Harry Whitmore

Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes.

RATIONALE Obstructive sleep apnea (OSA), a treatable sleep disorder that is associated with alterations in glucose metabolism in individuals without diabetes, is a highly prevalent comorbidity of type 2 diabetes. However, it is not known whether the severity of OSA is a predictor of glycemic control in patients with diabetes. OBJECTIVES To determine the impact of OSA on hemoglobin A1c (HbA1c), the major clinical indicator of glycemic control, in patients with type 2 diabetes. METHODS We performed polysomnography studies and measured HbA1c in 60 consecutive patients with diabetes recruited from outpatient clinics between February 2007 and August 2009. MEASUREMENTS AND MAIN RESULTS A total of 77% of patients with diabetes had OSA (apnea-hypopnea index [AHI] > or =5). Increasing OSA severity was associated with poorer glucose control, after controlling for age, sex, race, body mass index, number of diabetes medications, level of exercise, years of diabetes and total sleep time. Compared with patients without OSA, the adjusted mean HbA1c was increased by 1.49% (P = 0.0028) in patients with mild OSA, 1.93% (P = 0.0033) in patients with moderate OSA, and 3.69% (P < 0.0001) in patients with severe OSA (P < 0.0001 for linear trend). Measures of OSA severity, including total AHI (P = 0.004), rapid eye movement AHI (P = 0.005), and the oxygen desaturation index during total and rapid eye movement sleep (P = 0.005 and P = 0.008, respectively) were positively correlated with increasing HbA1c levels. CONCLUSIONS In patients with type 2 diabetes, increasing severity of OSA is associated with poorer glucose control, independent of adiposity and other confounders, with effect sizes comparable to those of widely used hypoglycemic drugs.

Eight Hours of Nightly Continuous Positive Airway Pressure Treatment of Obstructive Sleep Apnea Improves Glucose Metabolism in Patients with Prediabetes. A Randomized Controlled Trial

RATIONALE Although obstructive sleep apnea (OSA) is associated with impaired glucose tolerance and diabetes, it remains unclear whether OSA treatment with continuous positive airway pressure (CPAP) has metabolic benefits. OBJECTIVES To determine the effect of 8-hour nightly CPAP treatment on glucose metabolism in individuals with prediabetes and OSA. METHODS In a randomized controlled parallel group study, 39 participants were randomly assigned to receive either 8-hour nightly CPAP (n = 26) or oral placebo (n = 13). Sleep was polysomnographically recorded in the laboratory on each night. CPAP adherence was ensured by continuous supervision. Participants continued their daily routine activities outside the laboratory. Glucose metabolism was assessed at baseline and after 2 weeks of assigned treatment using both the oral and intravenous glucose tolerance tests. The primary outcome was the overall glucose response as quantified by the area under the curve for glucose during 2-hour oral glucose tolerance testing. Secondary outcomes included fasting and 2-hour glucose and insulin, the area under the curves for insulin and insulin secretion, norepinephrine, insulin sensitivity, acute insulin response to glucose, and 24-hour blood pressure. MEASUREMENTS AND MAIN RESULTS The overall glucose response was reduced (treatment difference: -1,276.9 [mg/dl] · min [95% confidence interval, -2,392.4 to -161.5]; P = 0.03) and insulin sensitivity was improved (treatment difference: 0.77 [mU/L](-1) · min(-1) [95% confidence interval, 0.03-1.52]; P = 0.04) with CPAP as compared with placebo. Additionally, norepinephrine levels and 24-hour blood pressure were reduced with CPAP as compared with placebo. CONCLUSIONS In patients with prediabetes, 8-hour nightly CPAP treatment for 2 weeks improves glucose metabolism compared with placebo. Thus, CPAP treatment may be beneficial for metabolic risk reduction. Clinical trial registered with www.clinicaltrials.gov (NCT 01156116).

Treatment of Obstructive Sleep Apnea Improves Cardiometabolic Function in Young Obese Women with Polycystic Ovary Syndrome

CONTEXT Women with polycystic ovary syndrome (PCOS) are insulin resistant and have a high risk of early-onset diabetes and cardiovascular disease. Obstructive sleep apnea (OSA) has adverse cardiometabolic consequences and is highly prevalent in women with PCOS. We sought to determine whether continuous positive airway pressure (CPAP) treatment of OSA has beneficial effects on cardiometabolic function in PCOS. METHODS Laboratory polysomnography and cardiometabolic measurements including insulin sensitivity and secretion (iv glucose tolerance test); 24-h profiles of plasma catecholamines, cortisol, and leptin; and daytime profiles of blood pressure and cardiac autonomic activity (heart rate variability) were obtained at baseline and again after 8 wk of home CPAP treatment with daily usage monitoring. RESULTS CPAP treatment modestly improved insulin sensitivity after controlling for body mass index (P = 0.013). The change in insulin sensitivity correlated positively with CPAP use (adjusted P = 0.027) and negatively with body mass index (adjusted P = 0.003). Daytime and nighttime norepinephrine levels were decreased after CPAP (P = 0.002), and the reductions were greater with increased CPAP use (P = 0.03). Epinephrine, cortisol, and leptin levels were not changed significantly. Daytime diastolic blood pressure decreased by an average of 2.3 mm Hg after CPAP (P = 0.035). Cardiac sympathovagal balance was 44% lower (P = 0.007) after CPAP, reflecting a shift toward lower sympathetic activity. CONCLUSIONS In young obese women with PCOS, successful treatment of OSA improves insulin sensitivity, decreases sympathetic output, and reduces diastolic blood pressure. The magnitude of these beneficial effects is modulated by the hours of CPAP use and the degree of obesity.

Temporal Disorganization of Circadian Rhythmicity and Sleep-Wake Regulation in Mechanically Ventilated Patients Receiving Continuous Intravenous Sedation

OBJECTIVES Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. DESIGN Observational study. SETTING Academic medical intensive care unit. PATIENTS Critically ill patients receiving MV and intravenous sedation. METHODS Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. MEASUREMENTS AND RESULTS We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). CONCLUSIONS The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

Reduced physical activity in adults at risk for type 2 diabetes who curtail their sleep

Adults with parental history of type 2 diabetes have high metabolic morbidity, which is exacerbated by physical inactivity. Self‐reported sleep <6 h/day is associated with increased incidence of obesity and diabetes, which may be mediated in part by sleep‐loss‐related reduction in physical activity. We examined the relationship between habitual sleep curtailment and physical activity in adults with parental history of type 2 diabetes. Forty‐eight young urban adults with parental history of type 2 diabetes (27 F/21 M; mean (s.d.) age 26 (4) years; BMI 23.8 (2.5) kg/m2) each completed 13 (2) days of sleep and physical activity monitoring by wrist actigraphy and waist accelerometry while following their usual lifestyle at home. Laboratory polysomnography was used to screen for sleep disorders. The primary outcome of the study was the comparison of total daily activity counts between participants with habitual sleep <6 vs. ≥6 h/night. Secondary measures included daily time spent sedentary and in light, moderate, and vigorous physical activity. Short sleepers had no sleep abnormalities and showed signs of increased sleep pressure consistent with a behavioral pattern of habitual sleep curtailment. Compared to participants who slept ≥6 h/night, short sleepers had 27% fewer daily activity counts (P = 0.042), spent less time in moderate‐plus‐vigorous physical activity (−43 min/day; P = 0.010), and remained more sedentary (+69 min/day; P = 0.026). Our results indicate that young urban adults with parental history of type 2 diabetes who habitually curtail their sleep have less daily physical activity and more sedentary living, which may enhance their metabolic risk.

Elevated ghrelin predicts food intake during experimental sleep restriction

Sleep curtailment has been linked to obesity, but underlying mechanisms remain to be elucidated. This study assessed whether sleep restriction alters 24‐h profiles of appetite‐regulating hormones ghrelin, leptin, and pancreatic polypeptide during a standardized diet and whether these hormonal alterations predict food intake during ad libitum feeding.

Changes in Insulin Secretion and Action in Adults With Familial Risk for Type 2 Diabetes Who Curtail Their Sleep

OBJECTIVE Experimental sleep deprivation is accompanied by changes in glucose regulation. However, the effects of chronic sleep insufficiency on insulin secretion and action in populations at high risk for type 2 diabetes are not known. This study examined the relationship between objectively documented habitual sleep curtailment and measures of insulin sensitivity, insulin secretion, and oral glucose tolerance in free-living adults with parental history of type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 47 healthy participants with parental history of type 2 diabetes (26 female/21 male, mean [SD] age 26 [4] years and BMI 23.8 [2.5] kg/m2) completed 13 (SD = 2) days of sleep and physical activity monitoring by wrist actigraphy and waist accelerometry while following their usual lifestyle at home. Laboratory polysomnography was used to screen for sleep disorders. Indices of diabetes risk based on oral glucose tolerance tests were compared between participants with habitual short sleep and those with usual sleep duration >6 h/day. RESULTS Consistent with a behavioral pattern of habitual sleep curtailment, short sleepers obtained an average of 1.5 h less sleep per night and showed signs of increased sleep pressure. Participants who habitually curtailed their sleep had considerably higher indices of insulin resistance and increased insulin secretion but maintained normal glucose tolerance similar to that of subjects who slept more. CONCLUSIONS Young lean adults with parental history of type 2 diabetes who habitually curtail their sleep have increased insulin resistance and compensatory hyperinsulinemia—a pattern that has been associated with higher risk of developing diabetes in such susceptible individuals.

REM sleep and depressive symptoms in a population-based study of middle-aged and elderly persons

Alterations in rapid eye movement sleep have been consistently related to depression in clinical studies. So far, there is limited evidence from population‐based studies for this association of rapid eye movement sleep alterations with depressive symptoms. In 489 participants of the Rotterdam Study, we assessed rapid eye movement sleep latency, rapid eye movement sleep duration and rapid eye movement density with ambulant polysomnography, and depressive symptoms with the Center of Epidemiologic Studies‐Depression Scale. A longer rapid eye movement sleep latency (B = 0.002, P = 0.025) and higher rapid eye movement density (B = 0.015, P = 0.046) were related to depressive symptoms after age–sex adjustment. When we excluded persons who used sleep medication or medication for the nervous system (n = 124), only rapid eye movement density remained related to depressive symptoms (B = 0.018, P = 0.027). Our results suggest that rapid eye movement density is a marker of depressive symptoms in the general population, and that associations of rapid eye movement sleep with depressive symptoms are modified by the use of medication.

Detection of Cortical Slow Waves in the Sleep EEG Using a Modified Matching Pursuit Method With a Restricted Dictionary

In this paper, an innovative knowledge-based methodological framework to detect sleep slow waves (SSW) in the human sleep electroencephalogram (EEG) is proposed. Based on a restricted matching pursuit (RMP) algorithm, automatic pattern recognition of SSW is implemented using a small dictionary of Gabor functions modeling the target waveform morphological characteristics. The method describes EEG signals in terms of SSW properties and provides detection thresholds based on the largest MP coefficients. A computer software implementation of this new method was tested on a database of overnight polysomnographic recordings collected in 15 young healthy subjects and visually scored by a trained sleep expert. In addition to full automation and fast application, the results obtained from the RMP algorithm, and evaluated using a rigorous performance evaluation metrics, showed excellent agreement as compared with expert scoring, with 97% of correct detections and a concordance of 67% in SSW time position and duration. The performances demonstrated by this new method were superior to that of a canonical detection algorithm introduced earlier, with an equivalent sensitivity but a significant 12% increase in precision (p = 0.0002). By mimicking the way human processes information while scoring SSW, the RMP algorithm proves stable over time and sleep/wake states, and may thus be used with virtually no human intervention.

Automated detection of sleep EEG slow waves based on matching pursuit using a restricted dictionary

In this paper, an original method to detect sleep slow waves (SSW) in electroencephalogram (EEG) recordings is proposed. This method takes advantage of a Matching Pursuit algorithm using a dictionary reduced to Gabor functions reproducing the main targeted waveform characteristics. By describing the EEG signals in terms of SSW properties, the corresponding algorithm is able to identify waveforms based on the largest matching coefficients. The implemented algorithm was tested on a database of whole night sleep EEG recordings collected in 9 young healthy subjects where SSW have been visually scored by an expert. Besides being fully automated and much faster than visual scoring analysis, the results obtained to the proposed method were in excellent agreement with the expert with 98% of correct detections and a 77% concordance in event time position and duration. These results were superior from those of the classical method both in terms of sensibility and precision.