Metabolic Consequences of Sleep-Disordered Breathing

Abstract

There is increasing evidence of a causal relationship between sleep-disordered breathing and metabolic dysfunction. Metabolic syndrome (MetS), a cluster of risk factors that promote atherosclerotic cardiovascular disease, comprises central obesity, insulin resistance, glucose intolerance, dyslipidemia, and hypertension, manifestations of altered total body energy regulation. Excess caloric intake is indisputably the key driver of MetS, but other environmental and genetic factors likely play a role; in particular, obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), may induce or exacerbate various aspects of MetS. Clinical studies show that OSA can affect glucose metabolism, cholesterol, inflammatory markers, and nonalcoholic fatty liver disease. Animal models of OSA enable scientists to circumvent confounders such as obesity in clinical studies. In the most widely used model, which involves exposing rodents to IH during their sleep phase, the IH alters circadian glucose homeostasis, impairs muscle carbohydrate uptake, induces hyperlipidemia, and upregulates cholesterol synthesis enzymes. Complicating factors such as obesity or a high-fat diet lead to progressive insulin resistance and liver inflammation, respectively. Mechanisms for these effects are not yet fully understood, but are likely related to energy-conserving adaptations to hypoxia, which is a strong catabolic stressor. Finally, IH may contribute to the morbidity of MetS by inducing inflammation and oxidative stress. Identification of OSA as a potential causative factor in MetS would have immense clinical impact and could improve the management and understanding of both disorders.

Visceral white fat remodelling contributes to intermittent hypoxia-induced atherogenesis

“…The relationship between fat inflammation, in particular macrophage-related inflammation in WAT, and insulin resistance is now largely described in the literature [14]. Our results are in agreement with clinical studies showing a progressive worsening of insulin resistance and metabolic syndrome with OSA severity [26]. Exposure to intermittent hypoxia also leads to decreased insulin sensitivity in healthy volunteers [29] and in lean mice [30].…”

“…We confirmed the atherogenic and dyslipidaemic effects of intermittent hypoxia; hypoxic mice exhibited larger aortic atherosclerotic lesions and higher plasmatic levels of cholesterol (total and LDL) and triglycerides. Lipid alterations, constituting an early step of atherogenesis [25], have been previously described both in OSA patients and in mice exposed to intermittent hypoxia [26]. Intermittent hypoxia also increased plasmatic glycerol and NEFA, and aggravated the insulin resistance.…”

Acute hypoxia induces hypertriglyceridemia by decreasing plasma triglyceride clearance in mice

“…We show that hypoxia has a striking impact on TG clearance and that neither chronicity nor intermittency of hypoxia is necessary; rather, the mean FiO 2 dictates the degree of TG elevation. In addition, we avoided influences of hypoxia on weight loss and decreased food intake, which accompany longer hypoxic exposures (2,31). Because all animals were fasted with the onset of hypoxia, we could attribute results to the effects of hypoxia itself.…”

Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome

“…112,113 With animal models of intermittent hypoxia, there may be more control over variables such as diet, genotypes, oxygen profile, obesity and sleep fragmentation. 114 The protocols may however vary in frequency, intermittent hypoxia cycle length and severity of the hypoxic stimulus. 47 Levels of intermittent hypoxia may be more severe than that seen in OSA.…”