Sleep apnea, metabolic disease, and the cutting edge of therapy

Abstract

Obstructive sleep apnea (OSA) is common, and many cross-sectional and longitudinal studies have established OSA as an independent risk factor for the development of a variety of adverse metabolic disease states, including hypertension, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and atherosclerosis. Nasal continuous positive airway pressure (CPAP) has long been the mainstay of therapy for OSA, but definitive studies demonstrating the efficacy of CPAP in improving metabolic outcomes, or in reducing incident disease burden, are lacking; moreover, CPAP has variable rates of adherence. Therefore, the future of OSA management, particularly with respect to limiting OSA-related metabolic dysfunction, likely lies in a coming wave of alternative approaches to endophenotyping OSA patients, personalized care, and defining and targeting mechanisms of OSA-induced adverse health outcomes.

Keywords: Hyperglycemia; Obesity; Sleep apnea endophenotypes; Sleep disordered breathing.

Figure 1. Potential mechanisms by which obstructive sleep apnea may lead to adverse metabolic outcomes

OSA causes sleep fragmentation and intermittent hypoxia, each of which has been linked to insulin resistance via sympathetic nervous system over-activation, mitochondrial dysfunction, and reduced muscle expression of GLUT-4. Oxidative stress may result in pancreatic β-cell apoptosis and inhibition of insulin signaling pathways. In experimental models of OSA, intermittent hypoxia causes hyperlipidemia and chronic inflammation, each of which may promote atherosclerosis. The mechanisms by which OSA worsens nonalcoholic fatty liver disease are less well developed, but may stem from tissue hypoxia and HIF-1 or HIF-2 activation.