Overexpression of HIF-2 alpha in pancreatic beta cells does not alter glucose homeostasis

摘要

Both type 1 and type 2 diabetes are associated with insufficient functional beta-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 beta-cell function. Previously, deletion of HIF-1 alpha or HIF-1 beta in pancreatic beta-cells, as well as constitutive activation of the HIF pathway in beta-cells, was shown to result in glucose intolerance and impaired insulin secretion. The objective of this study was to delineate roles of HIF-2 alpha overexpression in pancreatic beta-cells in vivo. We overexpressed HIF-2 alpha in pancreatic beta-cells by employing the Cre-loxP system driven by the Pdx1 promoter to delete a stop codon. Our study revealed that pancreatic HIF-2 alpha overexpression does not result in significant differences in glucose tolerance, insulin sensitivity or beta-cell area compared to wild-type littermates under basal conditions or after high fat diet. Together, our study shows excess HIF-2 alpha in the pancreatic beta-cells does not play a significant role in beta-cell function and glucose homeostasis.