image_1_Blockade of Endothelin-1 Receptor Type B Ameliorates Glucose Intolerance and Insulin Resistance in a Mouse Model of Obstructive Sleep Apnea.jpg

<p>Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ET_A and ET_B) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ET_A antagonist; 200 nmol/kg/day), BQ-788 (ET_B antagonist; 200 nmol/kg/day) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO₂ from 20.9% to 6%, 60/h) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1 mg/kg) was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05) and impaired glucose tolerance (AUC_glucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUC_glucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05) in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUC_glucose: 21,969 ± 662; p < 0.05). Fourteen-day IH also induced IR (AUC_glucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05). Treatment with BQ-788 decreased IR under IA (AUC_glucose: 5281 ± 401, p < 0.05) and reduced worsening of IR with IH (AUC_glucose: 7302 ± 401, p < 0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.</p

Intermittent hypoxia increased expression of toll-like receptor 2 in peripheral blood mononuclear cells.

<p>Expression of toll-like receptor two (TLR2) in peripheral blood mononuclear cells of healthy volunteers was measured during daytime exposure to intermittent hypoxia or control conditions for 5 hours and compared to baseline by real time PCR. The results are expressed as ratios to 18s. * denotes p < 0.05 for the difference between baseline and 5 hours data points.</p

Cross-over study design.

<p>Healthy volunteers underwent phlebotomy in the antecubital fossa and whole blood (15 ml) was collected in the ethylenediaminetetraacetic acid (EDTA) coated tube. The volunteers were exposed to intermittent hypoxia or control air conditions (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144725#sec002" target="_blank">Methods</a>) for 5 hours followed by whole blood collection. In one week, the volunteers underwent phlebotomy again and had an alternative exposure followed by whole blood collection. Peripheral blood mononuclear cells (PBMC, lymphocytes and monocytes) were isolated immediately after blood collection using Ficoll-Hypaque solution. RBC, red blood cells.</p

Associations of Sleep Characteristics and 24-hour Urine Free Cortisol, µg, Adjusted Means (95% Confidence Intervals).

a<p>Adjusted for age, race, apnea-hypopnea index.</p>b<p>Adjusted for age, race, apnea-hypopnea index, BMI, history of CVD, physical activity, number of depression symptoms.</p>c<p>Adjusted for age, race, apnea-hypopnea index, BMI, history of CVD, physical activity, number of depressive symptoms, sleep efficiency.</p

Baseline Characteristics.

*<p>CVD includes history of myocardial infarction, angina, congestive heart failure, bypass surgery, angioplasty, or pacemaker placement.</p

Association of self-reported sleep duration and 24-hour urine free cortisol among those without depression and those without a history of CVD.

<p>24-hour urine free cortisol results are adjusted means (95% confidence intervals). Results for the not depressed sub-group adjusted for age, race, apnea-hypopnea index, BMI, history of CVD and physical activity. Results from those without a history of CVD adjusted for age, race, apnea-hypopnea index, BMI, physical activity, and number of depressive symptoms.</p

Sleep Apnea, Sleep Duration and Brain MRI Markers of Cerebral Vascular Disease and Alzheimer’s Disease: The Atherosclerosis Risk in Communities Study (ARIC)

<div><p>Background</p><p>A growing body of literature has suggested that obstructive sleep apnea (OSA) and habitual short sleep duration are linked to poor cognitive function. Neuroimaging studies may provide insight into this relation.</p><p>Objective</p><p>We tested the hypotheses that OSA and habitual short sleep duration, measured at ages 54–73 years, would be associated with adverse brain morphology at ages 67–89 years.</p><p>Methods</p><p>Included in this analysis are 312 ARIC study participants who underwent in-home overnight polysomnography in 1996–1998 and brain MRI scans about 15 years later (2012–2013). Sleep apnea was quantified by the apnea-hypopnea index and categorized as moderate/severe (≥15.0 events/hour), mild (5.0–14.9 events/hour), or normal (<5.0 events/hour). Habitual sleep duration was categorized, in hours, as <7, 7 to <8, ≥8. MRI outcomes included number of infarcts (total, subcortical, and cortical) and white matter hyperintensity (WMH) and Alzheimer’s disease signature region volumes. Multivariable adjusted logistic and linear regression models were used. All models incorporated inverse probability weighting, to adjust for potential selection bias.</p><p>Results</p><p>At the time of the sleep study participants were 61.7 (SD: 5.0) years old and 54% female; 19% had moderate/severe sleep apnea. MRI imaging took place 14.8 (SD: 1.0) years later, when participants were 76.5 (SD: 5.2) years old. In multivariable models which accounted for body mass index, neither OSA nor abnormal sleep duration were statistically significantly associated with odds of cerebral infarcts, WMH brain volumes or regional brain volumes.</p><p>Conclusions</p><p>In this community-based sample, mid-life OSA and habitually short sleep duration were not associated with later-life cerebral markers of vascular dementia and Alzheimer’s disease. However, selection bias may have influenced our results and the modest sample size led to relatively imprecise associations.</p></div

Estimates and 95% confidence intervals in z-scores from inverse probability weighted linear regression models for Brain MRI volume measurements (2011–2013), stratified by sleep duration categories (1996–1998).

<p>Estimates and 95% confidence intervals in z-scores from inverse probability weighted linear regression models for Brain MRI volume measurements (2011–2013), stratified by sleep duration categories (1996–1998).</p

Demographic and clinical characteristics of the final analytic sample (n = 312) at the sleep exam (visit 4; 1996–1998), at the neurocognitive exam (2011–2013) and over follow-up (1996–2012), stratified by sleep exam obstructive sleep apnea categories.

<p>Demographic and clinical characteristics of the final analytic sample (n = 312) at the sleep exam (visit 4; 1996–1998), at the neurocognitive exam (2011–2013) and over follow-up (1996–2012), stratified by sleep exam obstructive sleep apnea categories.</p

Odds ratio and 95% confidence intervals from inverse probability weighted logistic regression models for Brain MRI measures (2011–2013), stratified by sleep duration categories (1996–1998).

<p>Odds ratio and 95% confidence intervals from inverse probability weighted logistic regression models for Brain MRI measures (2011–2013), stratified by sleep duration categories (1996–1998).</p