Overexpression of HIF-2α in pancreatic β cells does not alter glucose homeostasis

Abstract

Keywords: Hypoxia inducible factor b cell glucose homeostasis diabetes mellitus pancreas Abbreviations: 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-1a, hypoxia inducible factor-1 a; HIF-1b, hypoxia inducible factor-1 b; HIF-2a, hypoxia inducible factor-2 a; i.p., intraperitoneal; ITT, insulin tolerance test; OE, overexpression; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau; WT, wild-type.Both type 1 and type 2 diabetes are associated with insufficient functional b-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 b-cell function. Previously, deletion of HIF-1a or HIF-1b in pancreatic b-cells, as well as constitutive activation of the HIF pathway in b-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2a overexpression in pancreatic b-cells in vivo. We overexpressed HIF-2a in pancreatic b-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2a overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or b-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2a in the pancreatic b-cells does not play a significant role in b-cell function and glucose homeostasis.

HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes

“…These observations suggest that HIF-2α activity has no major role in the pancreatic islet’s response to either cellular or environmental hypoxia. Furthermore, previous studies showed that, in contrast to HIF-1α ( 23 ), overexpression of HIF-2α in β cells has no impact on glucose homeostasis ( 32 ). To ensure the absence of any negative impact of PX-478 on cell viability, we performed propidium iodide staining, which confirmed that, regardless of GKA50 cotreatment, treatment with PX-478 did not lead to an increase in cell death (fig.…”

Hypoxia signaling in human health and diseases: implications and prospects for therapeutics

“…Brunt et al suggested that overexpression of HIF-2α does not alter glucose homeostasis in pancreatic β cells. 177 However, recent studies have described a critical role of HIF-2α in hepatic glucose homeostasis. 178,179 Taniguchi et al uncovered that the increased hepatic HIF-2α, but not HIF-1α, improves glucose tolerance and insulin sensitivity to ameliorate diabetes.…”