Hypoxia-Induced Insulin Resistance Mediates the Elevated Cardiovascular Risk in Patients with Obstructive Sleep Apnea: A Comprehensive Review.

Abstract

Patients with obstructive sleep apnea (OSA) experience insulin resistance and its clinical consequences, including hypertriglyceridemia, reduced high density lipoprotein-associated cholesterol (HDL-c), visceral adiposity, hepatic steatosis, increased epicardial fat thickness, essential hypertension, glucose intolerance, increased risk for type 2 diabetes, chronic kidney disease, subclinical vascular damage, and increased risk for cardiovascular events. Obesity is a major contributor to OSA. The prevalence of OSA is almost universal among patients with severe obesity undergoing bariatric surgery. However, insulin resistance and its clinical complications occur in OSA patients irrespective of general obesity (body mass index). In OSA patients, apnea episodes during sleep induce oxyhemoglobin desaturation and tissue hypoxia. Insulin resistance is an adaptive response to tissue hypoxia and develops in conditions with limited tissue oxygen supply, including healthy subjects exposed to hypobaric hypoxia (high altitude) and OSA patients. Indicators of oxyhemoglobin desaturation have been robustly and independently linked to insulin resistance and its clinical manifestations in patients with OSA. Insulin resistance mediates the elevated rate of type 2 diabetes, chronic kidney disease, and cardiovascular disease unexplained with traditional cardiovascular risk factors present in OSA patients. Pathophysiological processes underlying hypoxia-induced insulin resistance involve hypoxia inducible factor-1 upregulation and peroxisome proliferator-activated receptor-gamma (PPAR- $\gamma$ ) downregulation. In human adipose tissue, PPAR- $\gamma$ activity promotes glucose transport into adipocytes, lipid droplet biogenesis, and whole-body insulin sensitivity. Silencing of PPAR- $\gamma$ in the adipose tissue reduces glucose uptake and fat accumulation into adipocytes and promotes insulin resistance. In conclusion, tissue hypoxia drives insulin resistance and its clinical consequences in patients with OSA, regardless of body mass index.