laybutt
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Gunton
mesh_terms: 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*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D014157:Transcription Factors; D005947:Glucose