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

The role of hypoxia-inducible factor (HIF)-1 in pancreatic β-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild type (WT), HIF-1α heterozygous (HET) as well as β-cell specific HIF-1-/- mice and mouse insulinoma (MIN6) cells exposed to IH patterned after blood O2 profiles during obstructive sleep apnea (OSA). WT mice treated with IH showed insulin resistance, and pancreatic β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose stimulated insulin secretion (GSIS) and these effects were absent in HIF-1α HET mice. IH increased HIF-1α expression and elevated reactive oxygen species (ROS) levels in β-cells of WT mice. The elevated ROS levels were due to transcriptional up regulation of NADPH oxidase (NOX)-4 mRNA, protein and enzymatic activity and these responses were absent in HIF-1α HET mice as well as in β-HIF-1-/- mice. IH-evoked β-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1α. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1α protein expression and these effects were abolished with genetic silencing of HIF-1α. IH- increased NOX4 mRNA, protein and enzyme activity in MIN6 cells and disruption of NOX4 function by siRNA or scavenging H2 O2 with PEG catalase blocked IH-evoked enhanced basal insulin secretion. These results demonstrate that HIF-1-mediated transcriptional activation of NOX4 and the ensuing increase in H2 O2 contribute to IH-induced pancreatic β-cell dysfunction.