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

Abstract

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), β-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 β-cell dysfunction manifested as augmented basal insulin secretion, and impaired glucose-stimulated insulin secretion 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 upregulation 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 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 β-cell dysfunction.

• Authors: Ning Wang, Xue-Feng Shi, Shakil A Khan, Benjamin Wang, Gregg L Semenza, Nanduri R Prabhakar, Jayasri Nanduri
• Journal: American journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 319 Issue 5 Pg. C922-C932 (11 01 2020) ISSN: 1522-1563 [Electronic] United States
• PMID: 32936698 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Insulin
• RNA, Small Interfering
• Digoxin
• Hydrogen Peroxide
• NADPH Oxidase 4
• Nox4 protein, mouse
• Glucose
• Oxygen

Topics

• Animals
• Digoxin (pharmacology)
• Disease Models, Animal
• Glucose (metabolism)
• Heterozygote
• Hydrogen Peroxide (antagonists & inhibitors, metabolism)
• Hypoxia (genetics, metabolism, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Insulin (metabolism)
• Insulin Resistance (genetics)
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NADPH Oxidase 4 (antagonists & inhibitors, genetics, metabolism)
• Oxygen (pharmacology)
• RNA, Small Interfering (genetics, metabolism)
• Sleep Apnea, Obstructive (genetics, metabolism, pathology)
• Transcriptional Activation