Association of insomnia and daytime napping with metabolic syndrome and its components in a Korean population: an analysis of data from the Korean Genome and Epidemiology Study.

OBJECTIVES: We investigated the association between metabolic syndrome (MetS) and the coexistence of insomnia and daytime napping, because limited data have been reported regarding this association. METHODS: The study population was 8,440 participants aged 40-65 years, who were from the Korean Genome and Epidemiology Study. Self-reported information on insomnia symptoms and nap duration was used to define exposure variables. Data on waist circumference (WC), blood pressure (BP), and fasting blood glucose (FBG), triglyceride (TG), and high-density lipoprotein cholesterol levels in blood were used to define MetS. Multivariate logistic regression analysis was performed to obtain odds ratio (OR) and 95% confidence interval (CI). RESULTS: In multivariate logistic regression analysis, the coexistence of insomnia and napping was not significantly associated with MetS. However, the insomnia and non-napping group showed higher ORs of high TG (OR, 1.19; 95% CI, 1.02 to 1.39) and high BP (OR, 1.28; 95% CI, 1.10 to 1.49) than the non-insomnia and non-napping group. The combination of non-insomnia and napping and that of insomnia and napping showed higher ORs of high TG (OR, 1.13; 95% CI, 1.00 to 1.29) and high FBG (OR, 1.59; 95% CI, 1.14 to 2.21), respectively. In analyses of insomnia symptoms, only the combination of difficulty in maintaining sleep (DMS) and non-napping showed a higher OR for MetS (OR, 1.25; 95% CI, 1.03 to 1.52) than the non-DMS and non-napping group. CONCLUSIONS: Individuals with insomnia, particularly those who do not take naps, were disproportionately likely to have MetS components, especially TG or BP. Information on these variables may help predict individuals' vulnerability to specific MetS components.

Melatonin Improves Glucose Homeostasis and Insulin Sensitivity by Mitigating Inflammation and Activating AMPK Signaling in a Mouse Model of Sleep Fragmentation.

Sleep fragmentation (SF) can increase inflammation and production of reactive oxygen species (ROS), leading to metabolic dysfunction. SF is associated with inflammation of adipose tissue and insulin resistance. Several studies have suggested that melatonin may have beneficial metabolic effects due to activating AMP-activated protein kinase (AMPK). However, it is unclear whether melatonin affects the AMPK signaling pathway in SF-induced metabolic dysfunction. Therefore, we hypothesize that SF induces metabolic impairment and inflammation in white adipose tissue (WAT), as well as altered intracellular homeostasis. We further hypothesize that these conditions could be improved by melatonin treatment. We conducted an experiment using adult male C57BL/6 mice, which were divided into three groups: control, SF, and SF with melatonin treatment (SF+Mel). The SF mice were housed in SF chambers, while the SF+Mel mice received daily oral melatonin. After 12 weeks, glucose tolerance tests, insulin tolerance tests, adipose tissue inflammation tests, and AMPK assessments were performed. The SF mice showed increased weight gain, impaired glucose regulation, inflammation, and decreased AMPK in WAT compared to the controls. Melatonin significantly improved these outcomes by mitigating SF-induced metabolic dysfunction, inflammation, and AMPK downregulation in adipose tissue. The therapeutic efficacy of melatonin against cardiometabolic impairments in SF may be due to its ability to restore adipose tissue homeostatic pathways.

Surface Active Salivary Metabolites Indicate Oxidative Stress and Inflammation in Obstructive Sleep Apnea.

PURPOSE: Obstructive sleep apnea (OSA), a highly prevalent and potentially serious sleep disorder, requires effective screening tools. Saliva is a useful biological fluid with various metabolites that might also influence upper airway patency by affecting surface tension in the upper airway. However, little is known about the composition and role of salivary metabolites in OSA. Therefore, we investigated the metabolomics signature in saliva from the OSA patients and evaluated the associations between identified metabolites and salivary surface tension. METHODS: We studied 68 subjects who visited sleep clinic due to the symptoms of OSA. All underwent full-night in-lab polysomnography. Patients with apnea-hypopnea index (AHI) < 10 were classified to the control, and those with AHI ≥ 10 were the OSA groups. Saliva samples were collected before and after sleep. The centrifuged saliva samples were analyzed by liquid chromatography with high-resolution mass spectrometry (ultra-performance liquid chromatography-tandem mass spectrometry; UPLC-MS/MS). Differentially expressed salivary metabolites were identified using open source software (XCMS) and Compound Discoverer 2.1. Metabolite set enrichment analysis (MSEA) was performed using MetaboAnalyst 5.0. The surface tension of the saliva samples was determined by the pendant drop method. RESULTS: Three human-derived metabolites (1-palmitoyl-2-[5-hydroxyl-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [PHOOA-PC], 1-palmitoyl-2-[5-keto-8-oxo-6-octenoyl]-sn-glycerol-3-phosphatidylcholine [KPOO-PC], and 9-nitrooleate) were significantly upregulated in the after-sleep salivary samples from the OSA patients compared to the control group samples. Among the candidate metabolites, only PHOOA-PC was correlated with the AHI. In OSA samples, salivary surface tension decreased after sleep. The differences in surface tension were negatively correlated with PHOOA-PC and 9-nitrooleate concentrations. Furthermore, MSEA revealed that arachidonic acid-related metabolism pathways were upregulated in the after-sleep samples from the OSA group. CONCLUSIONS: This study revealed that salivary PHOOA-PC was correlated positively with the AHI and negatively with salivary surface tension in the OSA group. Salivary metabolomic analysis may improve our understanding of upper airway dynamics and provide new insights into novel biomarkers and therapeutic targets in OSA.

Sleep Fragmentation Accelerates Carcinogenesis in a Chemical-Induced Colon Cancer Model.

Aims of this study were to test whether sleep fragmentation (SF) increased carcinogenesis and to investigate the possible mechanisms of carcinogenesis in a chemical-induced colon cancer model. In this study, eight-week-old C57BL/6 mice were divided into Home cage (HC) and SF groups. After the azoxymethane (AOM) injection, the mice in the SF group were subjected to SF for 77 days. SF was accomplished in a sleep fragmentation chamber. In the second protocol, mice were divided into 2% dextran sodium sulfate (DSS)-treated, HC, and SF groups and were exposed to the HC or SF procedures. Immunohistochemical and immunofluorescent stainings were conducted to determine the level of 8-OHdG and reactive oxygen species (ROS), respectively. Quantitative real-time polymerase chain reaction was used to assess the relative expression of inflammatory and ROS-generating genes. The number of tumors and average tumor size were significantly higher in the SF group than in the HC group. The intensity (%) of the 8-OHdG stained area was significantly higher in the SF group than in the HC group. The fluorescence intensity of ROS was significantly higher in the SF group than the HC group. SF accelerated cancer development in a murine AOM/DSS-induced model of colon cancer, and the increased carcinogenesis was associated with ROS- and oxidative stress-induced DNA damage.

Associations of Sleep Apnea, NRG1 Polymorphisms, Alcohol Consumption, and Cerebral White Matter Hyperintensities: Analysis with Genome-Wide Association Data.

STUDY OBJECTIVE: There are few studies on gene-environment interactions with obstructive sleep apnea (OSA). Our study aimed to explore genetic polymorphisms associated with OSA using genome-wide association (GWA) data and evaluate the effects of relevant polymorphisms on the association between risk factors, including obesity and alcohol consumption, and OSA. We also investigated on these associations in relation to cerebral white matter hyperintensities (WMH) on magnetic resonance images. DESIGN: A cross-sectional design. SETTING: A polysomnography study embedded in a population-based cohort from the Korean Genome Epidemiology Study was conducted in 2011-2013. PARTICIPANTS: 1,763 participants aged 48-78 years. RESULTS: 251 individuals were identified to have OSA with an apnea-hypopnea index ≥ 15. A common polymorphism of neuregulin-1 gene (NRG1), rs10097555, was selected as the most suggestive locus associated with OSA (P value < 10(-5)) based on the results of GWA analysis in a matched case-control subsample (n = 470). Among 1,763 participants, we found that the presence of the NRG1 polymorphism is inversely associated with OSA (P value < 0.01) even after taking into account potential risk factors; the multivariate odds ratio (95% confidence interval) for the mutant alleles was 0.57 (0.39-0.82) compared with the wild-type. We observed that this association is modified by alcohol consumption (P < 0.05), not by obesity. We also observed that WMH are positively associated with OSA independent of the NRG1 polymorphism and alcohol consumption (P < 0.05). CONCLUSIONS: These findings suggest that the neuregulin-1 gene (NRG1) may be involved in the etiological mechanisms of obstructive sleep apnea (OSA) and that carriers of a particular NRG1 mutation may be less likely to have OSA if they do not drink alcoholic beverages.

Effect of remote ischemic post-conditioning on systemic inflammatory response and survival rate in lipopolysaccharide-induced systemic inflammation model.

BACKGROUND: Remote ischemic preconditioning (RIPC) and postconditioning (RpostC) have protective effects on ischemia and reperfusion injury. The effects have been reported to activate heme oxygenase-1 (HO-1) and attenuate nuclear factor kappa B (NF-κB) and subsequently reduce systemic inflammation. Ischemic preconditioning prevented inflammatory responses by modulating HO-1 expression in endotoxic shock model. Therefore, we investigated whether RpostC could have protective effects on lipopolysaccharide (LPS)-induced systemic inflammation. METHODS: The LPS-induced sepsis mice received LPS (20 mg/kg) intraperitoneally. Remote ischemic conditioning was induced with three 10-min ischemia/10-min reperfusion cycles of the right hind limbs using tourniquet before LPS injection (RIPC) or after LPS injection (RpostC). The effects of RIPC and RpostC were examined for the survival rate, serum cytokines, NF-κB, HO-1 and liver pathology in the LPS injected mice. RESULTS: Survival rate within 120 hours significantly increased in the LPS injected and remote ischemic conditioned mice than in LPS only injected mice (60-65% vs 5%, respectively, p < 0.01). Tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6) increased markedly in the LPS only injected mice, however, remote ischemic conditioning suppressed the changes (p < 0.05). Interleukin-10 (IL-10) level was significantly higher in the LPS injected and RpostC treated mice than in the LPS only injected mice (p = 0.014). NF-κB activation was significantly attenuated (p < 0.05) and HO-1 levels were substantially higher in the LPS injected and remote ischemic conditioned mice than in the LPS only injected mice. Neutrophil infiltration was significantly attenuated in the LPS injected and remote ischemic conditioned mice than in the only LPS injected mice (p < 0.05). CONCLUSIONS: RpostC attenuated inflammatory responses and improved survival outcomes of mice with LPS-induced systemic inflammation. The mechanism may be caused by modifying NF-κB mediated expression of cytokines.

Increase in serum haptoglobin and apolipoprotein M in patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is a common syndrome, which is associated with a number of medical problems that impact morbidity and mortality. Although the precise mechanisms that underlie these associations are not fully understood, previous studies have suggested that patients with OSA show elevations of several biomarkers that are associated with cardiovascular risk. This study was undertaken to identify serum proteins associated with OSA by using a proteomics technique and to examine changes in identified protein levels after continuous positive airway pressure treatment. The study participants consisted of 40 male patients (aged 40-49 years) with severe OSA and 34 male control subjects matched for age and body mass index. All subjects underwent polysomnography. Using a proteomics approach, we identified nine proteins that were differentially expressed in patients with severe OSA and controls. Three of these nine proteins, haptoglobin, paraoxonase-1 and apolipoprotein M, were quantified by using enzyme-linked immunosorbent assays, kinetic assays and by using Western blotting. Multiple regression analysis showed that haptoglobin and apolipoprotein M levels are independently related to apnoea-hypopnoea index (P < 0.01). A further study is required to determine the nature of associations between these identified proteins and OSA in a large population.