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Metabolic consequences of intermittent hypoxia: Relevance to obstructive sleep apnea

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Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human OSA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human OSA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of OSA have improved our understanding of the metabolic impact of OSA, but further studies are needed before we can translate recent basic research findings to clinical practice.

Introduction

Obstructive sleep apnea (OSA) describes recurrent collapse of the upper airway during sleep.1 OSA is a common disorder affecting 4–24% of men and 2–9% of women in the US2, but the prevalence of OSA in obese individuals exceeds 50%.3 OSA is particularly prevalent in individuals with central (visceral) obesity. Emerging evidence suggests that OSA leads to high cardiovascular mortality and morbidity.*4, 5, 6 The cardiovascular risk imposed by OSA may be mediated through effects of OSA on glucose and lipid metabolism.

Several studies have shown that the impact of OSA on metabolic function is acutely or chronically reversible with continuous positive airway pressure (CPAP).7, 8 The respiratory events associated with OSA lead to changes in intrathoracic pressure, hypercapnea, arousals from sleep, and intermittent hypoxia (IH). IH is the best studied aspect of OSA in terms of metabolic effects. A number of animal and human studies demonstrated that IH causes disturbances in lipid and glucose metabolism.9, *10 In the present review, we will discuss experimental models of IH and effects of IH on metabolic function.

Section snippets

Models of intermittent hypoxia

Animal models of sleep-disordered breathing (SDB) were extensively reviewed elsewhere.9, *10 IH models are the most commonly used research models of OSA. IH has been predominantly employed in rodents. IH is administered by cyclic delivery of nitrogen, oxygen and air to a sealed chamber. There are two different types of rodent models of IH. The first type is sleep-dependent IH.11 In this model, IH is delivered exclusively during sleep. Sleep-dependent IH requires implantation of EEG and EMG

Intermittent hypoxia and lipid metabolism

We have recently reviewed relationships between OSA and dyslipidemia.20 Several cross-sectional studies suggest that OSA is independently associated with increased levels of total cholesterol, LDL and triglycerides, whereas others report no such relationships.21, 22, 23, 24 Several studies show that OSA treatment with CPAP may have a beneficial effect on lipid profile.8, 25, 26 However, the majority of the studies were not specifically designed to evaluate the lipid profile, ignoring important

Intermittent hypoxia and glucose metabolism

OSA is associated with increased prevalence of type 2 diabetes53 and has recently been shown to be a risk factor for incident diabetes.54 In non-diabetics, OSA is associated with insulin resistance in proportion to the degree of nocturnal hypoxemia.*47, *55, 56, 57 CPAP can reverse the insulin resistance of OSA both acutely (within 2 days) and chronically (after 4 months).7, 58 In patients with type 2 diabetes, OSA may worsen glycemic control59, which improves after CPAP.60, 61 We will focus on

Limitations and future directions

OSA is associated with dysregulation of lipid and glucose metabolism, but studying of these phenomena in patients with OSA has been challenging due to confounding effects of obesity.84 Animal and human work has determined that IH has an impact on metabolism that parallel findings in patients with OSA. However, mechanisms of metabolic effects of IH are still poorly understood. Potential mechanisms include tissue hypoxia/re-oxygenation, systemic catecholamine-mediated lipolysis and lipotoxicity,

Sources and funding

Luciano F. Drager and Jonathan Jun are Post-Doctoral Fellow at Johns Hopkins University. Dr. Drager is supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq # 200032/2009-7) and Fundação Zerbini, Brazil. Dr.Jun is supported by the National Sleep Foundation/American Lung Association Pickwick Grant (SF-78568N) and NIH T32 training grant (HL07534).

Vsevolod Y. Polotsky is supported by NIH (R01 HL80105, 5P50HL084945) and theUnited States Israel Binational Science

References (84)

  • M. Ahmadian et al.

    The skinny on fat: lipolysis and fatty acid utilization in adipocytes

    Trends in Endocrinology and Metabolism

    (2009)
  • M. Lafontan et al.

    Lipolysis and lipid mobilization in human adipose tissue

    Progress in Lipid Research

    (2009)
  • R. Zechner et al.

    Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores

    Journal of Lipid Research

    (2009)
  • M. Merkel et al.

    Lipoprotein lipase: genetics, lipid uptake, and regulation

    Journal of Lipid Research

    (2002)
  • L.K. Pulawa et al.

    Reduction of plasma triglycerides in apolipoprotein C-II transgenic mice overexpressing lipoprotein lipase in muscle

    Journal of Lipid Research

    (2007)
  • N. Botros et al.

    Obstructive sleep apnea as a risk factor for type 2 diabetes

    The American Journal of Medicine

    (2009)
  • N.M. Morton

    Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

    Molecular and Cellular Endocrinology

    (2010)
  • S. Kojima et al.

    Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice

    Peptides

    (2009)
  • M.S. Ip et al.

    Serum leptin and vascular risk factors in obstructive sleep apnea

    Chest

    (2000)
  • J. Xu et al.

    Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress

    Free Radical Biology & Medicine

    (2009)
  • T. Young et al.

    The occurrence of sleep-disordered breathing among middle-aged adults

    The New England Journal of Medicine

    (1993)
  • T. Young et al.

    Epidemiology of obstructive sleep apnea: a population health perspective

    American Journal of Respiratory and Critical Care Medicine

    (2002)
  • N.M. Punjabi et al.

    Sleep-disordered breathing and mortality: a prospective cohort study

    PLoS Medicine

    (2009)
  • H.K. Yaggi et al.

    Obstructive sleep apnea as a risk factor for stroke and death

    The New England Journal of Medicine

    (2005)
  • I.A. Harsch et al.

    The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes

    Respiration

    (2004)
  • J. Jun et al.

    Metabolic consequences of sleep-disordered breathing

    ILAR Journal

    (2009)
  • Y. Tagaito et al.

    A model of sleep-disordered breathing in the C57BL/6J mouse

    Journal of Applied Physiology

    (2001)
  • E.C. Fletcher et al.

    Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats

    Hypertension

    (1992)
  • S.C. Veasey et al.

    Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output

    American Journal of Respiratory and Critical Care Medicine

    (2004)
  • D. Gozal et al.

    Behavioral and anatomical correlates of chronic episodic hypoxia during sleep in the rat

    The Journal of Neuroscience

    (2001)
  • Y.J. Peng et al.

    Induction of sensory long-term facilitation in the carotid body by intermittent hypoxia: implications for recurrent apneas

    Proceedings of the National Academy of Sciences of the United States of America

    (2003)
  • V. Savransky et al.

    Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver

    American Journal of Physiology. Gastrointestinal and Liver Physiology

    (2007)
  • M. Louis et al.

    Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers

    Journal of Applied Physiology

    (2009)
  • L.F. Drager et al.

    Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis

    Current Opinion in Endocrinology, Diabetes, and Obesity

    (2010)
  • A.B. Newman et al.

    Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study

    American Journal of Epidemiology

    (2001)
  • C. Tsioufis et al.

    The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects

    Journal of Hypertension

    (2007)
  • L.F. Drager et al.

    Early signs of atherosclerosis in obstructive sleep apnea

    American Journal of Respiratory and Critical Care Medicine

    (2005)
  • F. Tokuda et al.

    Serum levels of adipocytokines, adiponectin and leptin, in patients with obstructive sleep apnea syndrome

    Internal Medicine

    (2008)
  • G.V. Robinson et al.

    Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials

    Thorax

    (2004)
  • J. Li et al.

    Intermittent hypoxia induces hyperlipidemia in lean mice

    Circulation Research

    (2005)
  • J. Li et al.

    Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia

    Journal of Applied Physiology

    (2007)
  • V. Savransky et al.

    Chronic intermittent hypoxia induces atherosclerosis

    American Journal of Respiratory and Critical Care Medicine

    (2007)
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