Brain insulin resistance: A link between obstructive sleep apnea and cognitive impairment.

OBJECTIVES: Insulin resistance has been an established risk factor for cognitive impairment. Patients with moderate to severe obstructive sleep apnea (OSA) are at an increased risk of insulin resistance. However, the correlation between insulin resistance and cognitive impairment in OSA has not yet been confirmed. This study aims to investigate the relationship between brain insulin resistance and mild cognitive impairment (MCI) in patients with OSA. METHODS: A total of 284 participants with complete clinical data were evaluated at baseline. Brain insulin resistance was assessed using phosphorylated insulin receptor substrate-1 (phospho-IRS-1) and IRS-1 phosphorylation at serine site 312 (pS312-IRS-1) from neuron-derived exosomes isolated by co-immunoprecipitation, while peripheral insulin resistance was evaluated using the triglyceride-glucose (TyG) index. Follow-up measurements of phospho-IRS-1 and pS312-IRS-1 were obtained in 23 patients after weight loss and in 23 patients after continuous positive airway pressure (CPAP) therapy. RESULTS: Higher TyG index, phospho-IRS-1, and pS312-IRS-1 levels were associated with an increased risk of cognitive impairment in OSA. Poor cognitive performance correlated with higher phospho-IRS-1 and pS312-IRS-1 levels but not the TyG index. Exploratory mediation models suggested that phospho-IRS-1 and pS312-IRS-1 may partly account for the association between hypoxia and cognitive impairment in OSA, with mediated proportions ranging from 79.64% to 252.03%. Areas under the receiver-operating characteristic curve for insulin resistance-associated proteins ranged from 0.775 to 0.914. Weight loss reduced the phospho-IRS-1 and pS312-IRS-1 levels, while CPAP therapy did not significantly change the phospho-IRS-1 or pS312-IRS-1 levels. CONCLUSIONS: This study provides evidence of brain insulin resistance in OSA, which has an essential effect on intermittent hypoxia-mediated cognitive impairment. Insulin sensitivity is improved with weight reduction but not CPAP therapy. Brain insulin resistance represents a potential target for early intervention in OSA.