Glucose-lipid metabolic dysregulation and sleep fragmentation in obstructive sleep apnea: insights from a large-scale cross-sectional study and exploratory hypoxia-related single-nucleus transcriptomic analysis.

BACKGROUND

Sleep fragmentation impairs health and quality of life, yet its relationship with glucose-lipid metabolic dysregulation remains unclear. This study investigated this association in obstructive sleep apnea (OSA), with a focus on nocturnal hypoxia and hypoxia-related brainstem cellular responses.

METHODS

This large-scale cross-sectional study included 5,885 adults with suspected OSA from the Shanghai Sleep Health Study. Glucose-lipid metabolic status was assessed using the triglyceride-glucose (TyG) index, TyG-body mass index (TyG-BMI), metabolic score for insulin resistance (METS-IR), and metabolic syndrome. Sleep fragmentation was quantified by the micro-arousal index (MAI). Multivariable regression, restricted cubic spline, threshold effect, multiplicative and additive interaction, stratified analyses, Benjamini-Hochberg false discovery rate (FDR) correction were performed. GEO single-nucleus analyses were conducted to explore intermittent hypoxia-related cellular and metabolic pathway responses in the brainstem (metabolic activity scoring, GSVA, scTenifoldKnk).

RESULTS

TyG, TyG-BMI, and METS-IR were independently positively associated with MAI. Each 1-unit increase in TyG was associated with a 4.0-unit increase in MAI (β = 4.0, p < 0.001). TyG-BMI and METS-IR showed significant nonlinear dose-response relationships with thresholds at 310.31 and 57.25, respectively. OSA severity and nocturnal hypoxia significantly strengthened these associations through both multiplicative and additive interactions. When AHI > 5, the associations of TyG (β = 4.04), TyG-BMI (β = 0.08), and METS-IR (β = 0.41) on MAI were more pronounced. Combined exposure was associated with 4.07-5.91-fold higher odds of elevated MAI. All primary associations remained significant after FDR correction. Single-nucleus analyses suggested widespread glucose-lipid metabolic reprogramming in brainstem cells, particularly neurons and oligodendrocytes.

CONCLUSION

Glucose-lipid metabolic abnormalities were significantly associated with OSA-related sleep fragmentation, and these associations were stronger among participants with greater OSA severity and nocturnal hypoxia.