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

Area of Science:

• Endocrinology
• Cell Biology
• Sleep Medicine

Background:

• Obstructive sleep apnea (OSA) involves intermittent hypoxia (IH).
• Pancreatic beta-cell dysfunction contributes to insulin resistance and diabetes.
• The role of hypoxia-inducible factor (HIF)-1 in beta-cell response to IH is not fully understood.

Purpose of the Study:

• To investigate the role of HIF-1 in pancreatic beta-cell dysfunction induced by IH.
• To elucidate the molecular mechanisms linking IH, HIF-1, and beta-cell dysfunction.

Main Methods:

• Studies utilized wild-type (WT), HIF-1α heterozygous (HET), and beta-cell-specific HIF-1 knockout mice, along with MIN6 cells.
• Exposure to IH mimicked blood O2 profiles during OSA.
• Assessed insulin secretion, HIF-1α expression, reactive oxygen species (ROS) levels, and NADPH oxidase (NOX) 4 activity.

Main Results:

• IH induced insulin resistance and beta-cell dysfunction (augmented basal insulin secretion, impaired glucose-stimulated insulin secretion) in WT mice, effects absent in HET mice.
• IH increased HIF-1α expression and ROS levels in WT beta-cells, mediated by NOX4 upregulation.
• These IH-evoked beta-cell responses were abolished in HET mice, beta-HIF-1 mice, and with HIF-1α inhibition (digoxin).
• In vitro IH on MIN6 cells enhanced basal insulin release and HIF-1α expression, blocked by HIF-1α silencing.
• IH increased NOX4 in MIN6 cells; NOX4 disruption or H2O2 scavenging blocked IH-evoked insulin secretion.

Conclusions:

• HIF-1 plays a critical role in mediating pancreatic beta-cell dysfunction under IH conditions.
• HIF-1-dependent transcriptional activation of NOX4 and subsequent H2O2 production contribute to IH-induced beta-cell dysfunction.
• Targeting the HIF-1/NOX4 pathway may offer therapeutic strategies for IH-related metabolic disorders.