Hypoxia-inducible factor-1 mediates pancreatic b-cell dysfunction by intermittent hypoxia

The role of hypoxia-inducible factor (HIF)-1 in pancreatic b-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1a heterozygous (HET), b-cell-specific HIF-1^-/^- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O₂ profiles during obstructive sleep apnea. WT mice treated with IH showed insulin resistance, and pancreatic b-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1a HET mice. IH increased HIF-1a expression and elevated reactive oxygen species (ROS) levels in b-cells of WT mice. The elevated ROS levels were due to transcriptional upregulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity, and these responses were absent in HIF-1a HET mice as well as in b -HIF-1^-/^- mice. IH-evoked b-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1a. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1a protein expression, and these effects were abolished with genetic silencing of HIF-1a. IH increased NOX4 mRNA, protein, and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H₂O₂ with polyethylene glycol catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H₂O₂ contribute to IH-induced pancreatic b-cell dysfunction.