title: Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis.
abstract: Both type 1 and type 2 diabetes are associated with insufficient functional β-cell mass. Understanding intracellular signaling pathways associated with this decline is important in broadening our understanding of the disease and potential therapeutic strategies. The hypoxia inducible factor pathway (HIF) plays a critical role in cellular adaptation to hypoxic conditions. Activation of this pathway increases expression of numerous genes involved in multiple cellular processes and has been shown to impact the regulation of β-cell function. Previously, deletion of HIF-1α or HIF-1β in pancreatic β-cells, as well as constitutive activation of the HIF pathway in β-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2α overexpression in pancreatic β-cells in vivo. We overexpressed HIF-2α in pancreatic β-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2α overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or β-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2α in the pancreatic β-cells does not play a significant role in β-cell function and glucose homeostasis.
authors.affiliation: a Toronto General Research Institute ; Toronto , Canada.
authors.forename: Jara J
authors.initials: JJ
authors.lastname: Brunt
authors.forename: Sally Yu
authors.initials: SY
authors.lastname: Shi
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schroer
authors.forename: Tharini
authors.initials: T
authors.lastname: Sivasubramaniyam
authors.forename: Erica P
authors.initials: EP
authors.lastname: Cai
authors.forename: Minna
authors.initials: M
authors.lastname: Woo
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism* / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology; D020287:In Situ Nick-End Labeling; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D005947:Glucose; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: ARNT, aryl hydrocarbon receptor nuclear translocator; EPAS1, endothelial PAS domain protein 1; GLUT1 glucose transporter 1; GTT, glucose tolerance test; HFD, high fat diet; HIF, hypoxia inducible factor; HIF-1α, hypoxia inducible factor-1 α; HIF-1β, hypoxia inducible factor-1 β; HIF-2α, hypoxia inducible factor-2 α; Hypoxia inducible factor β cell glucose homeostasis diabetes mellitus pancreas; ITT, insulin tolerance test; OE, overexpression; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WT, wild-type; i.p., intraperitoneal
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