| First Author | Wang N | Year | 2020 |
| Journal | Am J Physiol Cell Physiol | Volume | 319 |
| Issue | 5 | Pages | C922-C932 |
| PubMed ID | 32936698 | Mgi Jnum | J:299929 |
| Mgi Id | MGI:6490836 | Doi | 10.1152/ajpcell.00309.2020 |
| Citation | Wang N, et al. (2020) Hypoxia-inducible factor-1 mediates pancreatic beta-cell dysfunction by intermittent hypoxia. Am J Physiol Cell Physiol 319(5):C922-C932 |
| abstractText | The role of hypoxia-inducible factor (HIF)-1 in pancreatic beta-cell response to intermittent hypoxia (IH) was examined. Studies were performed on adult wild-type (WT), HIF-1alpha heterozygous (HET), beta-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 beta-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion and these effects were absent in HIF-1alpha HET mice. IH increased HIF-1alpha expression and elevated reactive oxygen species (ROS) levels in beta-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-1alpha HET mice as well as in beta-HIF-1(-/-) mice. IH-evoked beta-cell responses were absent in adult WT mice treated with digoxin, an inhibitor of HIF-1alpha. MIN6 cells treated with in vitro IH showed enhanced basal insulin release and elevated HIF-1alpha protein expression, and these effects were abolished with genetic silencing of HIF-1alpha. 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 beta-cell dysfunction. |
