Unraveling the Complexities of Oxidative Stress and Inflammation Biomarkers in Obstructive Sleep Apnea Syndrome: A Comprehensive Review.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS), affecting approximately 1 billion adults globally, is characterized by recurrent airway obstruction during sleep, leading to oxygen desaturation, elevated carbon dioxide levels, and disrupted sleep architecture. OSAS significantly impacts quality of life and is associated with increased morbidity and mortality, particularly in the cardiovascular and cognitive domains. The cyclic pattern of intermittent hypoxia in OSAS triggers oxidative stress, contributing to cellular damage. This review explores the intricate relationship between OSAS and oxidative stress, shedding light on molecular mechanisms and potential therapeutic interventions. METHODS: A comprehensive review spanning from 2000 to 2023 was conducted using the PubMed, Cochrane, and EMBASE databases. Inclusion criteria encompassed English articles focusing on adults or animals and reporting values for oxidative stress and inflammation biomarkers. RESULTS: The review delineates the imbalance between pro-inflammatory and anti-inflammatory factors in OSAS, leading to heightened oxidative stress. Reactive oxygen species biomarkers, nitric oxide, inflammatory cytokines, endothelial dysfunction, and antioxidant defense mechanisms are explored in the context of OSAS. OSAS-related complications include cardiovascular disorders, neurological impairments, metabolic dysfunction, and a potential link to cancer. This review emphasizes the potential of antioxidant therapy as a complementary treatment strategy. CONCLUSIONS: Understanding the molecular intricacies of oxidative stress in OSAS is crucial for developing targeted therapeutic interventions. The comprehensive analysis of biomarkers provides insights into the complex interplay between OSAS and systemic complications, offering avenues for future research and therapeutic advancements in this multifaceted sleep disorder.

A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance.

Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. We investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an antioxidant, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.

A novel OSA-related model of intermittent hypoxia in endothelial cells under flow reveals pronounced inflammatory pathway activation.

Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterized by recurrent episodes of upper airway obstruction and subsequent hypoxia. In patients with OSA, severity and number of these hypoxic events positively correlate with the extent of associated cardiovascular pathology. The molecular mechanisms underlying intermittent hypoxia (IH)-driven cardiovascular disease in OSA, however, remain poorly understood-partly due to the lack of adequate experimental models. Here, we present a novel experimental approach that utilizes primary human endothelial cells cultivated under shear stress. Oxygen partial pressure dynamics were adopted in our in vitro model according to the desaturation-reoxygenation patterns identified in polysomnographic data of severe OSA patients (n = 10, with 892 severe desaturations, SpO2<80%). Using western blot analysis, we detected a robust activation of the two major inflammatory pathways ERK and NF-κB in endothelial cells, whereas no HIF1α and HIF2α protein stabilization was observed. In line with these findings, mRNA and protein expression of the pro-inflammatory adhesion and signaling molecule ICAM-1 and the chemokine CCL2 were significantly increased. Hence, we established a novel in vitro model for deciphering OSA-elicited effects on the vascular endothelium. First data obtained in this model point to the endothelial activation of pro-inflammatory rather than hypoxia-associated pathways in OSA. Future studies in this model might contribute to the development of targeted strategies against OSA-induced, secondary cardiovascular disease.

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells.

Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells. Wound healing, spheroid expansion, proliferation and migration were evaluated in HepG2 cells following IH or SH exposure. The HIF-1α, endothelin-1 and VEGF protein levels and/or mRNA expression were assessed, as were the effects of HIF-1 (acriflavine), endothelin-1 (macitentan) and VEGF (pazopanib) inhibition. Both SH and IH stimulated wound healing, spheroid expansion and proliferation of HepG2 cells. HIF-1 and VEGF, but not endothelin-1, expression increased with IH exposure but not with SH exposure. Acriflavine prevented the effects of both IH and SH, and pazopanib blocked those of IH but not those of SH. Macitentan had no impact. Thus, IH and SH stimulate hepatic cancer cell proliferation via distinct signaling pathways that may act synergistically in OSA patients with cancer, leading to enhanced tumor progression.

Chronic intermittent hypoxia worsens brain damage and sensorimotor behavioral abnormalities after ischemic stroke: Effect on autonomic nervous activity and sleep patterns.

OBJECTIVE: Sleep apnea (SA) is characterized by intermittent hypoxia (IH), which increases sympathetic activity and sleep fragmentation, thus increasing the risk of stroke. SA is a highly prevalent disease and can worsen prognosis in patients with stroke. However, the correlation of changes in the cardiac autonomic nervous system and sleep patterns under IH with sensorimotor behavior and cerebral infarction after stroke remains unclear. We hypothesized that dysregulated autonomic activity and unstable sleep patterns induced by IH and correlated with cerebral infarction and abnormal sensorimotor behavior after middle cerebral artery occlusion (MCAO). METHODS: Wistar-Kyoto rats (WKY) were divided into IH (hypoxia: 5 % O2, 8 h/day) and RA group (room air) for 2 weeks and both groups were subjected to MCAO. After MCAO, the IH group was continuously exposed to IH for 1 week. The 24-h physiological signals, blood pressure, and sensorimotor behavior were recorded at baseline (Bas), the first and second weeks during IH (RA/IH1W and RA/IH2W, respectively), and poststroke. RESULTS: Before MCAO, IH caused sympathetic activity during sleep and parasympathetic activity of active waking (AW) to increase. Moreover, IH reduced the accumulated time and duration of paradoxical sleep (PS) and increased the interruption during sleep. After MCAO, IH increased blood pressure, more severe brain damage, and poor sensorimotor performance. Moreover, IH reduced autonomic activity after MCAO and decreased sympathetic activity was associated with poor sensorimotor performance. CONCLUSION: Autonomic activity and sleep patterns affected by IH were correlated with increased cerebral infarction and poor sensorimotor behavior after MCAO.

Caloric restriction prevents obesity- and intermittent hypoxia-induced cardiac remodeling in leptin-deficient ob/ob mice.

Background: Intermittent hypoxia (IH), a key characteristic of obstructive sleep apnea, is independently associated with cardiometabolic impairment. While endogenous leptin levels may provide cardioprotective effects against hypoxia, leptin resistance is common among obese individuals presenting with obstructive sleep apnea. Methods: Here, we assessed left ventricle (LV) function using M-mode echocardiography in lean wild-type, calorically-restricted ob/ob, and obese ob/ob mice before and after 6 days of IH to determine how obesity and intermittent hypoxia interact to affect cardiac function independent of leptin signaling. Results: Calorically-restricting ob/ob mice for 4 weeks prior to IH exposure prevented weight gain (-2.1 ± 1.4 g) compared to free-fed ob/ob mice (8.7 ± 1.1 g). Free-fed ob/ob mice exhibited increased LV mass (0.713 ± 0.008 g) relative to wild-type mice (0.685 ± 0.004 g) and increased posterior wall thickness (0.089 ± 0.006 cm) relative to calorically-restricted ob/ob mice (0.072 ± 0.004 cm). Following 6 days of IH, free-fed ob/ob mice exhibited increases in cardiac output (44.81 ± 2.97 pre-IH vs. 57.14 ± 3.09 ml/min post-IH), LV diameter (0.400 ± 0.007 pre-IH vs. 0.428 ± 0.009 cm post-IH) and end diastolic volume (0.160 ± 0.007 pre-IH vs. 0.195 ± 0.012 ml post-IH) that were not detected in wild-type or calorically-restricted ob/ob mice. Conclusion: Caloric restriction can prevent obesity-induced LV hypertrophy and protect against acute IH-induced cardiac remodeling independent of leptin signaling. These findings may have clinical implications for obstructive sleep apnea.

Intermittent Hypoxia Rewires the Liver Transcriptome and Fires up Fatty Acids Usage for Mitochondrial Respiration.

Sleep Apnea Syndrome (SAS) is one of the most common chronic diseases, affecting nearly one billion people worldwide. The repetitive occurrence of abnormal respiratory events generates cyclical desaturation-reoxygenation sequences known as intermittent hypoxia (IH). Among SAS metabolic sequelae, it has been established by experimental and clinical studies that SAS is an independent risk factor for the development and progression of non-alcoholic fatty liver disease (NAFLD). The principal goal of this study was to decrypt the molecular mechanisms at the onset of IH-mediated liver injury. To address this question, we used a unique mouse model of SAS exposed to IH, employed unbiased high-throughput transcriptomics and computed network analysis. This led us to examine hepatic mitochondrial ultrastructure and function using electron microscopy, high-resolution respirometry and flux analysis in isolated mitochondria. Transcriptomics and network analysis revealed that IH reprograms Nuclear Respiratory Factor- (NRF-) dependent gene expression and showed that mitochondria play a central role. We thus demonstrated that IH boosts the oxidative capacity from fatty acids of liver mitochondria. Lastly, the unbalance between oxidative stress and antioxidant defense is tied to an increase in hepatic ROS production and DNA damage during IH. We provide a comprehensive analysis of liver metabolism during IH and reveal the key role of the mitochondria at the origin of development of liver disease. These findings contribute to the understanding of the mechanisms underlying NAFLD development and progression during SAS and provide a rationale for novel therapeutic targets and biomarker discovery.

Intermittent Hypoxia Activates N-Methyl-D-Aspartate Receptors to Induce Anxiety Behaviors in a Mouse Model of Sleep-Associated Apnea.

Sleep apnea disrupts physiologic homeostasis and causes neuronal dysfunction. In addition to signs of mental disorders and cognitive dysfunction, patients with sleep apnea have a higher anxiety rate. Here, we examined the mechanisms underlying this critical health issue. We used a mouse model with sleep-associated chronic intermittent hypoxia (IH) to verify the effects of sleep apnea on neuronal dysfunction. To evaluate how IH alters neuronal function to yield anxiety-like behavior and cognitive dysfunction, we examined synaptic plasticity and neuronal inflammation in related brain areas, including the medial prefrontal cortex (mPFC), striatum, and hippocampus. Mice subjected to chronic IH for 10 days exhibited significant anxiety-like behaviors in the elevated plus maze test. IH mice spent less travel time in open arms and more travel time in enclosed arms compared to control mice. However, cognitive impairment was minimal in IH mice. Increased glutamate N-methyl-D-aspartate (NMDA) receptor subunits 2B (GluN2B) and phosphorylated-ERK1/2 were seen in the mPFC, striatum, and hippocampus of IH mice, but no significant microglial and astrocyte activation was found in these brain areas. Chronic IH in mice induced compensatory increases in GluN2B to disturb neuronal synaptic plasticity, without neuronal inflammation. The altered synaptic plasticity subsequently led to anxiety-like behavior in mice. Treatment with the NMDA receptor antagonist dextromethorphan attenuated chronic IH-induced anxiety-like behavior and GluN2B expression. Our findings provide mechanistic evidence of how IH may provoke anxiety and support for the importance of early intervention to alleviate anxiety-associated complications in patients with chronic sleep apnea.

Tim-3 is a potential regulator that inhibits monocyte inflammation in response to intermittent hypoxia in children with obstructive sleep apnea syndrome.

The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1ß, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO2, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.

Intermittent hypoxia induces turbinate mucosal hypertrophy via upregulating the gene expression related to inflammation and EMT in rats.

PURPOSE: Chronic intermittent hypoxia (IH) plays a pivotal role in the consequences of obstructive sleep apnea (OSA). It has been demonstrated that IH impairs nasomaxillary complex growth to reduce nasal airway cavity size in rodent models. Although turbinate dysfunction with inflammatory mucosal hypertrophy is related to OSA, the role of IH in turbinate hypertrophy with inflammation-driven fibrosis is unknown. Here, we aimed to clarify the pathogenesis of inflammatory mucosal hypertrophy and epithelial-mesenchymal transition (EMT) in the nasal turbinate under IH. METHODS: Seven-week-old male Sprague-Dawley rats were exposed to IH (4% O2 to 21% O2 with 0% CO2) at a rate of 20 cycles/h. RESULTS: Hypertrophy of the turbinate mucosa occurred after 3 weeks, with the turbinate mucosa of the experimental group becoming significantly thicker than in the control group. Immunostaining showed that IH increased the expression of TGFß and N-cadherin and decreased E-cadherin expression in the turbinate mucosa. Quantitative PCR analysis demonstrated that IH enhanced the expression of not only the inflammatory markers Tnf-a, Il-1b, and Nos2 but also the EMT markers Tgf-b1, Col1a1, and Postn. CONCLUSIONS: Collectively, these results suggest that IH induced turbinate hypertrophy via upregulation of gene expression related to inflammation and EMT in the nasal mucosa.

Intermittent Hypoxia Mediates Caveolae Disassembly That Parallels Insulin Resistance Development.

Repetitive complete or incomplete pharyngeal collapses are leading to chronic intermittent hypoxia (CIH), a hallmark feature of obstructive sleep apnea (OSA) syndrome responsible for many metabolic disorders. In humans, an association between OSA and insulin resistance has been found independently of the degree of obesity. Based on our previous work showing that hypoxia applied to adipocytes led to cellular insulin resistance associated with caveolae flattening, we have investigated the effects of CIH on caveolae structuration in adipose tissue. Original exploratory experiences demonstrate that 6 weeks-exposure of lean mice to CIH is characterized by systemic insulin resistance and translates into adipocyte insulin signaling alterations. Chronic intermittent hypoxia also induces caveolae disassembly in white adipose tissue (WAT) illustrated by reduced plasma membrane caveolae density and enlarged caveolae width, concomitantly to WAT insulin resistance state. We show that CIH downregulates caveolar gene and protein expressions, including cavin-1, cavin-2, and EHD2, underlying molecular mechanisms responsible for such caveolae flattening. Altogether, we provide evidences for adipose tissue caveolae disassembly following CIH exposure, likely linked to cavin protein downregulation. This event may constitute the molecular basis of insulin resistance development in OSA patients.

Differential expression of microRNAs in xenografted Lewis lung carcinomas subjected to intermittent hypoxia: a next-generation sequence analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cancer mortality, but the underlying mechanism remains poorly understood. MicroRNAs (miRNAs) are confirmed to be involved in tumorigenesis and tumor progression. However, whether miRNAs have any differential expressions in OSA population needs to be elucidated. The aim of this experimental study was to determine the alterations of various miRNAs in xenograft mice exposed to chronic intermittent hypoxia (IH) which is considered a hallmark of OSA. METHODS: Sequencing was applied to screen the miRNAs of tumor tissues in xenograft mice exposed to IH and normoxia (control, CTL), respectively. Most differentially expressed miRNAs were verified by the quantitative real-time polymerase chain reaction (qRT-PCR). Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway were performed to reveal the functional enrichment of the target genes regulated by the miRNAs. RESULTS: A total of 485 miRNAs (259 novel miRNAs and 226 known miRNAs) were differentially expressed between the IH and CTL groups. 154 miRNAs were upregulated and 331 miRNAs were downregulated among them. The top 5 differentially expressed known (miR-767, miR-466f-5p, miR-5122, miR-124-3p and miR-590-3p) and novel (miR-140, miR-130, miR-301, miR-177 and miR-90) miRNAs were validated by qRT-PCR. MiR-767, miR-124-3p, miR-590-3p and all novel miRNAs were upregulated while miR-466f-5p and miR-5122 were downregulated in IH-induced xenograft mice. In addition, GO and KEGG pathway analysis demonstrated that the predicted target genes, which were regulated by differentially expressed miRNAs were markedly enriched in related biological processes and pathways, including biological processes, cell metabolic and biosynthetic processes and molecular functions. CONCLUSIONS: Several altered miRNAs were detected in xenograft mice exposed to IH. The differentially expressed miRNAs in IH indicates that these miRNAs might involve in the molecular mechanism of tumorigenesis and tumor progression in OSA. Further studies are required to determinate the exact intermediation of certain miRNAs between IH and tumor progression.

Differential metabolic and inflammatory responses to intermittent hypoxia in substrains of lean and obese C57BL/6 mice.

AIMS: This study was to investigate the degree of susceptibility to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), between the two mice inbred lines C57BL/6N (6N) and C57BL/6J (6J). MATERIALS AND METHODS: Four-week old male mice of 6N and 6J substrains (n = 8) were randomized to standard diet (SD) group or high fat (HF) diet group. At the age of 13-week, all two groups of mice were subjected to either air or IH (IH30; thirty hypoxic events per hour) for one week. KEY FINDINGS: All mice fed with HF diet exhibited obesity with more body weight and fat mass (percentage to body weight) gain. IH reduced serum LDL, HDL and total cholesterol levels in lean 6J mice. In obese mice, IH lowered obesity-induced serum total cholesterol level in 6J substrain but raised further in 6N substrain. Furthermore, IH caused elevation of serum FFA and MDA levels, and pro-inflammatory cytokines MCP-1 and IL-6 levels in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of lean 6J but not lean 6N mice. There was reduced number of adipocytes and elevation of macrophages in SAT and VAT of HF-induced obese mice of both substrains. IH led to increased number of adipocytes and macrophages in SAT of lean 6J mice. SIGNIFICANCE: The genetic difference between 6N and 6J mice may have direct impact on metabolic and inflammatory responses after IH. Therefore, attention must be given for the selection of C57BL mice substrains in the experimental IH-exposed mouse model.

Intermittent hypoxia enhances the tumor programmed death ligand 1 expression in a mouse model of sleep apnea.

BACKGROUND: As a hallmark of obstructive sleep apnea (OSA), intermittent hypoxia (IH) promotes tumor progress. The high expression of programmed death 1 and programmed death ligand 1 (PD-L1) in tumor leads to immune evasion and subsequently aggravates tumor progress. This study aims to determine the tumor PD-L1 expression under the IH condition. METHODS: A total of 24 C57BL/6J mice were randomly assigned to the normoxia (control, CTL) group and the IH group. Mice in the IH group were subjected to the IH condition for 5 weeks. Lung cancer cells were injected into the flank of each mouse after 1 week of IH exposure. Tumor PD-L1 expression was detected by immunohistochemistry (IHC). Correlation between tumor weight, tumor volume, and expression of PD-L1 was analyzed. RESULTS: Compared to the CTL group, mice in the IH group had a high PD-L1 expression. The IH can enhance the tumor PD-L1 expression. Tumor weight, volume, and HIF-1α levels were closely associated with the PD-L1 expression in the IH group, while dissimilar findings were observed in the CTL group. CONCLUSIONS: The IH enhances tumor PD-L1 expression in OSA mimicking mice. Additional studies are required to clarify the underlying mechanism.

ESM-1 promotes adhesion between monocytes and endothelial cells under intermittent hypoxia.

Intermittent hypoxia (IH), the key property of obstructive sleep apnea (OSA), is closely associated with endothelial dysfunction. Endothelial-cell-specific molecule-1 (ESM-1, Endocan) is a novel, reported molecule linked to endothelial dysfunction. The aim of this study is to evaluate the effect of IH on ESM-1 expression and the role of ESM-1 in endothelial dysfunction. We found that serum concentration of ESM-1, inter-cellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) is significantly higher in patients with OSA than healthy volunteers (p < 0.01). The expression of ESM-1, hypoxia-inducible factor-1 alpha (HIF-1α), and vascular endothelial growth factor (VEGF) was significantly increased in human umbilical vein endothelial cells (HUVECs) by treated IH in a time-dependent manner. HIF-1α short hairpin RNA and vascular endothelial growth factor receptor (VEGFR) inhibitor inhibited the expression of ESM-1 in HUVECs. ICAM-1 and VCAM-1 expressions were significantly enhanced under IH status, accompanied by increased monocyte-endothelial cell adhesion rate ( p < 0.001). Accordingly, ESM-1 silencing decreased the expression of ICAM-1 and VCAM-1 in HUVECs, whereas ESM-1 treatment significantly enhanced ICAM-1 expression accompanied by increasing adhesion ability. ESM-1 is significantly upregulated by the HIF-1α/VEGF pathway under IH in endothelial cells, playing a critical role in enhancing adhesion between monocytes and endothelial cells, which might be a potential target for IH-induced endothelial dysfunction.

Mechanisms of cardiovascular disease in obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is recognized as a major public health burden conveying a significant risk of cardiovascular diseases (CVD) and mortality. Continuous positive airway pressure (CPAP) is the treatment of choice for the majority of patients with OSA but the benefit of CPAP on CVD is uncertain. Thus, a greater understanding of the mechanisms by which OSA leads to CVD might identify novel therapeutic approaches. Intermittent hypoxia (IH), a hallmark feature of OSA, plays a key role in the pathogenesis and experimental studies using animal and cell culture studies suggest that IH mediates CVD through activation of multiple mechanistic pathways such as sympathetic excitation, inflammation, oxidative stress or metabolic dysregulation. Recurrent arousals, intrathoracic pressure swings and concomitant obesity likely play important additive roles in this process. In this review, the available evidence of the pathophysiological mechanisms of CVD in OSA is explored with a specific emphasis on IH, recurrent arousals and intrathoracic pressure swings as the main pathophysiological triggers.

Insulin resistance, glucose intolerance and diabetes mellitus in obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a highly prevalent disorder, which conveys an increased risk of cardiovascular disease and death. Type 2 diabetes mellitus (T2DM), glucose intolerance and insulin resistance (IR) are common in subjects with OSA, but a shared intimate relationship with obesity makes discerning an independent link challenging. Nonetheless, mechanistic studies suggest that OSA could contribute to impaired glucose metabolism via the effects of sleep fragmentation, sympathetic excitation and intermittent hypoxia (IH) on pancreatic B-cell function, insulin sensitivity, and systemic inflammation. In particular, emerging data suggest that IH may have an important detrimental effect on adipose tissue function and inflammation. Similarly, data from population-and clinic-level studies suggest that OSA is independently related with the prevalence and incidence of T2DM and IR, and may also lead to worse glycaemic control in diabetics. However, the ability of continuous positive airway pressure (CPAP) therapy to make a meaningful impact on T2DM or IR remains uncertain. In this review we explore the available evidence linking OSA with IR, glucose intolerance and T2DM, and discuss potential pathobiological mechanisms by which sleep disordered breathing can affect metabolic health.