Summary

The term “sleep disturbance” is widely used to refer to a variety of conditions, including sleep insufficiency, sleep fragmentation, sleep disorders, such as sleep apnea, and misaligned sleep, as occurs in shift workers. Insufficient sleep and sleep fragmentation are linked to abnormal glucose metabolism, insulin sensitivity reduction of 20%–30%, and increased diabetes risk. Well-controlled laboratory studies have provided insights regarding the underlying mechanisms. Multiple large prospective studies have found that that these sleep disturbances increase the risk of incident diabetes by as much as 30%–50%. Obstructive sleep apnea (OSA), which combines sleep fragmentation and hypoxemia, has been identified as a risk factor for insulin resistance and diabetes. OSA is highly prevalent in patients with type 2 diabetes, affecting roughly two out of three patients, and its severity correlates with glycemic control. Whether glycemic control can be improved by treating OSA remains controversial. Sleep disturbances during pregnancy are linked to gestational diabetes and hyperglycemia, and there is evidence for potential adverse effects on maternal and fetal health. Evidence from animal models has identified disruption of the circadian system as a putative risk factor for adverse metabolic outcomes. Shift work, a condition of chronic circadian disruption, is linked to weight gain and incident obesity and diabetes.

As sleep disturbances are increasingly common in modern society and may play a role in the epidemic of type 2 diabetes, strategies to prevent diabetes or reduce its severity should consider optimizing sleep health in at-risk populations. Intervention studies demonstrating that treating sleep disturbances may help prevent diabetes or improve glycemic control are lacking but have become an area of intense research.

Introduction

Humans spend approximately one-third of their lifetime sleeping. Sleep is viewed as a state of energy conservation and replenishment of energy stores. Normal human sleep is composed of rapid-eye-movement (REM) sleep and stages N1, N2, and N3 of non-REM (NREM) sleep. N3 is the deepest stage of NREM sleep and is also known as slow wave sleep (SWS). Oscillations between REM and NREM stages occur roughly every 90 minutes and repeat four to six times throughout the night.

This important physiologic process is controlled in part by an internal circadian clock and in part by a homeostatic mechanism where the pressure for sleep increases in proportion to the duration of prior wakefulness. Human behavior may override these physiologic control mechanisms, resulting in alterations of sleep duration, quality, or timing. Increasing prevalence of sleep disorders, such as obstructive sleep apnea (OSA), parallels the increase in obesity rates. According to the definition proposed by the National Heart, Lung, and Blood Institute, “sleep deficiency” occurs when an individual has insufficient sleep, poor sleep, a diagnosed sleep disorder, or abnormal timing of sleep (1). Multiple reviews (2,3,4) have elected to use the term “sleep disturbances” to designate insufficient or excessive sleep duration, poor self-reported sleep quality, or a diagnosed sleep disorder, such as OSA. Experimental and epidemiologic data have linked insufficient sleep duration, abnormal sleep timing, and poor sleep quality to insulin resistance, increased risk of obesity, and diabetes. In patients with type 2 diabetes, sleep disturbances may adversely affect glycemic control.

OSA is well recognized as a risk factor for insulin resistance, independent of the degree of obesity, and is highly prevalent in patients with type 2 diabetes. OSA is a complex disorder involving intermittent hypoxia, sleep fragmentation, low amounts of SWS, and reduced total sleep time. Well-documented studies in animal models indicate that intermittent hypoxia is one of the mechanisms linking OSA to abnormal glucose metabolism. Whether treatment of OSA with continuous positive airway pressure (CPAP) may improve glucose metabolism remains controversial.

Pregnant women are a special population that may be particularly vulnerable to adverse effects of abnormal sleep. Sleep disturbances in pregnancy are associated with adverse maternal and fetal outcomes, including gestational diabetes, preeclampsia, and premature delivery. Because of these potential complications, the body of literature on this topic has grown rapidly.

Besides sleep duration, sleep quality, and OSA, emerging evidence from well-controlled clinical research studies has revealed that conditions where the behavioral sleep/wake cycle is not in synchrony with the biological circadian timing system, so-called “circadian misalignment,” may result in impaired glucose tolerance (IGT). In cross-sectional analyses, circadian misalignment is associated with increased diabetes risk in nondiabetic individuals and with poor glycemic control in patients with established type 2 diabetes.

This chapter summarizes the evidence linking different types of sleep disturbances to abnormal glucose metabolism, including insufficient sleep, sleep fragmentation, OSA, and circadian misalignment. Potential underlying mechanisms are discussed, as well as findings from prospective and cross-sectional epidemiologic studies and from intervention studies.

Insufficient Sleep

While it is important to note that the amount of sleep that optimizes physical and mental health is an individual characteristic that tends to decrease with age, it is generally considered that 7–8 hours of sleep nightly is adequate for most adults (5). Partly due to changes in work and social demands, sleep duration in the United States has been declining (6). In data from 110,441 adults participating in the National Health Interview Surveys 2004–2007, the prevalences of self-reported short sleep duration were 7.8% for sleeping ≤5 hours and 20.5% for sleeping 6 hours per day (7). In 2009, >30% of U.S. men and women age 30–65 years reported sleeping <6 hours per night on workdays (6).

Insufficient sleep has been linked to reduced insulin sensitivity and increased risk of type 2 diabetes, both in laboratory studies in healthy humans and in epidemiologic studies. A causative role of partial sleep restriction in promoting alterations in glucose metabolism was first established in 1999 (8). Intravenous glucose tolerance testing (IVGTT) following sleep restriction to 4 hours per night for five nights resulted in a 24% decrease in insulin sensitivity (Figure 25.1), as well as a 30% decrease in the acute insulin response to intravenous glucose (8,9). Moreover, an increase in the HOMA (homeostatic model assessment, an index of insulin resistance) response to breakfast was observed on the following day and occurred despite similar insulin secretory responses. These findings indicated that a state of sleep debt caused a decrease in insulin sensitivity that was not compensated by increased insulin release, leading to a more than 40% decrease in glucose tolerance compared to the fully rested condition.

FIGURE 25.1

Reduction in Insulin Sensitivity as Assessed by Intravenous Glucose Tolerance Test From Laboratory Studies Involving Sleep Restriction, Sleep Fragmentation, and Intermittent Hypoxia. h, hour; SWS, slow wave sleep.

Several subsequent, well-controlled experimental studies in healthy human subjects involving sleep restriction to 4–5.5 hours per night for 5–14 nights and assessments of glucose metabolism by IVGTT or euglycemic-hyperinsulinemic clamp have confirmed a reduction of insulin sensitivity ranging from 16% to 32% in response to sleep restriction without simultaneous increases in insulin levels, resulting in reduced glucose tolerance and an increased risk of diabetes (Figure 25.1) (10,11,12,13). A few studies that included assessments after sleep recovery found that the metabolic disturbances induced by sleep restriction were at least partially reversible (improved glucose tolerance as assessed by IVGTT (8) and a reduction in the insulin-to-glucose ratio (14)).

Further, 2 weeks of sleep extension in habitual short sleepers resulted in changes in indices of fasting insulin sensitivity that were correlated with the amount of sleep extension, with those obtaining more sleep having the largest increases in insulin sensitivity (15). Lastly, a small study indicated that three nights of in-laboratory “catch-up” sleep in men with chronic, repetitive, lifestyle-driven sleep restriction led to improved insulin sensitivity as assessed by a 2-hour frequently sampled glucose tolerance test (16).

Multiple cross-sectional epidemiologic studies have indicated that self-reported short sleep duration (usually <6 hours per night) is associated with increased odds of prediabetes and diabetes. Relevant population-based studies examining associations between these conditions of abnormal glucose tolerance and self-reported short sleep duration in the United States and Canada are listed in Tables 25.1 and 25.2. Importantly, 12 of 16 large prospective studies with a follow-up duration of 2–32 years have observed that short sleep duration is associated with an increased risk of incident diabetes (Table 25.3) (17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32). All five studies conducted in the United States, including the Nurses’ Health Study (17), National Health and Nutrition Examination Survey (NHANES) I (20), NIH-AARP Diet and Health Study (24), Massachusetts Male Aging Study (25), and Millennium Cohort by the Department of Defense (28), have found the associations. A meta-analysis including 11 of these 16 studies (total 447,124 participants) concluded that short sleep (≤5–6 hours per night) predicts the development of type 2 diabetes with a relative risk (RR) of 1.33 (95% confidence interval [CI] 1.20–1.48) (21). In addition, multiple studies, the majority of which were conducted in the United States, have found that long sleep duration (>8–9 hours per night) also predicts incident diabetes (Table 25.3) (17,20,22,24,25,30), with a meta-analysis indicating a pooled relative risk of 1.48 (33). This suggests a U-shaped relationship between sleep duration and risk of incident diabetes. The main limitation of these studies is that sleep duration was self-reported.

Only a few studies have examined the impact of insufficient sleep on glycemic control in patients with established type 2 diabetes. A questionnaire survey study of 161 African Americans with type 2 diabetes found that 3 hours of perceived sleep debt per day (i.e., a self-report of insufficient sleep duration) predicted a glycosylated hemoglobin (A1c) level of 1.1% above the median (34). The magnitude of this difference is comparable to the effect size of several U.S. Food and Drug Administration-approved diabetes medications. A U-shaped relationship may exist between sleep duration and glycemic control, with excessive sleep duration predicting poorer glycemic control. A large cross-sectional study of 4,870 Japanese participants revealed higher A1c levels in patients with self-reported sleep duration <5.5 hours per night and ≥8.5 hours per night compared to those with 6.5–7.4 hours per night (35). A study using data from the Korean National Health and Nutrition Examination Survey found a U-shaped relationship between sleep duration and fasting glucose and A1c values (36), while another study of 18,121 participants in China found that only long sleep (>9 hours) was significantly associated with poorer glycemic control (37). These findings from large studies based on self-reported sleep duration were not confirmed in the limited number of studies where sleep was measured using an objective method, such as actigraphy. Indeed, in these studies (total 91 participants), sleep duration was not found to be correlated with glycemic control in patients with type 2 diabetes (38,39). This contradiction between self-reported and objectively measured sleep duration on glycemic control could be due to a very small number of participants in the latter studies, and more research is needed to confirm the findings. Taken together, the epidemiologic evidence suggests a role of self-reported sleep duration on glycemic control in type 2 diabetes.

TABLE 25.1

Studies Exploring the Relationship Between Self-Reported Sleep Duration and Dysglycemia.

TABLE 25.2

Cross-Sectional Studies Exploring Associations Between Self-Reported Sleep Duration and Diabetes.

TABLE 25.3

Prospective Studies Exploring the Relationship Between Self-Reported Sleep Duration and Incident Diabetes.

Despite well-documented evidence for a causal relationship between sleep insufficiency and glucose metabolism, not a single interventional study to date has explored the role of sleep extension in diabetes prevention or treatment.

Sleep Fragmentation, Shallow Sleep, and Insomnia

Sleep fragmentation is a hallmark of poor sleep quality that can be objectively assessed by low sleep efficiency (a ratio of time spent asleep versus time in bed) or by a long cumulated “wake time after sleep onset [WASO]” by polysomnography (PSG), the “gold standard” diagnostic test used to study sleep patterns and circadian rhythms in the medical setting. (PSG is described in more detail in the section Obstructive Sleep Apnea: Disease Definition and Diagnosis.) Actigraphy recordings, from a device that is worn on the wrist for a week or more and is less cumbersome, also provide good estimations of sleep efficiency.

Even in the absence of sleep fragmentation, shallow sleep, as reflected polygraphically from PSG by a low amount of deep NREM sleep (also known as SWS), has also been shown to be associated with adverse metabolic consequences. A laboratory study of healthy volunteers demonstrated that SWS suppression without changes in total sleep duration results in abnormal glucose metabolism. Suppression of SWS using acoustic stimuli for three nights resulted in a 25% decrease in insulin sensitivity as assessed by minimal model analysis of a frequently sampled IVGTT (40) without a compensatory increase in insulin secretion as assessed by the acute insulin response to intravenous glucose (Figure 25.1) (41). The acoustic stimuli were calibrated as to not induce full arousals and thus not affect sleep efficiency. In a similar study, sleep fragmentation by acoustic stimuli and mechanical vibrations for two full nights was associated with a 25% decrease in insulin sensitivity (Figure 25.1) (42). The experimental manipulation resulted in a marked decrease of SWS and also of other sleep stages.

Insomnia is one of the manifestations of subjective poor sleep quality. According to Diagnostic and Statistical Manual of Mental Disorders-V criteria, insomnia symptoms include one or more of the following: a report of difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening with inability to return to sleep, or a report of unrefreshing sleep (43). Multiple cross-sectional studies in the United States have found a significant association between poor sleep quality or insomnia symptoms and prediabetes or diabetes (Table 25.4) (44,45,46,47,48). To date, 11 of 12 prospective studies have linked poor sleep quality to incident diabetes (Table 25.5) (19,26,27,28,29,49,50,51,52,53,54,55). One of the largest studies, conducted in U.S. military personnel, confirmed the association between trouble sleeping and diabetes risk (odds ratio [OR] 1.21, 95% CI 1.03–1.42) (28). Meta-analyses, pooling five of these studies, revealed that self-reported difficulty in maintaining sleep predicted the development of diabetes with a relative risk of 1.84 (total 24,192 participants), while self-reported difficulty in initiating sleep was associated with an increased relative risk of 1.57 (total 18,213 participants) (33). By comparison, estimates of the relative risk of developing diabetes associated with a family history of type 2 diabetes have ranged from 1.7 to 2.3 (56,57,58,59,60), with only one study in South African blacks estimating the relative risk at a substantially higher value of 4.1 (61). Thus, the relative risk of incident diabetes in individuals reporting insufficient sleep or difficulty initiating or maintaining sleep is of the same order of magnitude as the relative risk imparted by having a family history of type 2 diabetes, usually considered as one of the strongest predictors of diabetes risk. Interestingly, one study also found an association of poor sleep quality and an increased risk of autoimmune diabetes (53).

TABLE 25.4

Cross-Sectional Studies Exploring Associations Between Sleep Quality and Prediabetes or Diabetes.

TABLE 25.5

Prospective Studies Exploring the Relationship Between Sleep Quality or Insomnia Symptoms and Incident Prediabetes or Diabetes.

Only a few cross-sectional studies have examined the relationship between sleep quality and glycemic control in patients with type 2 diabetes. The largest study in the United States included 161 African American patients and found that in those with at least one diabetic complication (i.e., retinopathy, neuropathy, nephropathy, cardiovascular, or cerebrovascular diseases), there was a graded relationship between glycemic control as assessed by A1c and the score on the Pittsburgh Sleep Quality Index (PSQI) (34). Specifically, a 5-point increase in PSQI score predicted an elevation of A1c level of 1.9% above the median. Another cross-sectional study of 46 Taiwanese patients found an association between poor glycemic control (defined as A1c ≥7% [≥53 mmol/mol]) and poor sleep quality (PSQI ≥8), as well as poor sleep efficiency (62). Similarly, poor sleep quality as assessed by questionnaire in 551 Chinese type 2 diabetes patients found an association between lower sleep quality and higher insulin resistance as measured by HOMA-IR (63).

A few studies have utilized objective measurement of sleep quality. Knutson et al. reported a cross-sectional association between an objective estimation of sleep quality and markers of glucose metabolism in participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study (38). The sleep parameters were derived from actigraphy recordings, which have been shown to be well correlated with those obtained by PSG (64). While there were no correlations between sleep and metabolic variables in nondiabetic participants, sleep fragmentation and insomnia were associated with significantly higher fasting glucose, insulin, and HOMA levels in diabetic participants (38). Another study conducted in Italy, involving 47 patients with type 2 diabetes, reported that A1c correlates inversely with sleep efficiency as measured by actigraphy (39). Interestingly, in the NHANES 2005–2006, a study of 958 adults with prediabetes (fasting glucose 100–125 mg/dL [5.55–6.94 mmol/L], 2-hour oral glucose tolerance values of 140–199 mg/dL [7.77–11.04 mmol/L], or A1c 5.7%–6.4% [39–46 mmol/mol]) did not find a relationship between insomnia symptoms and A1c levels (65). However, those with insomnia symptoms were less active as measured by steps walked during the 2-day recordings. The findings suggest that insomnia in adults with prediabetes may be a barrier to adopting an active lifestyle.

Despite the link between poor sleep quality and diabetes risk or poor glycemic control in patients with type 2 diabetes, there has not been a single study so far exploring whether improving sleep quality may be a viable strategy to prevent diabetes or reduce its severity.

Pathways Involved in the Adverse Metabolic Impact of Insufficient Sleep and Poor Sleep Quality

Laboratory studies in healthy humans have provided evidence for the implication of multiple pathways in the link between reduced sleep duration and/or quality, insulin resistance, and hyperglycemia (Figure 25.2) (2).

Decreased Brain Glucose Utilization During Waking Hours

The brain utilizes glucose in an insulin-independent manner and is responsible for at least 50% of total glucose utilization in the fasting state. The rate of cerebral glucose metabolism as measured by positron emission tomography and ¹⁸Fluorine-2-deoxyglucose following a 24-hour period of total sleep deprivation has been found to be significantly decreased, especially in several cortical and subcortical areas (66). This is in agreement with the findings of a sleep debt study that revealed a 30% reduction in glucose effectiveness, an index of insulin-independent glucose disposal (8).

Increased Sympathetic Nervous System Activity

Sleep deprivation and sleep fragmentation lead to a shift in sympathovagal balance toward an increase in sympathetic nervous system activity as reflected by lower heart rate variability (8,41,42). Increased sympathetic nervous system activity has inhibitory effects on insulin secretion and promotes insulin resistance and the development of the metabolic syndrome (67,68). In addition, some studies have documented increased serum and urine norepinephrine and epinephrine concentrations following sleep deprivation (11,12,69). These hormones promote gluconeogenesis.

Alterations in the Hypothalamic-Pituitary-Adrenal Axis and Growth Hormone

Several studies observed an increase in salivary and serum cortisol levels following sleep deprivation, particularly in the evening and early part of the night, at the time when the levels are normally very low following the normal circadian pattern (8,12,70,71). In one study, there was no change in corticotropin (ACTH) level, suggesting an enhanced adrenal reactivity (70). Evening elevations of cortisol may promote morning insulin resistance (72). An increase in morning serum cortisol levels was also reported after sleep fragmentation (73). In a sleep debt study, growth hormone secretion was found to increase prior to sleep onset and to limit the amplitude of post-sleep onset growth hormone release (9). Prolonged nighttime exposure to growth hormone may promote hyperglycemia.

FIGURE 25.2

Pathways Linking Sleep Insufficiency and Fragmentation to Abnormal Glucose Metabolism and Type 2 Diabetes.

Increase in Systemic Inflammatory Response

Inflammatory responses to sleep deprivation have been reviewed in detail (74). Multiple studies have demonstrated increases in leukocyte and monocyte counts (75,76,77), as well as elevations in the levels of proinflammatory cytokines, including interleukin (IL)-1 beta, IL-6, IL-17, tumor necrosis factor (TNF)-alpha, and high sensitivity C-reactive protein (hsCRP) (13,78,79,80,81). Increased proinflammatory cytokines have been linked to insulin resistance (82). Some studies, however, did not observe an association between alterations in the circulating levels of some of these cytokines and sleep disturbances, possibly partly due to variability of baseline levels within the population, as well as timing of specimen collection relative to the circadian cycle (74).

Alterations in Appetite-Regulating Hormones and Increased Obesity Risk

Appetite-regulating hormones, including leptin, which is one of the satiety hormones, and ghrelin, which is a hunger hormone, have been studied in the context of sleep restriction experiments. The first study that assessed these changes involved two nights of 4 hours in bed versus two nights of 10 hours in bed in healthy, normal-weight young men (83). During sleep restriction, leptin decreased by 18% and ghrelin increased by 28%. These changes were associated with a 23% increase in hunger ratings and a 33% increase in appetite for carbohydrate-rich foods. More than 10 subsequent studies have explored these hormonal changes in response to sleep restriction with some variations in participants’ characteristics (i.e., adiposity and sex distribution), severity of sleep restriction, blood sampling methodology, and dietary protocols (ad libitum food access or controlled caloric consumption) (84,85). Not surprisingly, since leptin levels are highly sensitive to energy balance and modulated by sex and adiposity, the findings have been inconsistent, with decreased (83,86,87,88), unchanged (89,90), or increased (14,91,92,93) concentrations. However, most of the studies that utilized multiple blood samplings in normal-weight men under conditions of controlled food intake consistently revealed a reduction in leptin amplitude or mean levels, suggesting that the discrepancies may, at least in part, be due to modulation of leptin secretion by obesity, sex, and food intake. Whether the results obtained in short-term laboratory studies may be extrapolated to real-life conditions is debatable. In a field study of 80 obese adults, no associations were found between leptin levels and sleep duration or quality (94). In contrast, the Wisconsin Sleep Cohort Study (1,024 participants) found an association between reduced leptin levels, along with elevated ghrelin levels and increased body mass index (BMI), in those reporting sleeping 5 hours compared to 8 hours (95).

Multiple studies documented increased ghrelin levels along with increased hunger in response to partial sleep restriction (83,91,93), as well as increased caloric intake, mostly from snacks. Several studies have observed that the excessive caloric consumption was mostly from carbohydrate-rich foods, although increased intake of fat or of all macronutrients has also been reported (96,97,98,99,100). However, similar to the findings regarding leptin levels, not all studies observed increased ghrelin levels (11,97,101). Two studies utilizing functional magnetic resonance imaging revealed increased neuronal activity in certain brain areas involved in the reward system in response to presentation of food stimuli after total and partial sleep restriction (102,103). These imaging findings are consistent with a report showing an increase in the levels of circulating endocannabinoid 2-arachidonoylglycerol (2-AG) after three days of sleep restriction compared to normal sleep (89).

Since sleep restriction provides more wake time, it has been suggested that the caloric need of extended wakefulness may counterbalance the increase in hunger and food intake. Several studies have addressed changes in energy expenditure following sleep restriction. Surprisingly, three independent studies failed to detect an increase in energy expenditure assessed by the doubly labeled water method in individuals who underwent experimental partial sleep restriction (96,97,98). However, when the subjects were confined to a calorimetry room in order to monitor minute-to-minute energy expenditure during normal sleep and total sleep deprivation (104), the caloric cost per hour of wakefulness under sedentary conditions compared to sleep averaged only 17 Kcal, suggesting that the stimulation of hunger and food intake far exceeds the caloric need of extended wakefulness. A study involving 5 days of partial sleep restriction, similar to a work week, under controlled laboratory conditions indeed observed that the approximate 5% increase in daily energy expenditure was overcompensated by energy intake, particularly at night, resulting in significant weight gain (99). Additionally, there is evidence that the sleepiness and fatigue associated with insufficient sleep may result in a reduction in voluntary physical activity (105,106).

Collectively, these changes in appetite regulation in favor of increased hunger and food intake without commensurate increase in energy expenditure place individuals at risk for obesity. These results are supported by multiple prospective studies that found a significant association between short sleep and greater weight gain in both adults and children (107,108,109,110).

Abnormal Adipocyte Function

Adipocytes play a pivotal role in the regulation of energy balance and appear to play an important role in the changes in energy balance in response to sleep restriction (111). Leptin is released primarily from subcutaneous fat depot in direct proportion to insulin-stimulated glucose uptake and total subcutaneous fat mass (112). Increased sympathetic nervous activity leads to stimulation of lipolysis and increased free fatty acids which could lead to insulin resistance (113). A randomized crossover trial of 4 days of sleep restriction (4.5 hours per night) versus 4 days of normal sleep (8.5 hours per night) in healthy, young, lean men studied under controlled conditions of caloric intake and physical activity showed an increase in nocturnal free fatty acid levels that was correlated with the reduction in insulin sensitivity (114). In addition, elevated levels of glucocorticoids facilitate visceral fat accumulation, increased lipolysis, and insulin resistance. Molecular mechanisms involved in insulin signaling in adipocytes collected from individuals who were sleep restricted were examined by Broussard et al. (10) in a subset of the participants in the randomized crossover study of 4 days with 4.5 hours in bed versus 8.5 hours in bed. Subcutaneous fat biopsy under restricted sleep conditions revealed a 30% reduction in the ability of insulin to increase levels of phosphorylated Akt (also known as protein kinase B), a crucial early step in the insulin signaling pathway, compared to during normal sleep conditions. This impaired cellular insulin sensitivity paralleled the decrease in total body insulin sensitivity as assessed by IVGTT.

In summary, a large body of evidence supports a causal relationship between sleep insufficiency and sleep fragmentation and alterations in multiple physiologic pathways, resulting in abnormal glucose metabolism, increased diabetes risk, and possibly contributing to poor glycemic control in individuals who have prediabetes or diabetes. Further research studies should explore whether optimizing sleep duration and quality will, in the long term, result in decreased diabetes risk or improved glycemic control in patients with established type 2 diabetes.

Obstructive Sleep Apnea

Disease Definition and Diagnosis

OSA is a common sleep disorder that is characterized by recurrent episodes of complete or partial collapse of the upper airway during sleep. The cessation or reduction in airflow is often associated with decreased oxygen saturation and/or arousal from sleep. Patients with OSA present with a constellation of nocturnal symptoms that include loud disruptive snoring, bed partner-reported breathing pauses (apneas), choking and gasping episodes during sleep, and frequent awakenings. Common daytime consequences include excessive daytime sleepiness, fatigue, irritability, and deficits in attention and memory. Epidemiologic data from several community- and population-based studies from North America, Europe, and Asia indicate that sleep apnea affects approximately 3%–7% of adult men and 2%–5% of adult women (Table 25.6) (116). However, the prevalence is likely to have increased due to the increasing obesity rates. For example, between 1988–1994 and 2007–2010, the prevalence in the Wisconsin Sleep Cohort increased by as much as 55% (117). In 2007–2010, the estimates of OSA prevalence in obese adults ranged between 33% and 77% in men and between 11% and 46% in women (117). Despite the increasing body of literature recognizing the adverse health consequences and public health impact of sleep apnea, a considerable number of affected individuals remain undiagnosed (118,119).

The diagnosis of OSA is based on an overnight sleep study or a polysomnogram (PSG). It involves simultaneous recordings of several electrophysiological signals, including the right and left electrooculograms, the submental electromyogram, and the electro encephalogram (EEG). Collectively, these physiological signals are used to distinguish wakefulness from sleep and assess the distribution of various sleep stages. In addition, breathing patterns are assessed with measurements of respiratory effort, airflow, and oxygen saturation. Airflow is recorded with an oronasal thermistor (a probe sensitive to temperature changes that occur with breathing) and/or a nasal cannula configured to monitor pressure changes in the nasal airway. The PSG also includes other measurements, such as continuous electrocardiography, which is used to detect occurrence of cardiac arrhythmias during sleep. The analysis of the PSG for OSA requires identification of abnormal or disordered breathing patterns during sleep. Two basic types of disordered breathing events are assessed: apneas and hypopneas (Table 25.7). An apnea is defined as the complete cessation of airflow for at least 10 seconds. A hypopnea is defined as a reduction in airflow that is associated with an EEG arousal or a decrease in oxygen saturation (120).

TABLE 25.6

Studies on the Prevalence of Obstructive Sleep Apnea.

TABLE 25.7

Types of Disordered Breathing Events During Sleep.

Disordered breathing events are further classified into obstructive, central, or mixed events. The classification of an abnormal breathing event is dependent on whether, in the absence of oronasal airflow, there is evidence of respiratory effort. An obstructive event is defined as the absence of airflow in the presence of continued effort. In contrast, a central event is defined as the absence of airflow without associated effort. Finally, a mixed event manifests characteristics of an obstructive and a central event. Mixed events typically start with a period that meets the criteria for a central event but end with increasing effort but without associated airflow. Figure 25.3 illustrates tracings of the three types of abnormal breathing patterns (obstructive, central, and mixed apneas) during sleep (121). PSG yields a quantification of episodes of apnea and hypopnea per hour of sleep, an apnea-hypopnea index (AHI). A diagnosis of OSA is made when the AHI is ≥5.

Obstructive Sleep Apnea and Metabolic Dysfunction

In addition to reductions in sleep duration and quality, intermittent hypoxia is the hallmark of OSA. Only one experimental study in humans has examined the impact of intermittent hypoxemia on glucose metabolism. In this study, 13 healthy volunteers were subjected to 5 hours of intermittent hypoxia while awake, resulting in an average of 24.3 desaturation events per hour (122), equivalent to hypoxia in OSA of moderate severity (AHI ≥15–30). Insulin sensitivity and glucose effectiveness, as assessed by IVGTT, were reduced by 17% and 31%, respectively, without simultaneous increase in insulin secretion. These results suggest that hypoxic stress may have an intrinsic adverse impact on glucose metabolism and diabetes risk.

FIGURE 25.3

Types of Disordered Breathing Events. Three-minute recordings characteristic of obstructive, central, and mixed apneas during sleep. Traces shown represent oxyhemoglobin saturation, airflow, and thoracic and abdominal movement.

Over the last two decades, a number of observational studies have demonstrated that OSA is associated with insulin resistance, glucose intolerance, type 2 diabetes, and the metabolic syndrome, independent of such factors as age, sex, race, BMI, and measures of visceral adiposity (Tables 25.8 and 25.9). Epidemiologic data from community- and population-based cohorts, including the Sleep Heart Health Study (123) and the Wisconsin Sleep Cohort Study (124), have shown that the severity of OSA, as assessed by the AHI, is directly associated with fasting hyperglycemia, glucose intolerance, and the prevalence of physician-diagnosed type 2 diabetes. Irrespective of the method used for assessing insulin sensitivity, a majority of published reports indicate that the severity of OSA (i.e., AHI) is inversely related to the degree of insulin sensitivity. Moreover, metrics of nocturnal hypoxemia (e.g., oxyhemoglobin desaturation and average oxygen saturation during sleep) strongly correlate with the degree of whole body insulin resistance (Table 25.8).

TABLE 25.8

Studies on the Association Between Obstructive Sleep Apnea and Measures of Insulin Resistance.

To date, nine prospective cohort studies, with approximately 65,000 participants, have been conducted to explore whether the presence of OSA, using objective sleep assessments, at baseline predicted incident diabetes during a follow-up, after adjusting for BMI or other measures of adiposity and other confounders (Table 25.10) (28,124,125,126,127,128,129,130,131). The studies varied in the methods and criteria used to diagnose OSA (pulse oximetry vs. full or limited PSG, and cutoff for AHI/oxygen desaturation index), verification of diabetes diagnosis, and duration of follow-up period (2.7–16 years). A meta-analysis including five of these studies (total 5,953 participants) revealed that moderate to severe OSA was associated with a significantly greater risk of developing diabetes, with a relative risk of 1.63 (95% CI 1.09–2.45), compared to those without OSA (132). In those with mild OSA (AHI <15), the relative risk was 1.22 (95% CI 0.91–1.63), but this was not statistically significant. These data strongly support the concept that the presence of moderate to severe OSA is a risk factor for diabetes development independent of other confounding factors.

TABLE 25.9

Studies on the Association Between Obstructive Sleep Apnea, Glucose Tolerance, Type 2 Diabetes, and the Metabolic Syndrome.

In patients with an established diagnosis of type 2 diabetes, who were generally obese, OSA was shown to be highly prevalent, from a lowest estimate of 58% to a highest estimate of 86%, based on seven independent studies involving a total of 1,272 participants (Figure 25.4) (133,134,135,136,137,138,139). The weighted average was 67%.

This proportion is alarming given that, in 2011, 20.9 million Americans were estimated to have diabetes, which could possibly translate to as many as 14 million individuals suffering from both diabetes and OSA. Unfortunately, this highly prevalent comorbidity of type 2 diabetes often remains unrecognized. A retrospective analysis of 27 primary care practices involving 16,066 diabetes patients found that only 18% were diagnosed with OSA, suggesting that a majority of diabetic patients may not be diagnosed, and therefore, their OSA is left untreated (140).

TABLE 25.10

Prospective Studies on the Relationship Between Obstructive Sleep Apnea and Incident Diabetes.

FIGURE 25.4

Prevalence of Obstructive Sleep Apnea Among Persons With Type 2 Diabetes. Obstructive sleep apnea was assessed by polysomnogram in all studies.

Similar to nondiabetic populations, the severity of untreated OSA is associated with poorer glycemic control in diabetic populations. Aronsohn et al. utilized PSG to assess OSA severity in 60 diabetic patients (133). There was a graded relationship between the severity of untreated OSA as measured by AHI and higher A1c levels after adjusting for age, sex, race, BMI, years of diabetes, numbers of diabetes medications, exercise, and total sleep time, with an effect size as large as that associated with the impact of diabetes drugs. Another cross-sectional study in 52 diabetic patients also found that increased severity of OSA was associated with increased A1c levels, after adjusting for age, sex, BMI, diabetes duration, and insulin dose (139). Adjusted mean A1c was 8.6% (70 mmol/mol) in those without OSA, 9.4% (79 mmol/mol) in mild OSA, 10.6% (92 mmol/mol) in moderate OSA, and 9.9% (85 mmol/mol) in severe OSA. However, not all of the studies supported a link between OSA severity and glycemic control. The Sleep AHEAD study, involving obese type 2 diabetes patients, analyzed the relationship between sleep and metabolic parameters in 305 subjects (141). The only significant association was an inverse correlation between fasting glucose levels and sleep efficiency, but not AHI or other sleep variables. A limitation of this study is that PSG was performed in the homes of the participants and, thus, was often of lower quality and shorter duration than in the laboratory.

Altogether, evidence supports an adverse impact of OSA on glycemic control in patients with type 2 diabetes. As differences in A1c levels among patients with different degrees of severity of OSA are comparable to the effect size of the most powerful combinations of available diabetes medications, multiple studies have attempted to determine whether OSA treatment with CPAP in patients with diabetes improves glycemic control, as discussed later in this chapter.

Mechanistic Links Between Obstructive Sleep Apnea and Metabolic Dysfunction

If the link between OSA and abnormalities in glucose metabolism is eventually proven to be causal, what are the potential mechanisms that underlie the association? Most likely, alterations in glucose homeostasis induced by OSA are mediated by a complex set of interactive mechanisms that are triggered by the cyclical hypoxemia and recurrent arousals from sleep (Figure 25.5) (168). In the sections that follow, physiological systems that may play an important role in mediating the effects of OSA on glucose metabolism are highlighted. Particular focus is given to the sympathetic nervous system, the hypothalamic-pituitary-adrenal (HPA) axis, formation of reactive oxygen species (ROS), and low-grade systemic inflammation. It is important to recognize that for each physiological system influenced by OSA, intermittent hypoxemia and sleep fragmentation may perturb the system independently or synergistically.

FIGURE 25.5

Putative Mechanisms Linking Sleep Apnea to Type 2 Diabetes.

Role for the Sympathetic Nervous System

Compared to normal subjects, patients with OSA exhibit higher levels of sympathetic nervous system activity not just during sleep, but also during wakefulness (169). The decrease in oxyhemoglobin saturation and the concurrent increase in carbon dioxide with each disordered breathing event elicit a chemoreflex-mediated surge in sympathetic activity (170,171). Observational and experimental studies have demonstrated that even brief arousals from sleep can lead to a surge in sympathetic activity (172,173). Thus, intermittent hypoxemia and recurrent arousals from sleep can shift autonomic balance in patients with OSA. Although the exact mechanisms through which sympathetic activation affects insulin sensitivity are not well defined, there is little doubt that it has a central role in the regulation of glucose and fat metabolism (174). Catecholamines reduce insulin sensitivity and insulin-mediated glucose uptake (175). Administration of epinephrine in normal subjects can decrease insulin-mediated glycogenesis, increase glycolysis, and dampen the ability of glucose to stimulate its own disposal (176,177). Higher levels of sympathetic activity have lipolytic effects through signaling pathways that activate hormone-sensitive lipase, which can mobilize nonesterified fatty acids (178). An abrupt increase in circulating free fatty acids can worsen insulin sensitivity, while a decrease can improve insulin sensitivity, hyperinsulinemia, and glucose tolerance (179,180). In addition to the above effects, activation of the sympathetic nervous system can lead to systemic vasoconstriction, which can also affect glucose metabolism. A decrease in vascular lumen size in skeletal muscle from vasoconstriction shunts glucose and insulin to less metabolically active areas of skeletal muscle (181) and, thus, decreases overall glucose uptake (182). Sympathetic activation can also alter skeletal muscle morphology to a more insulin resistant type (183), inhibit insulin signaling, and decrease insulin-mediated glucose uptake by adipocytes (184). Thus, there is sufficient basis to speculate that an increase in sympathetic nervous system activity due to recurrent intermittent hypoxemia and sleep fragmentation plays a central role in altering glucose metabolism in sleep apnea.

Role of the Hypothalamic-Pituitary-Adrenal Axis

Recurrent intermittent hypoxemia and arousals in OSA could alter glucose metabolism by modulating the function of the HPA axis. Specifically, a stress-related increase in HPA activity and cortisol secretion could lead to insulin resistance and hyperglycemia. Observational data from studies of high altitude or of hypobaric conditions indicate that hypoxia modifies the diurnal pattern of the HPA axis and increases circulating cortisol (185,186,187,188,189,190,191). Moreover, brief arousals or sustained awakenings from sleep can activate the HPA axis and can further augment corticotropic function (192,193). However, experimentally induced micro-arousals designed to selectively suppress SWS for three consecutive nights in healthy young adults had no significant impact on the 24-hour profile of cortisol levels, despite an overall sleep fragmentation in the range of that associated with moderate to severe OSA (41). A notable limitation in many of the available studies on HPA axis activity in OSA is that corticotropic function was assessed with a single measurement of serum cortisol. While convenient, isolated cortisol measurements cannot reveal diurnal changes or the temporal variability in cortisol secretion.

Characterizing HPA dysfunction in OSA has scientific and clinical relevance, as it would help clarify its putative role in mediating insulin resistance and glucose intolerance. It is well established that cortisol and other glucocorticoids interfere with glucose metabolism at several different levels (194,195). Cortisol increases hepatic gluconeogenesis and causes protein degradation. It also activates lipoprotein lipase, which mobilizes nonesterified fatty acids and can greatly diminish insulin sensitivity. Moreover, cortisol inhibits beta cell secretion of insulin and sequentially modifies multiple aspects of the insulin-mediated glucose transport system. In a small study of CPAP treatment of OSA in obese women with the polycystic ovary syndrome, there was a trend for reduced evening cortisol concentrations following CPAP (196). Given the myriad of adverse metabolic effects of HPA dysfunction, further research is needed to determine whether OSA affects HPA activity and, thus, alters glucose metabolism function.

Reactive Oxygen Species as a Causal Intermediate

Repetitive cycles of hypoxemia followed by re-oxygenation in OSA could increase ROS production similar to what has been observed with ischemia-reperfusion injury (197,198). Data indeed suggest that OSA is associated with higher concentrations of ROS that may, in turn, negatively influence glucose metabolism. Using study samples of modest size along with assessments before and after initiation of CPAP therapy, a number of studies have shown abnormalities in lipid peroxidation, higher isoprostane levels, and elevated markers of DNA oxidation in patients with OSA compared to normal subjects and a decline in these markers after treatment with CPAP (199,200,201,202,203). Moreover, antioxidant defenses may also be diminished in OSA (204,205). Finally, a number of in vitro studies have shown that apneic patients have increased adhesion molecule expression and production of ROS in leukocytes (206), an augmented release of neutrophil superoxide (207), and increased oxidized low-density lipoprotein (LDL) autoantibodies (208).

Excessive concentrations of ROS can be harmful particularly to the pancreatic beta cell given that this cell population is relatively low in antioxidant enzyme mechanisms, such as catalase, glutathione peroxidase, and superoxide dismutase (209). ROS formation is also accompanied by an inhibition of insulin-stimulated substrate uptake in insulin-sensitive tissues, such as muscle and adipose tissue (210,211,212). Moreover, several studies also suggest that pharmacological doses of the antioxidants vitamin E, vitamin C, and lipoic acid in healthy volunteers and diabetic patients may improve insulin sensitivity and metabolic control (213,214,215,216). While mechanisms underlying the effects of an altered redox state on insulin sensitivity require further elucidation, several converging lines of evidence, including clinical and experimental data, indicate that oxidative stress is a causative factor. Thus, OSA-associated increase in free radical generation could represent a causal component for the development of insulin resistance.

Importance of Systemic Inflammation and Adipocytokines

Low-grade systemic inflammation may be yet another mechanism relating OSA to disorders of glucose metabolism. Compared to normal subjects, patients with OSA have higher levels of circulating adhesion molecules (217,218,219,220,221,222) and inflammatory cytokines, including IL-6 and TNF-alpha, which decrease with CPAP therapy (223,224,225,226). Studies examining specific leukocyte populations also reveal that OSA patients exhibit monocyte and lymphocyte activation, which improve with CPAP therapy (227,228,229). In normal subjects, hypoxia increases circulating leukocyte concentration and alters the functional characteristics of lymphocytes (230,231,232). Sympathetic hyperactivity in sleep apnea may also influence the innate immune response given that adrenergic stimulation enhances macrophage and lymphocyte activity and alters their proliferation, circulation, and cytokine production (233,234). A concern in invoking systemic inflammation as an intermediate between OSA and metabolic dysfunction is the confounding effects of obesity. Adipose tissue can increase systemic inflammation, as visceral adiposity has an enhanced capacity to produce numerous cytokines, including IL-6 and TNF-alpha. However, it appears that even after considering the effects of BMI and measures of visceral obesity, sleep apnea severity is independently correlated with the degree of inflammatory burden (235). Thus, low-grade systemic inflammation could potentially mediate the adverse metabolic effects of OSA.

In addition to the systemic inflammation, adipocyte-derived factors, such as leptin, adiponectin, and resistin, may play a role in the genesis of sleep apnea-related abnormalities in glucose metabolism. Leptin regulates hunger and weight gain by increasing anorexigenic and decreasing orexigenic neuropeptides in the hypothalamus (236). Peripherally, leptin appears to be involved in governing glucose homeostasis (237,238). A growing body of literature shows that patients with sleep apnea have higher leptin levels (239,240,241,242,243,244,245), which decrease with CPAP therapy independent of any changes in body weight (246,247,248,249). Moreover, exposure to hypoxic conditions increases leptin levels in normal subjects (250). Thus, higher leptin levels in OSA could certainly alter glucose metabolism. Adiponectin has endogenous insulin-sensitizing properties. Adiponectin is lower in patients with sleep apnea than in normal subjects, and circulating levels appear to correlate with the nadir in oxygen saturation (251,252,253,254,255,256,257). Resistin is another adipocytokine that inhibits insulin action and may have a role in the pathogenesis of type 2 diabetes (258,259). At present, there are limited data on whether resistin levels differ between patients with OSA and control subjects (251,260,261). Clearly, additional work is needed to determine whether adiponectin and resistin are affected by intermittent hypoxemia and recurrent arousals and whether these adipocytokines could be involved in causing metabolic dysfunction in OSA.

Sleep Disturbances During Pregnancy: Relationship With Glucose Metabolism and Gestational Diabetes

Sleep alterations are common during pregnancy due to hormonal and physical changes. Progesterone has sedative effects and can stimulate respiratory drive, while estrogen increases hyperemia, mucosal edema, and upper airway resistance, resulting in nasal stuffiness and snoring (272). Upward displacement of the diaphragm may cause a reduction in functional residual volume of the lungs and, therefore, oxygen reserve. Nausea, vomiting, frequent urination, and backache can decrease sleep efficiency and increase nocturnal awakenings.

During the first trimester, sleepiness is common, and women report an increase in sleep duration of approximately 0.7 hours (273). However, sleep efficiency and percentage of SWS decrease significantly (274). Sleep duration decreases in the late second trimester (274), although there is an observed increase in percentage of SWS (275). During the third trimester, a majority of women report sleep disturbances. There is a decrease in percentage of SWS and REM sleep (272) with an increase in time spent in light NREM sleep (stage N1) (276). Wake time after sleep onset increases, but total sleep time approximates the prepregnancy state (274). At this stage of pregnancy, a majority of women report taking daytime naps (277). Snoring is quite common, as two large studies, including in total more than 2,700 pregnant women, revealed that about one-third of participants reported snoring, with 25% reporting pregnancy-onset snoring (278,279). Symptoms of OSA increased during pregnancy in a prospective study, especially in women whose BMI exceeded 25 kg/m² (280).

Gestational diabetes mellitus affects 2%–25% of pregnant women and is associated with adverse maternal-fetal outcomes, as discussed in Chapter 4 Gestational Diabetes. An increased risk for gestational diabetes or hyperglycemia is associated with sleep disturbances, including OSA and snoring, short sleep duration, and increased daytime sleepiness. A review of the literature found 15 studies that investigated sleep and glucose intolerance in pregnancy: eight using questionnaires, six using objective sleep measurements, and one using both methods (Table 25.11) (278,279,281,282,283,284,285,286,287,288,289,290,291,292,293). Seven studies assessed sleep duration (five by self-report, one by combined self-report and PSG, and one by actigraphy) (281,282,284,286,289,290,293). Of these seven studies, four found a significant association between short sleep duration and increased risk for gestational diabetes/hyperglycemia (281,282,284,290). Twelve studies assessed symptoms of OSA or a diagnosis of OSA (278,279,281,282,283,284,287,288,289,291,292,293). Of the eight studies using questionnaires, five found significant associations between OSA symptoms and gestational diabetes or maternal hyperglycemia (279,281,282,284,289). Among the six studies using objective measurements (five used PSG and one used portable home monitoring) (287,288,289,291,292,293), four found a significant association between OSA and increased gestational diabetes/hyperglycemia risks (287,288,291,292). A meta-analysis included nine of these studies (total 9,795 participants) and found a significant association between OSA and gestational diabetes, with an odds ratio of 2.18 (95% CI 1.59–2.99) (294). When considering only studies including BMI as a covariate, the adjusted odds ratio was 3.06 (95% CI 1.89–4.96). One study found an association between severe daytime sleepiness and gestational diabetes, although the number of women with severe daytime sleepiness was small (285). In addition, increased daytime napping was found to be associated with maternal hyperglycemia in one study (289). The mechanisms by which sleep disturbances increase the risk for gestational diabetes are likely to overlap those linking sleep disturbances and metabolic alterations in nonpregnant populations but have not been studied specifically in pregnancy.

Short sleep, snoring, and OSA in pregnancy have been linked to other adverse maternal and fetal outcomes, including an increased risk of preeclampsia, gestational hypertension (GHTN), preterm birth, and unplanned caesarean delivery (278,279,288,295,296,297). A meta-analysis revealed an association between sleep-disordered breathing and GHTN, with an odds ratio of 2.34 (95% CI 1.60–3.03), as well as with low birth weight, with an odds ratio of 1.39 (95% CI 1.14–1.65) (298). Oxidative stress, release of proinflammatory cytokines, increased sympathetic activation, peripheral vasoconstriction, and endothelial dysfunction resulting from sleep disturbances are all likely to contribute to these complications (299).

Treatment with CPAP has been shown to be safe during pregnancy and to improve blood pressure control and pregnancy outcomes in women with hypertension and chronic snoring (300). The question of whether treating OSA during pregnancy improves glucose metabolism is crucial as maternal glycemia affects fetal health, but it has not yet been addressed.

TABLE 25.11

Studies Investigating the Association Between Sleep in Pregnancy and Gestational Diabetes or Hyperglycemia.

The Circadian System and Glucose Metabolism

The circadian system, controlled by the master circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, plays a major role in regulating daily rhythms of sleep/wake cycle, feeding behavior, central and peripheral tissue metabolism, and hormonal secretions (301). The clock in the SCN is synchronized to the 24-hour day primarily by light signal via the retinohypothalamic tract. It then relays the information via hormonal and neuronal pathways to the rest of the brain and to peripheral organs, such as the heart, liver, adipose tissue, muscle, adrenals, and pancreas, which all possess “peripheral clocks,” leading to coordinated rhythms and behaviors (Figure 25.6) (2,302). The central clock mechanism consists of a transcription-translation negative feedback loop involving several core clock genes including Clock (circadian locomotor output cycles kaput), Bmal1 (brain and muscle Arnt-like protein-1), Per 1–3 (Period 1–3), and Cry 1–2 (Cryptochrome 1–2), as well as feedback signals from nutrient intake (303).

There is evidence that circadian disruption has detrimental effects on energy metabolism. It was first shown that Clock mutant mice shift their feeding and activity behavior to their normally inactive phase and develop obesity and the metabolic syndrome (hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia) (304). Habitual sleep duration in this mutant animal is about 1 hour shorter than in the wild type animal, thus resulting in a condition of lifelong insufficient sleep (304). In another study, wild type mice exposed to dim light during their usual biological night were shown to shift their food intake into the inactive phase. This was associated with reduced glucose tolerance and a greater gain in body mass, suggesting that eating at an adverse circadian time may contribute to metabolic dysfunction (305).

In humans, living in modern industrialized societies with 24-hour access to light coupled with work/social obligations often leads to behaviors that are inappropriately timed relative to endogenous circadian rhythms. This mismatch in timing is termed “circadian misalignment.” Night shift work is an example of severe circadian misalignment, as workers are awake, active, and eating during their biological night and trying to sleep and fast during their biological day. In 2004, 14.8% of all workers in the United States had work schedules differing from a daytime schedule (306). This proportion was much higher for workers in service occupations, such as security (50.6%), and for health care professionals (38.3%). Shift work is associated with abnormal glucose metabolism, including IGT and diabetes. In a retrospective study of 6,413 participants in Japan followed for 9.9 years, two groups of rotating shift workers with slightly different schedules both had a significantly increased risk of developing IGT (defined as A1c ≥5.9% [≥41 mmol/mol]) with hazard ratios of 1.78 (95% CI 1.49–2.14) and 2.62 (95% CI 2.17–3.14) (307). In addition, longer duration of shift work, in a dose response fashion, was associated with a gradual increase in A1c levels over time in those without diabetes at baseline (308). Most cross-sectional studies, all outside the United States, have also found an association between shift work and prevalence of diabetes (Table 25.12).

FIGURE 25.6

Illustration of the Circadian System Regulation. SCN, suprachiasmatic nuclei.

To date, 11 of 12 prospective and retrospective cohort studies demonstrated that shift work was associated with an increased risk of developing diabetes (Table 25.13) (29,30,309,310,311,312,313,314,315,316,317,318). The largest study, the Nurses’ Health Study I and II, followed 177,184 participants for 18–20 years and found that those who worked rotating night shifts had increased hazard ratios for diabetes of 1.03–1.24, after adjusting for traditional diabetes risk factors, as well as BMI, with higher risk in those who had a longer duration of shift work compared to those reporting no shift work (314). The risk was estimated to be a 5% increase for every 5 years of shift work. Night shift work was found to be associated with incident diabetes in participants of the Black Women’s Health Study (2005–2013), with increasing risk according to the number of years night shift work was performed (HR 1.17, 95% CI 1.04–1.31, for 1–2 years; HR 1.23, 95% CI 1.06–1.41, for 3–9 years; and HR 1.42, 95% CI 1.19–1.70, for ≥10 years) (318).

There may be several reasons why shift workers are at higher risk for developing diabetes. Besides circadian misalignment, insufficient sleep and poor sleep quality, themselves associated with increased diabetes risk, are very common among shift workers. Compared to day workers, shift workers have higher rates of obesity and more unfavorable lifestyle factors, including physical inactivity, alcohol consumption, and habitual smoking (313,315,319). In addition, there is evidence for excessive total energy intake (319), although it is not consistent (320,321). Adjusting for adiposity and lifestyle factors attenuated the relationship between shift work and diabetes in some studies, but significant residual effects remained (312,313,314,315). One meta-analysis of cohort studies revealed that shift work was associated with incident diabetes with an odds ratio of 1.12 (95% CI 1.06–1.19) (322), while another found a pooled adjusted relative risk for rotating shift work of 1.15 (95% CI 1.06–1.25) (323). Although the magnitude of the increased risk associated with shift work was relatively modest when other risk factors were controlled, the findings suggest that shift work may compound the risk imparted by traditional risk factors.

TABLE 25.12

Cross-Sectional Studies Exploring Associations Between Shift Work and Diabetes.

TABLE 25.13

Cohort Studies of the Relationship Between Shift Work and Incident Diabetes or Impaired Glucose Tolerance.

Human experiments in controlled laboratory settings have provided insights into metabolic alterations under experimentally induced circadian misalignment. Ten healthy adults underwent a 10-day laboratory protocol that involved sleeping and eating on a 28-hour “day.” Circadian misalignment, when the participants ate and slept 12 hours out of phase from their habitual times, was associated with a 6% increase in glucose levels despite a 22% increase in insulin concentration. Further, leptin levels decreased. Three subjects had postprandial glucose responses in a prediabetic range (324). Another carefully conducted experiment combined sleep restriction with circadian disruption and involved 24 participants studied for more than 5 weeks in a controlled laboratory setting (325). After 3 weeks of sleep restriction to 5.6 hours per day sleep and recurring 28-hour “days,” fasting and postprandial glucose levels were increased by 8% and 14%, respectively. These changes were apparently caused by decreased beta cell function, as plasma insulin decreased by 12% during fasting and 27% after meals. The metabolic derangements returned to baseline levels after 9 days of sleep recovery. There is also evidence that adverse effects of circadian misalignment on glucose metabolism can occur independently of sleep loss. Experimental circadian misalignment with sleep restriction (5 hours) in healthy volunteers led to a reduction in insulin sensitivity and an increase in inflammatory markers, compared to sleep-restricted participants who maintained regular nocturnal bedtimes, despite nearly identical sleep duration between the two groups (13). In addition, a 6-day simulated shift work experiment in 14 healthy adults found reduced total daily energy expenditure during nightshift schedules, as well as in response to dinner consumed late at night (326). Lastly, an experimental study designed to distinguish the effects of the behavioral cycles (sleep/wake, fasting/feeding, and activity schedules), the endogenous circadian system, and circadian disruption on glucose and lipid metabolisms was conducted in 14 volunteers (327). The protocol involved two 8-day crossover studies when the behavioral cycles were aligned or misaligned (12-hour shift) with endogenous circadian rhythms. Glucose tolerance was assessed at 8 a.m. and 8 p.m. in response to an identical mixed meal. Postprandial glucose levels were 17% higher in the biological evening than in the morning, and the early phase postprandial insulin response was 27% lower in the biological evening, indicative of insufficient beta cell response. This endogenous circadian effect was much larger than that of the behavioral cycle effect. In addition, circadian misalignment (12-hour behavioral cycle inversion) increased postprandial glucose levels by 6% despite a 14% higher late phase postprandial insulin response, suggesting reduced insulin sensitivity during misalignment. This study reveals potential mechanisms by which shift workers who are awake and eating during their biological night may increase the risk of weight gain, obesity, and diabetes (326).

In patients with established diabetes, shift work may be associated with poor glycemic control, but the data are scarce. In a small study of 32 patients with diabetes, there were no differences in glycemic control between those working day and shift schedules (328). However, after being moved to a rotating shift pattern, insulin-treated patients had significant deterioration in their glycemic control after 6 months. In another study of 120 day and 120 shift workers in Thailand, fasting glucose levels were significantly lower in day compared to shift workers (329). A larger study was conducted in 296 type 1 diabetes patients in the United Kingdom, 23% of whom performed shift work (330). A1c levels were significantly higher in shift compared to day workers with a mean 9.02% (75 mmol/mol) versus 8.35% (68 mmol/mol) (p<0.01). As the world now requires a 24-hour workforce, while the number of diabetes patients and the cost of care are increasing, attention should be paid to the metabolic health of shift workers. Pharmacotherapy improves alertness and sleep quality in those with shift work disorders, including melatonin (to improve daytime sleep) and modafinil or armodafinil (wake-promoting agents) (331). It is unknown whether these agents also help improve glucose metabolism in shift workers, but a placebo-controlled study of the metabolic impact of 1 week of sleep restriction found no beneficial effect of modafinil (12). Interestingly, a study in 43 workers on different shift schedules found that those with fast clockwise direction of shift work had lower fasting glucose levels and HOMA index than those with slow counterclockwise rotation and day workers (332). The study is limited by the small sample size, and the results need to be confirmed in a larger study.

Many individuals in modern society experience a form of mild circadian misalignment, especially during the work or school week, as they follow social rhythms imposed by professional obligations, school schedules, family, and other commitments rather than their own biological rhythms (333). The degree of misalignment is dependent on the individual’s “chronotype” (333). Chronotype is a construct that captures an individual’s preference for being a “morning” or “evening” person. Late chronotype is typically associated with a greater degree of misalignment between social rhythms and the circadian clock (333). Chronotype can be evaluated in several ways. In 1976, Horne and Ostberg developed the Morningness-Eveningness questionnaire to categorize respondents into five types (definitely morning, moderately morning, neither morning nor evening, moderately evening, and definitely evening) (334). These chronotypes correlate with the participants’ circadian timing of core body temperature. The core body temperature minimum is a classic phase marker and usually occurs during the second half of the habitual sleep period (334). Subsequently, Roenneberg et al. proposed the mid-sleep time on free days (MSF) as a metric of chronotype. MSF is derived from mid-sleep time (midpoint between sleep start and wake time) on weekend nights with further correction for calculated sleep debt, with the assumption that sleep timing on days when unconstrained by the social clock would more accurately reflect the underlying phase of the circadian system (335,336). A large cross-sectional study in Finland involving 4,589 participants found that those who were evening types had an odds ratio of 2.5 (95% CI 1.5–4.4) for type 2 diabetes compared to morning types. This association was independent of sleep duration and sleep sufficiency (337). Two separate cohorts (1,244 and 483 participants, respectively) provided similar findings, where eveningness was associated with increased risk of the metabolic syndrome (OR 1.4 and OR 2.2, respectively) (338,339) and diabetes (OR 2.0) (339). In addition, several genetic studies have shown that individuals carrying specific variants of the canonical circadian genes Clock and Bmal-1 had evening preference, resistance to weight loss, the metabolic syndrome, and susceptibility to type 2 diabetes (340,341,342).

Furthermore, evening chronotype in nondiabetic individuals was found to be associated with unfavorable cardiometabolic profiles (343). A study involving 119 obese short sleepers (≤6.5 hours per night) revealed that eveningness was associated with eating later and larger food portion size, an increase in BMI, and lower high-density lipoprotein (HDL) cholesterol level. Evening types were also found to have more sleep apnea and higher stress hormones. These results are suggestive of a higher risk of cardiovascular disease in this population.

The first study to address the contribution of chronotype on glycemic control in patients with type 2 diabetes involved comprehensive questionnaires to assess sleep and eating habits in 194 non-shift worker participants who all had an established diagnosis of diabetes (344).

After adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetic complications, and perceived sleep debt, chronotype, as assessed by MSF, was significantly associated with glycemic control (Figure 25.7). The difference in median A1c between participants in the 4th quartile of MSF compared to the 1st quartile was approximately 1.3%, a remarkably strong effect size. Besides having significant later bedtime/wake time and poorer glycemic control, participants with later chronotype were more depressed, had a higher BMI, and were significantly more likely to require insulin. This finding suggested that patients with type 2 diabetes who have a late chronotype may be more hypoinsulinemic, consistent with the findings in the Clock mutant mice. Subsequently, two studies in Japanese type 2 diabetes patients (total 826 participants) found that more evening preference as assessed by questionnaire was associated with higher A1c and lower HDL cholesterol levels, as well as poorer sleep quality (345,346).

Another neurohormone that plays an important role in circadian regulation is melatonin, secreted by the pineal gland. Its secretion is modulated by the light-dark cycle via the retinohypothalamic tract and the SCN and by the sympathetic nervous system (347). Melatonin is released during the biological night and inhibited by light exposure. Melatonin secretion follows a diurnal pattern with low levels during the day, an abrupt increase 1–2 hours before habitual bedtime, high levels throughout the night, and a progressive decrease initiated prior to habitual wake-up time (348,349). Melatonin exerts its effects through membrane receptors belonging to the class of G-protein coupled receptors (350). In mammals, there are two receptor isoforms: MT1 and MT2 (found in the brain, SCN, retina, and peripheral tissues) (351). Melatonin can entrain circadian rhythms due to the presence of MT1 and MT2 receptors in the SCN (352). In addition, both isoforms of melatonin receptors are found in the pancreatic beta cells and alpha cells (350), and melatonin has been shown to modulate insulin secretion through rather complex cascades involving several secondary messengers and possibly through alpha cell stimulation (350,353). Therefore, melatonin may act as a mediator between the central circadian regulation and peripheral metabolism, as well as an internal signal synchronizing the central circadian clock and clocks in peripheral tissues. A review has suggested that the increased duration of exposure to light that is common in modern society may inhibit melatonin release and disrupt seasonal cycles. The authors further suggest that these factors could be involved in causing metabolic disturbances (354).

FIGURE 25.7

Median A1c Levels Across Quartiles of Mid-Sleep Time on Free Days. Those with later chronotypes had significantly higher A1c levels and later bedtimes/wake times than those with earlier chronotypes. Error bars represent interquartile ranges. Conversions (more...)

Genetic studies have linked the gene encoding MT2, MTNR1B, to abnormal glucose metabolism and diabetes risk (355,356,357,358). In a study involving 19,605 Europeans, the MTNR1B intronic variant, rs10830963, was associated with a significantly increased risk of impaired fasting glucose with an odds ratio of 1.6 (355). In addition, analyses in subgroups of this population revealed an association of this genetic variant with increased type 2 diabetes risk with odds ratios of 1.19 (95% CI 1.08–1.32) (French case-control study) and 1.23 (95% CI 1.10–1.37) (Danish case-control study). This allele was associated with decreased insulin secretion after oral and intravenous glucose challenges. Another study in 1,276 healthy individuals of European ancestry revealed that this MTNR1B variant was associated with higher fasting glucose levels, decreased early insulin response, and decreased beta cell glucose sensitivity as evaluated by an oral glucose tolerance test (OGTT) and a euglycemic-hyperinsulinemic clamp (356). Because the effect of this allele on diabetes risk was modest, a large-scale exon resequencing was conducted in 7,632 Europeans, including 2,186 individuals with type 2 diabetes (359). This identified 40 nonsynonymous variants, including 36 very rare variants, which were associated with a much higher increased risk for type 2 diabetes (OR 3.31, 95% CI 1.78–6.18). Among the rare variants, those with partial or total loss of function (i.e., complete loss of melatonin binding and signaling capabilities), but not the neutral ones, significantly contributed to diabetes risk (OR 5.67, 95% CI 2.17–14.82).

A well-documented epidemiologic study demonstrated a link between low nocturnal melatonin secretion and development of diabetes (360). In this case-control study nested within the Nurses’ Health Study Cohort, 370 women who developed type 2 diabetes during a follow-up of 10–12 years were matched with 370 controls. Women with the lowest baseline urine secretion of 6-sulfatoxymelatonin, a major metabolite of melatonin, had an increased risk of subsequent diabetes development with an odds ratio of 2.17 (95% CI 1.18–3.98) compared to those with the highest levels, after adjusting for demographic factors, lifestyle habits, sleep duration, snoring, and biomarkers of inflammation and endothelial dysfunction. The authors postulated several mechanisms by which low melatonin may be associated with diabetes, including reduced sleep duration and sleep apnea, which are known to be associated with low melatonin levels (361,362) but could not be accurately captured by the study questionnaires.

Increasing melatonin level by exogenous supplementation in patients with diabetes was tested in a randomized, double blinded, cross-over study involving 36 type 2 diabetes patients with insomnia (363). Prolonged-release melatonin administration significantly improved sleep efficiency and reduced wake time after sleep onset as assessed by actigraphy at 3 weeks, but without changes in glucose levels. A1c improved significantly at 5 months during the open-labeled phase (−0.6% compared to baseline) without changes in C-peptide levels, but the magnitude of this improvement was not predicted by sleep improvements as assessed by actigraphy. The study was limited by the lack of assessment of the circadian system. Interestingly, an experimental study in 21 healthy women revealed that acute melatonin administration, both in the morning and evening, resulted in IGT as assessed by OGTT (364). Therefore, the role of melatonin in human glucose metabolism remains controversial.

Taken together, these human experimental studies, results from cross-sectional studies, and genetic data support the contribution of the circadian system and sleep timing in metabolic regulation. Prospective and interventional studies are required to evaluate the role of the circadian system in the development and severity of type 2 diabetes.

Combined Effects of Multiple Disturbances of Sleep and/or Circadian Function on Glucose Metabolism

While there has been little systematic study of the combined effects of the presence of several subtypes of sleep disturbances in the same individual, this situation may be very common. For example, since population studies have associated shift work with higher BMI, it is possible that a substantial proportion of shift workers in the United States have OSA, while suffering at the same time from insufficient sleep and circadian misalignment. Another example is that of insomnia with short sleep duration. Lastly, individuals with poor sleep quality, particularly shallow sleep that may be easily fragmented, often have shorter sleep duration. Despite the fact that coexistence of multiple sleep disturbances may be a common condition, there have been few studies addressing the potential metabolic consequences.

In a cross-sectional study of insomnia evaluating glucose regulation by an OGTT, 14 nondiabetic participants with insomnia and short sleep (PSG confirmed sleep efficiency ≤80% and overnight sleeping ≤6 hours) were compared to 14 participants with insomnia and >6 hours of sleep (365). While A1c and glucose values were similar between the two groups, those with insomnia with short-sleep had lower fasting insulin and glucose-stimulated insulin secretion, but increased insulin sensitivity. The authors speculated that these alterations in glucose metabolism could represent an adaptive mechanism in response to increased fuel needs related to the physiologic hyperarousal thought to be a hallmark of insomnia. Furthermore, analyses of the Penn State Cohort, a large prospective study of 1,741 participants who had one night of laboratory PSG and were followed for 14 years, found that men with a complaint of insomnia for ≥1 year who also had a sleep duration of <6 hours on PSG had significantly higher mortality compared to men with “normal sleep duration and no insomnia” (OR 4.00, 95% CI 1.14–13.99) after adjusting for confounders (366). This analysis suggested that “insomnia with short sleep” may be a more biologically severe phenotype than insomnia with normal sleep duration, at least in men. Insomnia with short sleep in women was not associated with increased mortality. In the same cohort, the risk of type 2 diabetes was nearly threefold higher in individuals with insomnia with PSG-defined sleep duration <5 hours, irrespective of sex, while those with insomnia with longer sleep duration did not have an increased risk (48). The fact that sleep duration was assessed via a single night of PSG is a limitation of these Penn State Cohort studies. In another cross-sectional study of 15,227 U.S. Hispanics/Latinos, those with short sleep (self-reported <6 hours) and insomnia were more likely to have diabetes (OR 1.46, 95% CI 1.02–2.11) than average sleepers (>6–9 hours) with insomnia (OR 1.28, 95% CI 1.02–1.61) (367). These associations, however, were attenuated after adjusting for BMI.

A combination between OSA and short sleep duration has been explored in a few studies. In participants of the Korean Genome and Epidemiology Study, the combination of self-reported short sleep duration (<5 hours) and presence of OSA (as assessed by a portable home sleep device) was associated with a much higher risk of having visceral obesity (OR 4.40, 95% CI 1.80–10.77) than sleeping ≥7 hours and not having OSA (368). Interestingly, the adjusted odds ratio for visceral obesity was 2.05 (95% CI 1.09–3.86) in individuals sleeping <5 hours compared with those sleeping >7 hours, while the adjusted odds ratio for visceral obesity was 1.57 (95% CI 1.08–2.26) in individuals with OSA compared with those without OSA. This study thus suggests a synergy in the adverse effects of insufficient sleep and OSA, respectively, on adiposity. Another study in 136 Japanese participants with and without the metabolic syndrome, matched by age and BMI, revealed that the severity of OSA (as measured by a portable monitor) was comparable between the two groups (369). However, participants with the metabolic syndrome had significantly shorter sleep duration (5.8 vs. 6.1 hours) assessed by actigraphy. The combination of insufficient sleep and OSA could potentially also affect glycemic control in type 2 diabetes. In a small study of 71 type 2 diabetes patients with untreated OSA, sleep duration (measured by actigraphy) was inversely associated with A1c, while AHI itself was not. Each hour of reduction in sleep duration was associated with a 4.8% increase in A1c above its reference value (95% CI 1.5–8.0) (370).

Shift workers may be at risk of having sleep disturbances aside from having circadian misalignment. In a study of 26,463 workers in China, shift work was significantly associated with poor sleep quality as assessed by questionnaires. Sleep quality improved after leaving shift work. In another study of 121 hospital employees performing shift work and 150 day-workers, shift work status was associated with poor sleep quality, as well as with the metabolic syndrome (OR 2.29, 95% CI 1.12–4.70) (371). Interestingly, poor sleep quality did not mediate the relationship between shift work and the metabolic syndrome. The combined presence of shift work and OSA has also been explored in a few studies, although none addressed metabolic aspects. Two studies of shift workers with OSA (total 52 participants) found that the AHI assessed by PSG was significantly higher if the PSG was performed after a night shift compared to after a day shift (372,373).

Whether the repeated exposure to a higher severity of OSA during daytime sleep after a night of work may affect the metabolic health of shift workers is not known. Lastly, an experimental study has compared the metabolic impact of 8 days of sleep restriction (5 hours per night) with or without circadian misalignment. The reduction in insulin sensitivity (derived from intravenous glucose tolerance testing) was nearly twofold higher when the subjects were exposed to both insufficient sleep and circadian misalignment than when they were exposed to sleep restriction alone (13).

The existing evidence thus suggests that some combinations of sleep disturbances may be more detrimental to metabolic health than each component alone, but more research in this area is needed.

Conclusions

Disturbances of different aspects of sleep, including sleep duration, quality, respiratory function during sleep, and circadian timing have all been linked to abnormal glucose metabolism. Epidemiologic studies controlled for age and adiposity in the analyses. Many studies also included some measure of self-perceived stress or of socioeconomic status (e.g., using income and/or education as surrogate measures) in their analyses. The epidemiologic evidence linking sleep and adverse metabolic outcomes has come from a very large number of studies conducted in a wide variety of social and geographic environments, as well as in populations with very different demographic characteristics. Nonetheless, the findings have been remarkably consistent. Well-controlled in-laboratory experiments have provided causative evidence and suggested mechanistic pathways. As the prevalence and costs of care for the metabolic syndrome, type 2 diabetes, and gestational diabetes show no signs of decline, the efficacy and effectiveness of interventions that optimize sleep and circadian function to prevent the development or reduce the severity of these metabolic disorders need to be urgently evaluated.

List of Abbreviations

A1c

glycosylated hemoglobin

AHI

apnea-hypopnea index

BMI

body mass index

CI

confidence interval

CPAP

continuous positive airway pressure

EEG

electroencephalogram

GHTN

gestational hypertension

HDL

high-density lipoprotein

HOMA/HOMA-IR

homeostatic model assessment, an index of insulin resistance

HPA

hypothalamic-pituitary-adrenal

IGT

impaired glucose tolerance

IL

interleukin

IVGTT

intravenous glucose tolerance test

MSF

mid-time sleep on free days

MT1/MT2

melatonin receptors 1 and 2

NHANES

National Health and Nutrition Examination Survey

NREM

non-REM sleep

OGTT

oral glucose tolerance test

OR

odds ratio

OSA

obstructive sleep apnea

PSG

polysomnography/polysomnogram

PSQI

Pittsburgh Sleep Quality Index

RCT

randomized controlled trial

REM

rapid-eye-movement sleep

ROS

reactive oxygen species

RR

relative risk

SCN

suprachiasmatic nuclei

SWS

slow wave sleep

TNF

tumor necrosis factor

References

1.

National Heart, Lung, and Blood Institute: What are sleep deprivation and deficiency? [article online], 2012. Available from https://www​.nhlbi.nih​.gov/health/health-topics/topics/sdd. Accessed 31 March 2016

2.

Reutrakul S, Van Cauter E: Interactions between sleep, circadian function, and glucose metabolism: implications for risk and severity of diabetes. Ann N Y Acad Sci 1311:151–173, 2014 [PubMed: 24628249]

3.

Koren D, O’Sullivan KL, Mokhlesi B: Metabolic and glycemic sequelae of sleep disturbances in children and adults. Curr Diab Rep 15:562, 2015 [PMC free article: PMC4467532] [PubMed: 25398202]

4.

Izci-Balserak B, Pien GW: The relationship and potential mechanistic pathways between sleep disturbances and maternal hyperglycemia. Curr Diab Rep 14:459, 2014 [PMC free article: PMC4065785] [PubMed: 24398662]

5.

National Heart, Lung, and Blood Institute: How much sleep is enough? [article online], 2012. Available from https://www​.nhlbi.nih​.gov/health/health-topics​/topics/sdd/howmuch. Accessed 31 March 2016

6.

National Sleep Foundation: 2009 Sleep in America poll—health and safety [article online], 2016. Available from https:​//sleepfoundation​.org/sleep-polls-data​/sleep-in-america-poll​/2009-health-and-safety. Accessed 31 March 2016

7.

Krueger PM, Friedman EM: Sleep duration in the United States: a cross-sectional population-based study. Am J Epidemiol 169:1052–1063, 2009 [PMC free article: PMC2727237] [PubMed: 19299406]

8.

Spiegel K, Leproult R, Van Cauter E: Impact of sleep debt on metabolic and endocrine function. Lancet 354:1435–1439, 1999 [PubMed: 10543671]

9.

Leproult R, Van Cauter E: Role of sleep and sleep loss in hormonal release and metabolism. Endocr Dev 17:11–21, 2010 [PMC free article: PMC3065172] [PubMed: 19955752]

10.

Broussard JL, Ehrmann DA, Van Cauter E, Tasali E, Brady MJ: Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study. Ann Intern Med 157:549–557, 2012 [PMC free article: PMC4435718] [PubMed: 23070488]

11.

Nedeltcheva AV, Kessler L, Imperial J, Penev PD: Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab 94:3242–3250, 2009 [PMC free article: PMC2819825] [PubMed: 19567526]

12.

Buxton OM, Pavlova M, Reid EW, Wang W, Simonson DC, Adler GK: Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes 59:2126–2133, 2010 [PMC free article: PMC2927933] [PubMed: 20585000]

13.

Leproult R, Holmback U, Van Cauter E: Circadian misalignment augments markers of insulin resistance and inflammation, independently of sleep loss. Diabetes 63:1860–1869, 2014 [PMC free article: PMC4030107] [PubMed: 24458353]

14.

van Leeuwen WM, Hublin C, Sallinen M, Harma M, Hirvonen A, Porkka-Heiskanen T: Prolonged sleep restriction affects glucose metabolism in healthy young men. Int J Endocrinol 2010:108641, 2010 [PMC free article: PMC2857625] [PubMed: 20414467]

15.

Leproult R, Deliens G, Gilson M, Peigneux P: Beneficial impact of sleep extension on fasting insulin sensitivity in adults with habitual sleep restriction. Sleep 38:707–715, 2015 [PMC free article: PMC4402666] [PubMed: 25348128]

16.

Killick R, Hoyos CM, Melehan KL, Dungan GC, 2nd, Poh J, Liu PY: Metabolic and hormonal effects of ‘catch-up’ sleep in men with chronic, repetitive, lifestyle-driven sleep restriction. Clin Endocrinol (Oxf) 83:498–507, 2015 [PMC free article: PMC4858168] [PubMed: 25683266]

17.

Ayas NT, White DP, Al-Delaimy WK, Manson JE, Stampfer MJ, Speizer FE, Patel S, Hu FB: A prospective study of self-reported sleep duration and incident diabetes in women. Diabetes Care 26:380–384, 2003 [PubMed: 12547866]

18.

Beihl DA, Liese AD, Haffner SM: Sleep duration as a risk factor for incident type 2 diabetes in a multiethnic cohort. Ann Epidemiol 19:351–357, 2009 [PubMed: 19362278]

19.

Bjorkelund C, Bondyr-Carlsson D, Lapidus L, Lissner L, Mansson J, Skoog I, Bengtsson C: Sleep disturbances in midlife unrelated to 32-year diabetes incidence: the prospective population study of women in Gothenburg. Diabetes Care 28:2739–2744, 2005 [PubMed: 16249549]

20.

Gangwisch JE, Heymsfield SB, Boden-Albala B, Buijs RM, Kreier F, Pickering TG, Rundle AG, Zammit GK, Malaspina D: Sleep duration as a risk factor for diabetes incidence in a large U.S. sample. Sleep 30:1667–1673, 2007 [PMC free article: PMC2276127] [PubMed: 18246976]

21.

Holliday EG, Magee CA, Kritharides L, Banks E, Attia J: Short sleep duration is associated with risk of future diabetes but not cardiovascular disease: a prospective study and meta-analysis. PLOS ONE 8:e82305, 2013 [PMC free article: PMC3840027] [PubMed: 24282622]

22.

Tuomilehto H, Peltonen M, Partinen M, Lavigne G, Eriksson JG, Herder C, Aunola S, Keinanen-Kiukaanniemi S, Ilanne-Parikka P, Uusitupa M, Tuomilehto J, Lindstrom J; Finnish Diabetes Prevention Study Group: Sleep duration, lifestyle intervention, and incidence of type 2 diabetes in impaired glucose tolerance: the Finnish Diabetes Prevention Study. Diabetes Care 32:1965–1971, 2009 [PMC free article: PMC2768215] [PubMed: 19651919]

23.

von Ruesten A, Weikert C, Fietze I, Boeing H: Association of sleep duration with chronic diseases in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. PLOS ONE 7:e30972, 2012 [PMC free article: PMC3266295] [PubMed: 22295122]

24.

Xu Q, Song Y, Hollenbeck A, Blair A, Schatzkin A, Chen H: Day napping and short night sleeping are associated with higher risk of diabetes in older adults. Diabetes Care 33:78–83, 2010 [PMC free article: PMC2797990] [PubMed: 19825823]

25.

Yaggi HK, Araujo AB, McKinlay JB: Sleep duration as a risk factor for the development of type 2 diabetes. Diabetes Care 29:657–661, 2006 [PubMed: 16505522]

26.

Hayashino Y, Fukuhara S, Suzukamo Y, Okamura T, Tanaka T, Ueshima H; HIPOP-OHP Research Group: Relation between sleep quality and quantity, quality of life, and risk of developing diabetes in healthy workers in Japan: the High-risk and Population Strategy for Occupational Health Promotion (HIPOP-OHP) Study. BMC Public Health 7:129, 2007 [PMC free article: PMC1924854] [PubMed: 17597542]

27.

Mallon L, Broman JE, Hetta J: High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middle-aged population. Diabetes Care 28:2762–2767, 2005 [PubMed: 16249553]

28.

Boyko EJ, Seelig AD, Jacobson IG, Hooper TI, Smith B, Smith TC, Crum-Cianflone NF; Millennium Cohort Study Team: Sleep characteristics, mental health, and diabetes risk: a prospective study of U.S. military service members in the Millennium Cohort Study. Diabetes Care 36:3154–3161, 2013 [PMC free article: PMC3781550] [PubMed: 23835691]

29.

Kita T, Yoshioka E, Satoh H, Saijo Y, Kawaharada M, Okada E, Kishi R: Short sleep duration and poor sleep quality increase the risk of diabetes in Japanese workers with no family history of diabetes. Diabetes Care 35:313–318, 2012 [PMC free article: PMC3263910] [PubMed: 22210572]

30.

Chaput JP, Despres JP, Bouchard C, Astrup A, Tremblay A: Sleep duration as a risk factor for the development of type 2 diabetes or impaired glucose tolerance: analyses of the Quebec Family Study. Sleep Med 10:919–924, 2009 [PubMed: 19332380]

31.

Gutierrez-Repiso C, Soriguer F, Rubio-Martin E, Esteva de Antonio I, Ruiz de Adana MS, Almaraz MC, Olveira-Fuster G, Morcillo S, Valdes S, Lago-Sampedro AM, Garcia-Fuentes E, Rojo-Martinez G: Night-time sleep duration and the incidence of obesity and type 2 diabetes. Findings from the prospective Pizarra study. Sleep Med 15:1398–1404, 2014 [PubMed: 25262361]

32.

Heianza Y, Kato K, Fujihara K, Tanaka S, Kodama S, Hanyu O, Sato K, Sone H: Role of sleep duration as a risk factor for type 2 diabetes among adults of different ages in Japan: the Niigata Wellness Study. Diabet Med 31:1363–1367, 2014 [PubMed: 25124930]

33.

Cappuccio FP, D’Elia L, Strazzullo P, Miller MA: Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care 33:414–420, 2010 [PMC free article: PMC2809295] [PubMed: 19910503]

34.

Knutson KL, Ryden AM, Mander BA, Van Cauter E: Role of sleep duration and quality in the risk and severity of type 2 diabetes mellitus. Arch Intern Med 166:1768–1774, 2006 [PubMed: 16983057]

35.

Ohkuma T, Fujii H, Iwase M, Kikuchi Y, Ogata S, Idewaki Y, Ide H, Doi Y, Hirakawa Y, Nakamura U, Kitazono T: Impact of sleep duration on obesity and the glycemic level in patients with type 2 diabetes: the Fukuoka Diabetes Registry. Diabetes Care 36:611–617, 2013 [PMC free article: PMC3579358] [PubMed: 23150286]

36.

Kim BK, Kim BS, An SY, Lee MS, Choi YJ, Han SJ, Chung YS, Lee KW, Kim DJ: Sleep duration and glycemic control in patients with diabetes mellitus: Korea National Health and Nutrition Examination Survey 2007–2010. J Korean Med Sci 28:1334–1339, 2013 [PMC free article: PMC3763108] [PubMed: 24015039]

37.

Zheng Y, Wang A, Pan C, Lu J, Dou J, Lu Z, Ba J, Wang B, Mu Y: Impact of night sleep duration on glycemic and triglyceride levels in Chinese with different glycemic status. J Diabetes 7:24–30, 2015 [PubMed: 24981368]

38.

Knutson KL, Van Cauter E, Zee P, Liu K, Lauderdale DS: Cross-sectional associations between measures of sleep and markers of glucose metabolism among subjects with and without diabetes: the Coronary Artery Risk Development in Young Adults (CARDIA) Sleep Study. Diabetes Care 34:1171–1176, 2011 [PMC free article: PMC3114508] [PubMed: 21411507]

39.

Trento M, Broglio F, Riganti F, Basile M, Borgo E, Kucich C, Passera P, Tibaldi P, Tomelini M, Cavallo F, Ghigo E, Porta M: Sleep abnormalities in type 2 diabetes may be associated with glycemic control. Acta Diabetol 45:225–229, 2008 [PubMed: 18685806]

40.

Bergman RN: Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes 38:1512–1527, 1989 [PubMed: 2684710]

41.

Tasali E, Leproult R, Ehrmann DA, Van Cauter E: Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A 105:1044–1049, 2008 [PMC free article: PMC2242689] [PubMed: 18172212]

42.

Stamatakis KA, Punjabi NM: Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 137:95–101, 2010 [PMC free article: PMC2803120] [PubMed: 19542260]

43.

American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA, American Psychiatric Publishing, 2013

44.

Engeda J, Mezuk B, Ratliff S, Ning Y: Association between duration and quality of sleep and the risk of pre-diabetes: evidence from NHANES. Diabet Med 30:676–680, 2013 [PMC free article: PMC3660430] [PubMed: 23425048]

45.

Liu J, Hay J, Faught BE: The association of sleep disorder, obesity status, and diabetes mellitus among US adults—the NHANES 2009–2010 survey results. Int J Endocrinol 2013:234129, 2013 [PMC free article: PMC3730157] [PubMed: 23956743]

46.

Foley D, Ancoli-Israel S, Britz P, Walsh J: Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res 56:497–502, 2004 [PubMed: 15172205]

47.

Budhiraja R, Roth T, Hudgel DW, Budhiraja P, Drake CL: Prevalence and polysomnographic correlates of insomnia comorbid with medical disorders. Sleep 34:859–867, 2011 [PMC free article: PMC3119827] [PubMed: 21731135]

48.

Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Bixler EO: Insomnia with objective short sleep duration is associated with type 2 diabetes: a population-based study. Diabetes Care 32:1980–1985, 2009 [PMC free article: PMC2768214] [PubMed: 19641160]

49.

Eriksson AK, Ekbom A, Granath F, Hilding A, Efendic S, Ostenson CG: Psychological distress and risk of pre-diabetes and type 2 diabetes in a prospective study of Swedish middle-aged men and women. Diabet Med 25:834–842, 2008 [PubMed: 18513304]

50.

Kawakami N, Takatsuka N, Shimizu H: Sleep disturbance and onset of type 2 diabetes. Diabetes Care 27:282–283, 2004 [PubMed: 14694011]

51.

Meisinger C, Heier M, Loewel H; MONICA/KORA Augsburg Cohort Study: Sleep disturbance as a predictor of type 2 diabetes mellitus in men and women from the general population. Diabetologia 48:235–241, 2005 [PubMed: 15645205]

52.

Nilsson PM, Roost M, Engstrom G, Hedblad B, Berglund G: Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care 27:2464–2469, 2004 [PubMed: 15451917]

53.

Olsson L, Ahlbom A, Grill V, Midthjell K, Carlsson S: Sleep disturbances and low psychological well-being are associated with an increased risk of autoimmune diabetes in adults. Results from the Nord-Trondelag Health Study. Diabetes Res Clin Pract 98:302–311, 2012 [PubMed: 23010555]

54.

Rod NH, Vahtera J, Westerlund H, Kivimaki M, Zins M, Goldberg M, Lange T: Sleep disturbances and cause-specific mortality: results from the GAZEL cohort study. Am J Epidemiol 173:300–309, 2011 [PMC free article: PMC3105272] [PubMed: 21193534]

55.

Zhang J, Lam SP, Li SX, Li AM, Wing YK: The longitudinal course and impact of non-restorative sleep: a five-year community-based follow-up study. Sleep Med 13:570–576, 2012 [PubMed: 22445230]

56.

Knowler WC, Pettitt DJ, Savage PJ, Bennett PH: Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 113:144–156, 1981 [PubMed: 7468572]

57.

Shaten BJ, Smith GD, Kuller LH, Neaton JD: Risk factors for the development of type II diabetes among men enrolled in the usual care group of the Multiple Risk Factor Intervention Trial. Diabetes Care 16:1331–1339, 1993 [PubMed: 8269790]

58.

Burchfiel CM, Curb JD, Rodriguez BL, Yano K, Hwang LJ, Fong KO, Marcus EB: Incidence and predictors of diabetes in Japanese-American men. The Honolulu Heart Program. Ann Epidemiol 5:33–43, 1995 [PubMed: 7728283]

59.

Sargeant LA, Wareham NJ, Khaw KT: Family history of diabetes identifies a group at increased risk for the metabolic consequences of obesity and physical inactivity in EPIC-Norfolk: a population-based study. The European Prospective Investigation into Cancer. Int J Obes Relat Metab Disord 24:1333–1339, 2000 [PubMed: 11093296]

60.

Harrison TA, Hindorff LA, Kim H, Wines RC, Bowen DJ, McGrath BB, Edwards KL: Family history of diabetes as a potential public health tool. Am J Prev Med 24:152–159, 2003 [PubMed: 12568821]

61.

Erasmus RT, Blanco Blanco E, Okesina AB, Mesa Arana J, Gqweta Z, Matsha T: Importance of family history in type 2 black South African diabetic patients. Postgrad Med J 77:323–325, 2001 [PMC free article: PMC1742028] [PubMed: 11320276]

62.

Tsai YW, Kann NH, Tung TH, Chao YJ, Lin CJ, Chang KC, Chang SS, Chen JY: Impact of subjective sleep quality on glycemic control in type 2 diabetes mellitus. Fam Pract 29:30–35, 2012 [PubMed: 21795758]

63.

Tang Y, Meng L, Li D, Yang M, Zhu Y, Li C, Jiang Z, Yu P, Li Z, Song H, Ni C: Interaction of sleep quality and sleep duration on glycemic control in patients with type 2 diabetes mellitus. Chin Med J (Engl) 127:3543–3547, 2014 [PubMed: 25316226]

64.

Kushida CA, Chang A, Gadkary C, Guilleminault C, Carrillo O, Dement WC: Comparison of actigraphic, polysomnographic, and subjective assessment of sleep parameters in sleep-disordered patients. Sleep Med 2:389–396, 2001 [PubMed: 14592388]

65.

Chasens ER, Yang K: Insomnia and physical activity in adults with prediabetes. Clin Nurs Res 21:294–308, 2012 [PubMed: 21788447]

66.

Thomas M, Sing H, Belenky G, Holcomb H, Mayberg H, Dannals R, Wagner H, Thorne D, Popp K, Rowland L, Welsh A, Balwinski S, Redmond D: Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 9:335–352, 2000 [PubMed: 11123521]

67.

Grassi G, Dell’Oro R, Quarti-Trevano F, Scopelliti F, Seravalle G, Paleari F, Gamba PL, Mancia G: Neuroadrenergic and reflex abnormalities in patients with metabolic syndrome. Diabetologia 48:1359–1365, 2005 [PubMed: 15933859]

68.

Tentolouris N, Argyrakopoulou G, Katsilambros N: Perturbed autonomic nervous system function in metabolic syndrome. Neuromolecular Med 10:169–178, 2008 [PubMed: 18224460]

69.

Irwin M, Thompson J, Miller C, Gillin JC, Ziegler M: Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications. J Clin Endocrinol Metab 84:1979–1985, 1999 [PubMed: 10372697]

70.

Reynolds AC, Dorrian J, Liu PY, Van Dongen HP, Wittert GA, Harmer LJ, Banks S: Impact of five nights of sleep restriction on glucose metabolism, leptin and testosterone in young adult men. PLOS ONE 7:e41218, 2012 [PMC free article: PMC3402517] [PubMed: 22844441]

71.

Leproult R, Copinschi G, Buxton O, Van Cauter E: Sleep loss results in an elevation of cortisol levels the next evening. Sleep 20:865–870, 1997 [PubMed: 9415946]

72.

Plat L, Leproult R, L’Hermite-Baleriaux M, Fery F, Mockel J, Polonsky KS, Van Cauter E: Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metab 84:3082–3092, 1999 [PubMed: 10487669]

73.

Stamatakis KA, Punjabi NM: Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest 137:95–101, 2010 [PMC free article: PMC2803120] [PubMed: 19542260]

74.

Mullington JM, Simpson NS, Meier-Ewert HK, Haack M: Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 24:775–784, 2010 [PMC free article: PMC3548567] [PubMed: 21112025]

75.

Boudjeltia KZ, Faraut B, Stenuit P, Esposito MJ, Dyzma M, Brohee D, Ducobu J, Vanhaeverbeek M, Kerkhofs M: Sleep restriction increases white blood cells, mainly neutrophil count, in young healthy men: a pilot study. Vasc Health Risk Manag 4:1467–1470, 2008 [PMC free article: PMC2663438] [PubMed: 19337560]

76.

Faraut B, Boudjeltia KZ, Dyzma M, Rousseau A, David E, Stenuit P, Franck T, Van Antwerpen P, Vanhaeverbeek M, Kerkhofs M: Benefits of napping and an extended duration of recovery sleep on alertness and immune cells after acute sleep restriction. Brain Behav Immun 25:16–24, 2011 [PubMed: 20699115]

77.

Boyum A, Wiik P, Gustavsson E, Veiby OP, Reseland J, Haugen AH, Opstad PK: The effect of strenuous exercise, calorie deficiency and sleep deprivation on white blood cells, plasma immunoglobulins and cytokines. Scand J Immunol 43:228–235, 1996 [PubMed: 8633203]

78.

Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, Chrousos GP: Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab 89:2119–2126, 2004 [PubMed: 15126529]

79.

Irwin MR, Wang M, Campomayor CO, Collado-Hidalgo A, Cole S: Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 166:1756–1762, 2006 [PubMed: 16983055]

80.

van Leeuwen WM, Lehto M, Karisola P, Lindholm H, Luukkonen R, Sallinen M, Harma M, Porkka-Heiskanen T, Alenius H: Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLOS ONE 4:e4589, 2009 [PMC free article: PMC2643002] [PubMed: 19240794]

81.

Shearer WT, Reuben JM, Mullington JM, Price NJ, Lee BN, Smith EO, Szuba MP, Van Dongen HP, Dinges DF: Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 107:165–170, 2001 [PubMed: 11150007]

82.

Wieser V, Moschen AR, Tilg H: Inflammation, cytokines and insulin resistance: a clinical perspective. Arch Immunol Ther Exp (Warsz) 61:119–125, 2013 [PubMed: 23307037]

83.

Spiegel K, Tasali E, Penev P, Van Cauter E: Brief communication: sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 141:846–850, 2004 [PubMed: 15583226]

84.

Morselli LL, Guyon A, Spiegel K: Sleep and metabolic function. Pflugers Arch 463:139–160, 2012 [PMC free article: PMC3289068] [PubMed: 22101912]

85.

Killick R, Banks S, Liu PY: Implications of sleep restriction and recovery on metabolic outcomes. J Clin Endocrinol Metab 97:3876–3890, 2012 [PMC free article: PMC5393445] [PubMed: 22996147]

86.

Guilleminault C, Powell NB, Martinez S, Kushida C, Raffray T, Palombini L, Philip P: Preliminary observations on the effects of sleep time in a sleep restriction paradigm. Sleep Med 4:177–184, 2003 [PubMed: 14592319]

87.

Spiegel K, Leproult R, L’Hermite-Baleriaux M, Copinschi G, Penev PD, Van Cauter E: Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 89:5762–5771, 2004 [PubMed: 15531540]

88.

Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, Meier-Ewert HK, Dinges DF, Mantzoros CS: Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol 15:851–854, 2003 [PubMed: 12899679]

89.

Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, de Wit H, Hillard CJ, Van Cauter E: Sleep restriction enhances the daily rhythm of circulating levels of endocannabinoid 2-arachidonoylglycerol. Sleep 39:653–664, 2016 [PMC free article: PMC4763355] [PubMed: 26612385]

90.

Broussard JL, Kilkus JM, Delebecque F, Abraham V, Day A, Whitmore HR, Tasali E: Elevated ghrelin predicts food intake during experimental sleep restriction. Obesity (Silver Spring) 24:132–138, 2016 [PMC free article: PMC4688118] [PubMed: 26467988]

91.

Nedeltcheva AV, Kilkus JM, Imperial J, Schoeller DA, Penev PD: Insufficient sleep undermines dietary efforts to reduce adiposity. Ann Intern Med 153:435–441, 2010 [PMC free article: PMC2951287] [PubMed: 20921542]

92.

Omisade A, Buxton OM, Rusak B: Impact of acute sleep restriction on cortisol and leptin levels in young women. Physiol Behav 99:651–656, 2010 [PubMed: 20138072]

93.

Schmid SM, Hallschmid M, Jauch-Chara K, Born J, Schultes B: A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men. J Sleep Res 17:331–334, 2008 [PubMed: 18564298]

94.

Knutson KL, Galli G, Zhao X, Mattingly M, Cizza G; NIDDK Sleep Extension Study: No association between leptin levels and sleep duration or quality in obese adults. Obesity (Silver Spring) 19:2433–2435, 2011 [PMC free article: PMC3235501] [PubMed: 21799479]

95.

Taheri S, Lin L, Austin D, Young T, Mignot E: Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLOS Med 1:e62, 2004 [PMC free article: PMC535701] [PubMed: 15602591]

96.

Nedeltcheva AV, Kilkus JM, Imperial J, Kasza K, Schoeller DA, Penev PD: Sleep curtailment is accompanied by increased intake of calories from snacks. Am J Clin Nutr 89:126–133, 2009 [PMC free article: PMC2615460] [PubMed: 19056602]

97.

Bosy-Westphal A, Hinrichs S, Jauch-Chara K, Hitze B, Later W, Wilms B, Settler U, Peters A, Kiosz D, Muller MJ: Influence of partial sleep deprivation on energy balance and insulin sensitivity in healthy women. Obes Facts 1:266–273, 2008 [PMC free article: PMC6515888] [PubMed: 20054188]

98.

St-Onge MP, Roberts AL, Chen J, Kelleman M, O’Keeffe M, RoyChoudhury A, Jones PJ: Short sleep duration increases energy intakes but does not change energy expenditure in normal-weight individuals. Am J Clin Nutr 94:410–416, 2011 [PMC free article: PMC3142720] [PubMed: 21715510]

99.

Markwald RR, Melanson EL, Smith MR, Higgins J, Perreault L, Eckel RH, Wright KP, Jr.: Impact of insufficient sleep on total daily energy expenditure, food intake, and weight gain. Proc Natl Acad Sci U S A 110:5695–5700, 2013 [PMC free article: PMC3619301] [PubMed: 23479616]

100.

Spaeth AM, Dinges DF, Goel N: Effects of experimental sleep restriction on weight gain, caloric intake, and meal timing in healthy adults. Sleep 36:981–990, 2013 [PMC free article: PMC3669080] [PubMed: 23814334]

101.

Schmid SM, Hallschmid M, Jauch-Chara K, Wilms B, Benedict C, Lehnert H, Born J, Schultes B: Short-term sleep loss decreases physical activity under free-living conditions but does not increase food intake under time-deprived laboratory conditions in healthy men. Am J Clin Nutr 90:1476–1482, 2009 [PubMed: 19846546]

102.

Benedict C, Brooks SJ, O’Daly OG, Almen MS, Morell A, Aberg K, Gingnell M, Schultes B, Hallschmid M, Broman JE, Larsson EM, Schioth HB: Acute sleep deprivation enhances the brain’s response to hedonic food stimuli: an fMRI study. J Clin Endocrinol Metab 97:E443–E447, 2012 [PubMed: 22259064]

103.

St-Onge MP, McReynolds A, Trivedi ZB, Roberts AL, Sy M, Hirsch J: Sleep restriction leads to increased activation of brain regions sensitive to food stimuli. Am J Clin Nutr 95:818–824, 2012 [PMC free article: PMC3302360] [PubMed: 22357722]

104.

Jung CM, Melanson EL, Frydendall EJ, Perreault L, Eckel RH, Wright KP: Energy expenditure during sleep, sleep deprivation and sleep following sleep deprivation in adult humans. J Physiol 589:235–244, 2011 [PMC free article: PMC3039272] [PubMed: 21059762]

105.

Bromley LE, Booth JN, 3rd, Kilkus JM, Imperial JG, Penev PD: Sleep restriction decreases the physical activity of adults at risk for type 2 diabetes. Sleep 35:977–984, 2012 [PMC free article: PMC3369233] [PubMed: 22754044]

106.

Booth JN, Bromley LE, Darukhanavala AP, Whitmore HR, Imperial JG, Penev PD: Reduced physical activity in adults at risk for type 2 diabetes who curtail their sleep. Obesity (Silver Spring) 20:278–284, 2012 [PMC free article: PMC3262101] [PubMed: 21996665]

107.

Lopez-Garcia E, Faubel R, Leon-Munoz L, Zuluaga MC, Banegas JR, Rodriguez-Artalejo F: Sleep duration, general and abdominal obesity, and weight change among the older adult population of Spain. Am J Clin Nutr 87:310–316, 2008 [PubMed: 18258619]

108.

Hairston KG, Bryer-Ash M, Norris JM, Haffner S, Bowden DW, Wagenknecht LE: Sleep duration and five-year abdominal fat accumulation in a minority cohort: the IRAS family study. Sleep 33:289–295, 2010 [PMC free article: PMC2831422] [PubMed: 20337186]

109.

Watanabe M, Kikuchi H, Tanaka K, Takahashi M: Association of short sleep duration with weight gain and obesity at 1-year follow-up: a large-scale prospective study. Sleep 33:161–167, 2010 [PMC free article: PMC2817903] [PubMed: 20175399]

110.

Chaput JP, Despres JP, Bouchard C, Tremblay A: The association between sleep duration and weight gain in adults: a 6-year prospective study from the Quebec Family Study. Sleep 31:517–523, 2008 [PMC free article: PMC2279744] [PubMed: 18457239]

111.

Broussard J, Brady MJ: The impact of sleep disturbances on adipocyte function and lipid metabolism. Best Pract Res Clin Endocrinol Metab 24:763–773, 2010 [PMC free article: PMC3031100] [PubMed: 21112024]

112.

Ahima RS, Saper CB, Flier JS, Elmquist JK: Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 21:263–307, 2000 [PubMed: 10882542]

113.

Hucking K, Hamilton-Wessler M, Ellmerer M, Bergman RN: Burst-like control of lipolysis by the sympathetic nervous system in vivo. J Clin Invest 111:257–264, 2003 [PMC free article: PMC151855] [PubMed: 12531882]

114.

Broussard JL, Chapotot F, Abraham V, Day A, Delebecque F, Whitmore HR, Tasali E: Sleep restriction increases free fatty acids in healthy men. Diabetologia 58:791–798, 2015 [PMC free article: PMC4358810] [PubMed: 25702040]

115.

Knutson KL, Leproult R: Apples to oranges: comparing long sleep to short sleep. J Sleep Res 19:118, 2010 [PubMed: 20470264]

116.

Punjabi NM: The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 5:136–143, 2008 [PMC free article: PMC2645248] [PubMed: 18250205]

117.

Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM: Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 177:1006–1014, 2013 [PMC free article: PMC3639722] [PubMed: 23589584]

118.

Young T, Evans L, Finn L, Palta M: Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep 20:705–706, 1997 [PubMed: 9406321]

119.

Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J: Underdiagnosis of sleep apnea syndrome in U.S. communities. Sleep Breath 6:49–54, 2002 [PubMed: 12075479]

120.

Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. The Report of an American Academy of Sleep Medicine Task Force. Sleep 22:667–689, 1999 [PubMed: 10450601]

121.

Aurora RN, Punjabi NM: Obstructive sleep apnoea and type 2 diabetes mellitus: a bidirectional association. Lancet Respir Med 1:329–338, 2013 [PubMed: 24429158]

122.

Louis M, Punjabi NM: Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol 106:1538–1544, 2009 [PMC free article: PMC2681331] [PubMed: 19265062]

123.

Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE; Sleep Heart Health Study Investigators: Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 160:521–530, 2004 [PubMed: 15353412]

124.

Reichmuth KJ, Austin D, Skatrud JB, Young T: Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 172:1590–1595, 2005 [PMC free article: PMC2718458] [PubMed: 16192452]

125.

Botros N, Concato J, Mohsenin V, Selim B, Doctor K, Yaggi HK: Obstructive sleep apnea as a risk factor for type 2 diabetes. Am J Med 122:1122–1127, 2009 [PMC free article: PMC2799991] [PubMed: 19958890]

126.

Celen YT, Hedner J, Carlson J, Peker Y: Impact of gender on incident diabetes mellitus in obstructive sleep apnea: a 16-year follow-up. J Clin Sleep Med 6:244–250, 2010 [PMC free article: PMC2883035] [PubMed: 20572417]

127.

Lindberg E, Theorell-Haglow J, Svensson M, Gislason T, Berne C, Janson C: Sleep apnea and glucose metabolism: a long-term follow-up in a community-based sample. Chest 142:935–942, 2012 [PubMed: 22499826]

128.

Marshall NS, Wong KK, Phillips CL, Liu PY, Knuiman MW, Grunstein RR: Is sleep apnea an independent risk factor for prevalent and incident diabetes in the Busselton Health Study? J Clin Sleep Med 5:15–20, 2009 [PMC free article: PMC2637161] [PubMed: 19317376]

129.

Muraki I, Tanigawa T, Yamagishi K, Sakurai S, Ohira T, Imano H, Kiyama M, Kitamura A, Sato S, Shimamoto T, Konishi M, Iso H; CIRCS Investigators: Nocturnal intermittent hypoxia and metabolic syndrome; the effect of being overweight: the CIRCS study. J Atheroscler Thromb 17:369–377, 2010 [PubMed: 20103974]

130.

Appleton SL, Vakulin A, McEvoy RD, Wittert GA, Martin SA, Grant JF, Taylor AW, Antic NA, Catcheside PG, Adams RJ: Nocturnal hypoxemia and severe obstructive sleep apnea are associated with incident type 2 diabetes in a population cohort of men. J Clin Sleep Med 11:609–614, 2015 [PMC free article: PMC4442221] [PubMed: 25766697]

131.

Kendzerska T, Gershon AS, Hawker G, Tomlinson G, Leung RS: Obstructive sleep apnea and incident diabetes. A historical cohort study. Am J Respir Crit Care Med 190:218–225, 2014 [PubMed: 24897551]

132.

Wang X, Bi Y, Zhang Q, Pan F: Obstructive sleep apnoea and the risk of type 2 diabetes: a meta-analysis of prospective cohort studies. Respirology 18:140–146, 2013 [PubMed: 22988888]

133.

Aronsohn RS, Whitmore H, Van Cauter E, Tasali E: Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med 181:507–513, 2010 [PMC free article: PMC2830401] [PubMed: 20019340]

134.

Foster GD, Sanders MH, Millman R, Zammit G, Borradaile KE, Newman AB, Wadden TA, Kelley D, Wing RR, Sunyer FX, Darcey V, Kuna ST; Sleep AHEAD Research Group: Obstructive sleep apnea among obese patients with type 2 diabetes. Diabetes Care 32:1017–1019, 2009 [PMC free article: PMC2681024] [PubMed: 19279303]

135.

Resnick HE, Redline S, Shahar E, Gilpin A, Newman A, Walter R, Ewy GA, Howard BV, Punjabi NM; Sleep Heart Health Study: Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. Diabetes Care 26:702–709, 2003 [PubMed: 12610025]

136.

Laaban JP, Daenen S, Leger D, Pascal S, Bayon V, Slama G, Elgrably F: Prevalence and predictive factors of sleep apnoea syndrome in type 2 diabetic patients. Diabetes Metab 35:372–377, 2009 [PubMed: 19683953]

137.

Einhorn D, Stewart DA, Erman MK, Gordon N, Philis-Tsimikas A, Casal E: Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. Endocr Pract 13:355–362, 2007 [PubMed: 17669711]

138.

Harada Y, Oga T, Chin K, Takegami M, Takahashi K, Sumi K, Nakamura T, Nakayama-Ashida Y, Minami I, Horita S, Oka Y, Wakamura T, Fukuhara S, Mishima M, Kadotani H: Differences in relationships among sleep apnoea, glucose level, sleep duration and sleepiness between persons with and without type 2 diabetes. J Sleep Res 21:410–418, 2012 [PubMed: 22320933]

139.

Pillai A, Warren G, Gunathilake W, Idris I: Effects of sleep apnea severity on glycemic control in patients with type 2 diabetes prior to continuous positive airway pressure treatment. Diabetes Technol Ther 13:945–949, 2011 [PubMed: 21714680]

140.

Heffner JE, Rozenfeld Y, Kai M, Stephens EA, Brown LK: Prevalence of diagnosed sleep apnea among patients with type 2 diabetes in primary care. Chest 141:1414–1421, 2012 [PubMed: 22095313]

141.

St-Onge MP, Zammit G, Reboussin DM, Kuna ST, Sanders MH, Millman R, Newman AB, Wadden TA, Wing RR, Pi-Sunyer FX, Foster GD; Sleep AHEAD Research Group: Associations of sleep disturbance and duration with metabolic risk factors in obese persons with type 2 diabetes: data from the Sleep AHEAD Study. Nat Sci Sleep 4:143–150, 2012 [PMC free article: PMC3630980] [PubMed: 23620687]

142.

Kosseifi S, Bailey B, Price R, Roy TM, Byrd RP, Jr., Peiris AN: The association between obstructive sleep apnea syndrome and microvascular complications in well-controlled diabetic patients. Mil Med 175:913–916, 2010 [PubMed: 21121505]

143.

Tahrani AA, Ali A, Raymond NT, Begum S, Dubb K, Mughal S, Jose B, Piya MK, Barnett AH, Stevens MJ: Obstructive sleep apnea and diabetic neuropathy: a novel association in patients with type 2 diabetes. Am J Respir Crit Care Med 186:434–441, 2012 [PMC free article: PMC3443800] [PubMed: 22723291]

144.

Rudrappa S, Warren G, Idris I: Obstructive sleep apnoea is associated with the development and progression of diabetic retinopathy, independent of conventional risk factors and novel biomarkers for diabetic retinopathy. Br J Ophthalmol 96:1535, 2012 [PubMed: 23077225]

145.

Fenik VB, Davies RO, Kubin L: REM sleep-like atonia of hypoglossal (XII) moto-neurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 172:1322–1330, 2005 [PMC free article: PMC5222563] [PubMed: 16100007]

146.

Mokhlesi B, Punjabi NM: “REM-related” obstructive sleep apnea: an epiphenomenon or a clinically important entity? Sleep 35:5–7, 2012 [PMC free article: PMC3242688] [PubMed: 22215911]

147.

Findley LJ, Wilhoit SC, Suratt PM: Apnea duration and hypoxemia during REM sleep in patients with obstructive sleep apnea. Chest 87:432–436, 1985 [PubMed: 3979129]

148.

Grimaldi D, Beccuti G, Touma C, Van Cauter E, Mokhlesi B: Association of obstructive sleep apnea in rapid eye movement sleep with reduced glycemic control in type 2 diabetes: therapeutic implications. Diabetes Care 37:355–363, 2014 [PMC free article: PMC3898763] [PubMed: 24101701]

149.

Reichmuth KJ, Austin D, Skatrud JB, Young T: Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med 172:1590–1595, 2005 [PMC free article: PMC2718458] [PubMed: 16192452]

150.

Punjabi NM; Workshop Participants: Do sleep disorders and associated treatments impact glucose metabolism? Drugs 69(Suppl 2):13–27, 2009 [PubMed: 20047348]

151.

Chakhtoura M, Azar ST: Continuous positive airway pressure and type 2 diabetes mellitus. Diabetes Metab Syndr 6:176–179, 2012 [PubMed: 23158985]

152.

Harsch IA, Schahin SP, Radespiel-Troger M, Weintz O, Jahreiss H, Fuchs FS, Wiest GH, Hahn EG, Lohmann T, Konturek PC, Ficker JH: Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 169:156–162, 2004 [PubMed: 14512265]

153.

Coughlin SR, Mawdsley L, Mugarza JA, Wilding JP, Calverley PM: Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 29:720–727, 2007 [PubMed: 17251237]

154.

West SD, Nicoll DJ, Wallace TM, Matthews DR, Stradling JR: Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 62:969–974, 2007 [PMC free article: PMC2117137] [PubMed: 17557769]

155.

Nguyen PK, Katikireddy CK, McConnell MV, Kushida C, Yang PC: Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea. J Cardiovasc Magn Reson 12:50, 2010 [PMC free article: PMC2945335] [PubMed: 20815898]

156.

Kohler M, Stoewhas AC, Ayers L, Senn O, Bloch KE, Russi EW, Stradling JR: Effects of continuous positive airway pressure therapy withdrawal in patients with obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 184:1192–1199, 2011 [PubMed: 21836134]

157.

Sivam S, Phillips CL, Trenell MI, Yee BJ, Liu PY, Wong KK, Grunstein RR: Effects of 8 weeks of continuous positive airway pressure on abdominal adiposity in obstructive sleep apnoea. Eur Respir J 40:913–918, 2012 [PubMed: 22267762]

158.

Hoyos CM, Killick R, Yee BJ, Phillips CL, Grunstein RR, Liu PY: Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study. Thorax 67:1081–1089, 2012 [PubMed: 22561530]

159.

Lam JC, Lam B, Yao TJ, Lai AY, Ooi CG, Tam S, Lam KS, Ip MS: A randomised controlled trial of nasal continuous positive airway pressure on insulin sensitivity in obstructive sleep apnoea. Eur Respir J 35:138–145, 2010 [PubMed: 19608589]

160.

Weinstock TG, Wang X, Rueschman M, Ismail-Beigi F, Aylor J, Babineau DC, Mehra R, Redline S: A controlled trial of CPAP therapy on metabolic control in individuals with impaired glucose tolerance and sleep apnea. Sleep 35:617–625B, 2012 [PMC free article: PMC3321420] [PubMed: 22547887]

161.

Shaw JE, Punjabi NM, Naughton MT, Willes L, Bergenstal RM, Cistulli PA, Fulcher GR, Richards GN, Zimmet PZ: The effect of treatment of obstructive sleep apnea on glycemic control in type 2 diabetes. Am J Respir Crit Care Med 194:486–492, 2016 [PubMed: 26926656]

162.

Iftikhar IH, Blankfield RP: Effect of continuous positive airway pressure on hemoglobin A(1c) in patients with obstructive sleep apnea: a systematic review and meta-analysis. Lung 190:605–611, 2012 [PubMed: 22773248]

163.

Yang D, Liu Z, Yang H, Luo Q: Effects of continuous positive airway pressure on glycemic control and insulin resistance in patients with obstructive sleep apnea: a meta-analysis. Sleep Breath 17:33–38, 2013 [PubMed: 22411171]

164.

Hecht L, Mohler R, Meyer G: Effects of CPAP-respiration on markers of glucose metabolism in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis. Ger Med Sci 9:Doc20, 2011 [PMC free article: PMC3158650] [PubMed: 21863134]

165.

Chen L, Pei JH, Chen HM: Effects of continuous positive airway pressure treatment on glycaemic control and insulin sensitivity in patients with obstructive sleep apnoea and type 2 diabetes: a meta-analysis. Arch Med Sci 10:637–642, 2014 [PMC free article: PMC4175764] [PubMed: 25276145]

166.

Iftikhar IH, Khan MF, Das A, Magalang UJ: Meta-analysis: continuous positive airway pressure improves insulin resistance in patients with sleep apnea without diabetes. Ann Am Thorac Soc 10:115–120, 2013 [PMC free article: PMC3960898] [PubMed: 23607839]

167.

Pamidi S, Wroblewski K, Stepien M, Sharif-Sidi K, Kilkus J, Whitmore H, Tasali E: Eight hours of nightly continuous positive airway pressure treatment of obstructive sleep apnea improves glucose metabolism in patients with prediabetes. A randomized controlled trial. Am J Respir Crit Care Med 192:96–105, 2015 [PMC free article: PMC4511421] [PubMed: 25897569]

168.

Moon K, Punjabi NM, Aurora RN: Obstructive sleep apnea and type 2 diabetes in older adults. Clin Geriatr Med 31:139–147, ix, 2015 [PMC free article: PMC4864861] [PubMed: 25453306]

169.

Narkiewicz K, Somers VK: Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand 177:385–390, 2003 [PubMed: 12609010]

170.

Narkiewicz K, van de Borne PJ, Montano N, Dyken ME, Phillips BG, Somers VK: Contribution of tonic chemoreflex activation to sympathetic activity and blood pressure in patients with obstructive sleep apnea. Circulation 97:943–945, 1998 [PubMed: 9529260]

171.

Narkiewicz K, van de Borne PJ, Pesek CA, Dyken ME, Montano N, Somers VK: Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 99:1183–1189, 1999 [PubMed: 10069786]

172.

Loredo JS, Ziegler MG, Ancoli-Israel S, Clausen JL, Dimsdale JE: Relationship of arousals from sleep to sympathetic nervous system activity and BP in obstructive sleep apnea. Chest 116:655–659, 1999 [PubMed: 10492267]

173.

Horner RL, Brooks D, Kozar LF, Tse S, Phillipson EA: Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol 79:151–162, 1995 [PubMed: 7559214]

174.

Nonogaki K: New insights into sympathetic regulation of glucose and fat metabolism. Diabetologia 43:533–549, 2000 [PubMed: 10855527]

175.

Deibert DC, DeFronzo RA: Epinephrine-induced insulin resistance in man. J Clin Invest 65:717–721, 1980 [PMC free article: PMC371414] [PubMed: 6243677]

176.

Avogaro A, Toffolo G, Valerio A, Cobelli C: Epinephrine exerts opposite effects on peripheral glucose disposal and glucose-stimulated insulin secretion. A stable label intravenous glucose tolerance test minimal model study. Diabetes 45:1373–1378, 1996 [PubMed: 8826974]

177.

Raz I, Katz A, Spencer MK: Epinephrine inhibits insulin-mediated glycogenesis but enhances glycolysis in human skeletal muscle. Am J Physiol 260:E430–E435, 1991 [PubMed: 1900669]

178.

Lafontan M, Berlan M: Fat cell alpha 2-adrenoceptors: the regulation of fat cell function and lipolysis. Endocr Rev 16:716–738, 1995 [PubMed: 8747832]

179.

Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI: Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859–2865, 1996 [PMC free article: PMC507380] [PubMed: 8675698]

180.

Santomauro AT, Boden G, Silva ME, Rocha DM, Santos RF, Ursich MJ, Strassmann PG, Wajchenberg BL: Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 48:1836–1841, 1999 [PubMed: 10480616]

181.

Julius S, Gudbrandsson T, Jamerson K, Andersson O: The interconnection between sympathetics, microcirculation, and insulin resistance in hypertension. Blood Press 1:9–19, 1992 [PubMed: 1345145]

182.

Jamerson KA, Julius S, Gudbrandsson T, Andersson O, Brant DO: Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 21:618–623, 1993 [PubMed: 8491496]

183.

Zeman RJ, Ludemann R, Easton TG, Etlinger JD: Slow to fast alterations in skeletal muscle fibers caused by clenbuterol, a beta 2-receptor agonist. Am J Physiol 254:E726–E732, 1988 [PubMed: 3377073]

184.

Klein J, Fasshauer M, Ito M, Lowell BB, Benito M, Kahn CR: Beta(3)-adrenergic stimulation differentially inhibits insulin signaling and decreases insulin-induced glucose uptake in brown adipocytes. J Biol Chem 274:34795–34802, 1999 [PubMed: 10574950]

185.

Moncloa F, Velasco I, Beteta L: Plasma cortisol concentration and disappearance rate of 4-14C-cortisol in newcomers to high altitude. J Clin Endocrinol Metab 28:379–382, 1968 [PubMed: 5642689]

186.

Humpeler E, Skrabal F, Bartsch G: Influence of exposure to moderate altitude on the plasma concentraton of cortisol, aldosterone, renin, testosterone, and gonadotropins. Eur J Appl Physiol Occup Physiol 45:167–176, 1980 [PubMed: 6780338]

187.

Maresh CM, Noble BJ, Robertson KL, Harvey JS, Jr.: Aldosterone, cortisol, and electrolyte responses to hypobaric hypoxia in moderate-altitude natives. Aviat Space Environ Med 56:1078–1084, 1985 [PubMed: 4074261]

188.

Anand IS, Chandrashekhar Y, Rao SK, Malhotra RM, Ferrari R, Chandana J, Ramesh B, Shetty KJ, Boparai MS: Body fluid compartments, renal blood flow, and hormones at 6,000 m in normal subjects. J Appl Physiol 74:1234–1239, 1993 [PubMed: 8482663]

189.

Obminski Z, Golec L, Stupnicki R, Hackney AC: Effects of hypobaric-hypoxia on the salivary cortisol levels of aircraft pilots. Aviat Space Environ Med 68:183–186, 1997 [PubMed: 9056024]

190.

Barnholt KE, Hoffman AR, Rock PB, Muza SR, Fulco CS, Braun B, Holloway L, Mazzeo RS, Cymerman A, Friedlander AL: Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. Am J Physiol Endocrinol Metab 290:E1078–E1088, 2006 [PubMed: 16380390]

191.

Coste O, Beers PV, Bogdan A, Charbuy H, Touitou Y: Hypoxic alterations of cortisol circadian rhythm in man after simulation of a long duration flight. Steroids 70:803–810, 2005 [PubMed: 16019044]

192.

Follenius M, Brandenberger G, Bandesapt JJ, Libert JP, Ehrhart J: Nocturnal cortisol release in relation to sleep structure. Sleep 15:21–27, 1992 [PubMed: 1557591]

193.

Spath-Schwalbe E, Gofferje M, Kern W, Born J, Fehm HL: Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol Psychiatry 29:575–584, 1991 [PubMed: 1647222]

194.

Dinneen S, Alzaid A, Miles J, Rizza R: Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest 92:2283–2290, 1993 [PMC free article: PMC288409] [PubMed: 8227343]

195.

Andrews RC, Walker BR: Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond) 96:513–523, 1999 [PubMed: 10209084]

196.

Tasali E, Chapotot F, Leproult R, Whitmore H, Ehrmann DA: Treatment of obstructive sleep apnea improves cardiometabolic function in young obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 96:365–374, 2011 [PMC free article: PMC3048326] [PubMed: 21123449]

197.

Lavie L, Lavie P: Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J 33:1467–1484, 2009 [PubMed: 19483049]

198.

Lavie L: Oxidative stress—a unifying paradigm in obstructive sleep apnea and comorbidities. Prog Cardiovasc Dis 51:303–312, 2009 [PubMed: 19110132]

199.

Barcelo A, Miralles C, Barbe F, Vila M, Pons S, Agusti AG: Abnormal lipid peroxidation in patients with sleep apnoea. Eur Respir J 16:644–647, 2000 [PubMed: 11106206]

200.

Christou K, Markoulis N, Moulas AN, Pastaka C, Gourgoulianis KI: Reactive oxygen metabolites (ROMs) as an index of oxidative stress in obstructive sleep apnea patients. Sleep Breath 7:105–110, 2003 [PubMed: 14569521]

201.

Lavie L, Vishnevsky A, Lavie P: Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 27:123–128, 2004 [PubMed: 14998248]

202.

Yamauchi M, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Suzuki T, Kimura H: Oxidative stress in obstructive sleep apnea. Chest 127:1674–1679, 2005 [PubMed: 15888845]

203.

Tan KC, Chow WS, Lam JC, Lam B, Wong WK, Tam S, Ip MS: HDL dysfunction in obstructive sleep apnea. Atherosclerosis 184:377–382, 2006 [PubMed: 15975582]

204.

Christou K, Moulas AN, Pastaka C, Gourgoulianis KI: Antioxidant capacity in obstructive sleep apnea patients. Sleep Med 4:225–228, 2003 [PubMed: 14592326]

205.

Jung HH, Han H, Lee JH: Sleep apnea, coronary artery disease, and antioxidant status in hemodialysis patients. Am J Kidney Dis 45:875–882, 2005 [PubMed: 15861353]

206.

Dyugovskaya L, Lavie P, Lavie L: Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 165:934–939, 2002 [PubMed: 11934717]

207.

Schulz R, Mahmoudi S, Hattar K, Sibelius U, Olschewski H, Mayer K, Seeger W, Grimminger F: Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 162:566–570, 2000 [PubMed: 10934088]

208.

Saarelainen S, Lehtimaki T, Jaak-kola O, Poussa T, Nikkila M, Solakivi T, Nieminen MM: Autoantibodies against oxidised low-density lipoprotein in patients with obstructive sleep apnoea. Clin Chem Lab Med 37:517–520, 1999 [PubMed: 10418741]

209.

Tiedge M, Lortz S, Drinkgern J, Lenzen S: Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733–1742, 1997 [PubMed: 9356019]

210.

Paolisso G, D’Amore A, Di Maro G, Galzerano D, Tesauro P, Varricchio M, D’Onofrio F: Evidence for a relationship between free radicals and insulin action in the elderly. Metabolism 42:659–663, 1993 [PubMed: 8492724]

211.

Paolisso G, D’Amore A, Volpe C, Balbi V, Saccomanno F, Galzerano D, Giugliano D, Varricchio M, D’Onofrio F: Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (type II) diabetic patients. Metabolism 43:1426–1429, 1994 [PubMed: 7968598]

212.

Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N: Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 47:1562–1569, 1998 [PubMed: 9753293]

213.

Paolisso G, Di Maro G, Pizza G, D’Amore A, Sgambato S, Tesauro P, Varricchio M, D’Onofrio F: Plasma GSH/GSSG affects glucose homeostasis in healthy subjects and non-insulin-dependent diabetics. Am J Physiol 263:E435–E440, 1992 [PubMed: 1415522]

214.

Caballero B: Vitamin E improves the action of insulin. Nutr Rev 51:339–340, 1993 [PubMed: 8108035]

215.

Paolisso G, D’Amore A, Balbi V, Volpe C, Galzerano D, Giugliano D, Sgambato S, Varricchio M, D’Onofrio F: Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am J Physiol 266:E261–E268, 1994 [PubMed: 8141285]

216.

Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K: Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 27:309–314, 1999 [PubMed: 10468203]

217.

Ohga E, Nagase T, Tomita T, Teramoto S, Matsuse T, Katayama H, Ouchi Y: Increased levels of circulating ICAM-1, VCAM-1, and L-selectin in obstructive sleep apnea syndrome. J Appl Physiol 87:10–14, 1999 [PubMed: 10409552]

218.

Chin K, Nakamura T, Shimizu K, Mishima M, Nakamura T, Miyasaka M, Ohi M: Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 109:562–567, 2000 [PubMed: 11063958]

219.

El-Solh AA, Mador MJ, Sikka P, Dhillon RS, Amsterdam D, Grant BJ: Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 121:1541–1547, 2002 [PubMed: 12006441]

220.

Ohga E, Tomita T, Wada H, Yamamoto H, Nagase T, Ouchi Y: Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 94:179–184, 2003 [PubMed: 12391099]

221.

O’Brien LM, Serpero LD, Tauman R, Gozal D: Plasma adhesion molecules in children with sleep-disordered breathing. Chest 129:947–953, 2006 [PubMed: 16608943]

222.

Ursavas A, Karadag M, Rodoplu E, Yilmaztepe A, Oral HB, Gozu RO: Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome. Respiration 74:525–532, 2007 [PubMed: 17148932]

223.

Alberti A, Sarchielli P, Gallinella E, Floridi A, Floridi A, Mazzotta G, Gallai V: Plasma cytokine levels in patients with obstructive sleep apnea syndrome: a preliminary study. J Sleep Res 12:305–311, 2003 [PubMed: 14633242]

224.

Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M: Elevated levels of c-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 107:1129–1134, 2003 [PubMed: 12615790]

225.

Minoguchi K, Tazaki T, Yokoe T, Minoguchi H, Watanabe Y, Yamamoto M, Adachi M: Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome. Chest 126:1473–1479, 2004 [PubMed: 15539715]

226.

Ryan S, Taylor CT, McNicholas WT: Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112:2660–2667, 2005 [PubMed: 16246965]

227.

Dyugovskaya L, Lavie P, Hirsh M, Lavie L: Activated CD8+ T-lymphocytes in obstructive sleep apnoea. Eur Respir J 25:820–828, 2005 [PubMed: 15863638]

228.

Dyugovskaya L, Lavie P, Lavie L: Phenotypic and functional characterization of blood gammadelta T cells in sleep apnea. Am J Respir Crit Care Med 168:242–249, 2003 [PubMed: 12724124]

229.

Dyugovskaya L, Lavie P, Lavie L: Lymphocyte activation as a possible measure of atherosclerotic risk in patients with sleep apnea. Ann N Y Acad Sci 1051:340–350, 2005 [PubMed: 16126976]

230.

Klokker M, Kharazmi A, Galbo H, Bygbjerg I, Pedersen BK: Influence of in vivo hypobaric hypoxia on function of lymphocytes, neutrocytes, natural killer cells, and cytokines. J Appl Physiol 74:1100–1106, 1993 [PubMed: 8387070]

231.

Facco M, Zilli C, Siviero M, Ermolao A, Travain G, Baesso I, Bonamico S, Cabrelle A, Zaccaria M, Agostini C: Modulation of immune response by the acute and chronic exposure to high altitude. Med Sci Sports Exerc 37:768–774, 2005 [PubMed: 15870630]

232.

Zhang Y, Hu Y, Wang F: Effects of a 28-day “living high—training low” on T-lymphocyte subsets in soccer players. Int J Sports Med 28:354–358, 2007 [PubMed: 17024647]

233.

Madden KS, Sanders VM, Felten DL: Catecholamine influences and sympathetic neural modulation of immune responsiveness. Annu Rev Pharmacol Toxicol 35:417–448, 1995 [PubMed: 7598501]

234.

Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES: The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 52:595–638, 2000 [PubMed: 11121511]

235.

Punjabi NM, Beamer BA: C-reactive protein is associated with sleep disordered breathing independent of adiposity. Sleep 30:29–34, 2007 [PMC free article: PMC1978354] [PubMed: 17310862]

236.

Ahima RS, Flier JS: Leptin. Annu Rev Physiol 62:413–437, 2000 [PubMed: 10845097]

237.

Ceddia RB, Koistinen HA, Zierath JR, Sweeney G: Analysis of paradoxical observations on the association between leptin and insulin resistance. FASEB J 16:1163–1176, 2002 [PubMed: 12153984]

238.

Margetic S, Gazzola C, Pegg GG, Hill RA: Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord 26:1407–1433, 2002 [PubMed: 12439643]

239.

Ozturk L, Unal M, Tamer L, Celikoglu F: The association of the severity of obstructive sleep apnea with plasma leptin levels. Arch Otolaryngol Head Neck Surg 129:538–540, 2003 [PubMed: 12759266]

240.

Patel SR, Palmer LJ, Larkin EK, Jenny NS, White DP, Redline S: Relationship between obstructive sleep apnea and diurnal leptin rhythms. Sleep 27:235–239, 2004 [PubMed: 15124716]

241.

Shimura R, Tatsumi K, Nakamura A, Kasahara Y, Tanabe N, Takiguchi Y, Kuriyama T: Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest 127:543–549, 2005 [PubMed: 15705994]

242.

Tatsumi K, Kasahara Y, Kurosu K, Tanabe N, Takiguchi Y, Kuriyama T: Sleep oxygen desaturation and circulating leptin in obstructive sleep apnea-hypopnea syndrome. Chest 127:716–721, 2005 [PubMed: 15764749]

243.

Ulukavak Ciftci T, Kokturk O, Bukan N, Bilgihan A: Leptin and ghrelin levels in patients with obstructive sleep apnea syndrome. Respiration 72:395–401, 2005 [PubMed: 16088283]

244.

McArdle N, Hillman D, Beilin L, Watts G: Metabolic risk factors for vascular disease in obstructive sleep apnea: a matched controlled study. Am J Respir Crit Care Med 175:190–195, 2007 [PubMed: 17068329]

245.

Sharma SK, Kumpawat S, Goel A, Banga A, Ramakrishnan L, Chaturvedi P: Obesity, and not obstructive sleep apnea, is responsible for metabolic abnormalities in a cohort with sleep-disordered breathing. Sleep Med 8:12–17, 2007 [PubMed: 17157064]

246.

Saarelainen S, Lahtela J, Kallonen E: Effect of nasal CPAP treatment on insulin sensitivity and plasma leptin. J Sleep Res 6:146–147, 1997 [PubMed: 9377535]

247.

Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, Mishima M, Nakamura T, Nakao K, Ohi M: Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 100:706–712, 1999 [PubMed: 10449691]

248.

Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH: Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment. Eur Respir J 22:251–257, 2003 [PubMed: 12952256]

249.

Sanner BM, Kollhosser P, Buechner N, Zidek W, Tepel M: Influence of treatment on leptin levels in patients with obstructive sleep apnoea. Eur Respir J 23:601–604, 2004 [PubMed: 15083761]

250.

Tschop M, Strasburger CJ, Topfer M, Hautmann H, Riepl R, Fischer R, Hartmann G, Morrison K, Appenzeller M, Hildebrandt W, Biollaz J, Bartsch P: Influence of hypobaric hypoxia on leptin levels in men. Int J Obes Relat Metab Disord 24(Suppl 2):S151, 2000 [PubMed: 10997640]

251.

Harsch IA, Wallaschofski H, Koebnick C, Pour Schahin S, Hahn EG, Ficker JH, Lohmann T: Adiponectin in patients with obstructive sleep apnea syndrome: course and physiological relevance. Respiration 71:580–586, 2004 [PubMed: 15627868]

252.

Wolk R, Svatikova A, Nelson CA, Gami AS, Govender K, Winnicki M, Somers VK: Plasma levels of adiponectin, a novel adipocyte-derived hormone, in sleep apnea. Obes Res 13:186–190, 2005 [PubMed: 15761179]

253.

Zhang XL, Yin KS, Mao H, Wang H, Yang Y: Serum adiponectin level in patients with obstructive sleep apnea hypopnea syndrome. Chin Med J (Engl) 117:1603–1606, 2004 [PubMed: 15569472]

254.

Masserini B, Morpurgo PS, Donadio F, Baldessari C, Bossi R, Beck-Peccoz P, Orsi E: Reduced levels of adiponectin in sleep apnea syndrome. J Endocrinol Invest 29:700–705, 2006 [PubMed: 17033258]

255.

Zhang XL, Yin KS, Wang H, Su S: Serum adiponectin levels in adult male patients with obstructive sleep apnea hypopnea syndrome. Respiration 73:73–77, 2006 [PubMed: 16205042]

256.

Zhang XL, Yin KS, Li C, Jia EZ, Li YQ, Gao ZF: Effect of continuous positive airway pressure treatment on serum adiponectin level and mean arterial pressure in male patients with obstructive sleep apnea syndrome. Chin Med J (Engl) 120:1477–1481, 2007 [PubMed: 17908452]

257.

Nakagawa Y, Kishida K, Kihara S, Sonoda M, Hirata A, Yasui A, Nishizawa H, Nakamura T, Yoshida R, Shimomura I, Funahashi T: Nocturnal reduction in circulating adiponectin concentrations related to hypoxic stress in severe obstructive sleep apnea-hypopnea syndrome. Am J Physiol Endocrinol Metab 294:E778–E784, 2008 [PubMed: 18198351]

258.

Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature 409:307–312, 2001 [PubMed: 11201732]

259.

Asano T, Sakosda H, Fujishiro M, Anai M, Kushiyama A, Horike N, Kamata H, Ogihara T, Kurihara H, Uchijima Y: Physiological significance of resistin and resistin-like molecules in the inflammatory process and insulin resistance. Curr Diabetes Rev 2:449–454, 2006 [PubMed: 18220647]

260.

Harsch IA, Koebnick C, Wallaschofski H, Schahin SP, Hahn EG, Ficker JH, Lohmann T, Konturek PC: Resistin levels in patients with obstructive sleep apnoea syndrome—the link to subclinical inflammation? Med Sci Monit 10:CR510–CR515, 2004 [PubMed: 15328483]

261.

Tauman R, Serpero LD, Capdevila OS, O’Brien LM, Goldbart AD, Kheirandish-Gozal L, Gozal D: Adipokines in children with sleep disordered breathing. Sleep 30:443–449, 2007 [PubMed: 17520788]

262.

Lecube A, Sampol G, Lloberes P, Romero O, Mesa J, Hernandez C, Simo R: Diabetes is an independent risk factor for severe nocturnal hypoxemia in obese patients. A case-control study. PLOS ONE 4:e4692, 2009 [PMC free article: PMC2650786] [PubMed: 19262746]

263.

Bottini P, Redolfi S, Dottorini ML, Tantucci C: Autonomic neuropathy increases the risk of obstructive sleep apnea in obese diabetics. Respiration 75:265–271, 2008 [PubMed: 17347559]

264.

Keller T, Hader C, De Zeeuw J, Rasche K: Obstructive sleep apnea syndrome: the effect of diabetes and autonomic neuropathy. J Physiol Pharmacol 58(Suppl 5):313–318, 2007 [PubMed: 18204141]

265.

Neumann C, Martinez D, Schmid H: Nocturnal oxygen desaturation in diabetic patients with severe autonomic neuropathy. Diabetes Res Clin Pract 28:97–102, 1995 [PubMed: 7587925]

266.

Rees PJ, Prior JG, Cochrane GM, Clark TJ: Sleep apnoea in diabetic patients with autonomic neuropathy. J R Soc Med 74:192–195, 1981 [PMC free article: PMC1438271] [PubMed: 7205856]

267.

Hein MS, Schlenker EH, Patel KP: Altered control of ventilation in streptozotocin-induced diabetic rats. Proc Soc Exp Biol Med 207:213–219, 1994 [PubMed: 7938052]

268.

Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, Sorbini CA: Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients. Chest 112:145–153, 1997 [PubMed: 9228370]

269.

Kashine S, Kishida K, Funahashi T, Nakagawa Y, Otuki M, Okita K, Iwahashi H, Kihara S, Nakamura T, Matsuzawa Y, Shimomura I: Characteristics of sleep-disordered breathing in Japanese patients with type 2 diabetes mellitus. Metabolism 59:690–696, 2010 [PubMed: 19913847]

270.

Noradina AT, Hamidon BB, Roslan H, Raymond AA: Risk factors for developing sleep-disordered breathing in patients with recent ischaemic stroke. Singapore Med J 47:392–399, 2006 [PubMed: 16645689]

271.

Tada T, Kusano KF, Ogawa A, Iwasaki J, Sakuragi S, Kusano I, Takatsu S, Miyazaki M, Ohe T: The predictors of central and obstructive sleep apnoea in haemodialysis patients. Nephrol Dial Transplant 22:1190–1197, 2007 [PubMed: 17277346]

272.

Pien GW, Schwab RJ: Sleep disorders during pregnancy. Sleep 27:1405–1417, 2004 [PubMed: 15586794]

273.

Hedman C, Pohjasvaara T, Tolonen U, Suhonen-Malm AS, Myllyla VV: Effects of pregnancy on mothers’ sleep. Sleep Med 3:37–42, 2002 [PubMed: 14592252]

274.

Lee KA, Zaffke ME, McEnany G: Parity and sleep patterns during and after pregnancy. Obstet Gynecol 95:14–18, 2000 [PubMed: 10636494]

275.

Driver HS, Shapiro CM: A longitudinal study of sleep stages in young women during pregnancy and postpartum. Sleep 15:449–453, 1992 [PubMed: 1455129]

276.

Hertz G, Fast A, Feinsilver SH, Albertario CL, Schulman H, Fein AM: Sleep in normal late pregnancy. Sleep 15:246–251, 1992 [PubMed: 1621025]

277.

Mindell JA, Jacobson BJ: Sleep disturbances during pregnancy. J Obstet Gynecol Neonatal Nurs 29:590–597, 2000 [PubMed: 11110329]

278.

O’Brien LM, Bullough AS, Owusu JT, Tremblay KA, Brincat CA, Chames MC, Kalbfleisch JD, Chervin RD: Pregnancy-onset habitual snoring, gestational hypertension, and preeclampsia: prospective cohort study. Am J Obstet Gynecol 207:487.e1–487.e9, 2012 [PMC free article: PMC3505221] [PubMed: 22999158]

279.

Bourjeily G, Raker CA, Chalhoub M, Miller MA: Pregnancy and fetal outcomes of symptoms of sleep-disordered breathing. Eur Respir J 36:849–855, 2010 [PubMed: 20525714]

280.

Maasilta P, Bachour A, Teramo K, Polo O, Laitinen LA: Sleep-related disordered breathing during pregnancy in obese women. Chest 120:1448–1454, 2001 [PubMed: 11713118]

281.

Qiu C, Enquobahrie D, Frederick IO, Abetew D, Williams MA: Glucose intolerance and gestational diabetes risk in relation to sleep duration and snoring during pregnancy: a pilot study. BMC Womens Health 10:17, 2010 [PMC free article: PMC2885310] [PubMed: 20470416]

282.

Facco FL, Grobman WA, Kramer J, Ho KH, Zee PC: Self-reported short sleep duration and frequent snoring in pregnancy: impact on glucose metabolism. Am J Obstet Gynecol 203:142.e1–142.e5, 2010 [PMC free article: PMC3178265] [PubMed: 20510182]

283.

Ugur MG, Boynukalin K, Atak Z, Ustuner I, Atakan R, Baykal C: Sleep disturbances in pregnant patients and the relation to obstetric outcome. Clin Exp Obstet Gynecol 39:214–217, 2012 [PubMed: 22905467]

284.

Reutrakul S, Zaidi N, Wroblewski K, Kay HH, Ismail M, Ehrmann DA, Van Cauter E: Sleep disturbances and their relationship to glucose tolerance in pregnancy. Diabetes Care 34:2454–2457, 2011 [PMC free article: PMC3198297] [PubMed: 21926292]

285.

Bourjeily G, El Sabbagh R, Sawan P, Raker C, Wang C, Hott B, Louis M: Epworth sleepiness scale scores and adverse pregnancy outcomes. Sleep Breath 17:1179–1186, 2013 [PubMed: 23420179]

286.

O’Brien LM, Bullough AS, Chames MC: Sleep duration and glucose levels in pregnant women (Abstract). Sleep 36(Suppl):A400, 2013

287.

Facco FL, Liu CS, Cabello AA, Kick A, Gribman WA, Zee PC: Sleep-disordered breathing: a risk factor for adverse pregnancy outcomes? Am J Perinatol 29:277–282, 2012 [PubMed: 22105436]

288.

Chen YH, Kang JH, Lin CC, Wang IT, Keller JJ, Lin HC: Obstructive sleep apnea and the risk of adverse pregnancy outcomes. Am J Obstet Gynecol 206:136.e1–136.e5, 2012 [PubMed: 22000892]

289.

Izci Balserak B, Jackson N, Ratcliffe SA, Pack AI, Pien GW: Sleep-disordered breathing and daytime napping are associated with maternal hyperglycemia. Sleep Breath 17:1093–1102, 2013 [PMC free article: PMC3696035] [PubMed: 23354511]

290.

Herring SJ, Nelson DB, Pien GW, Homko CJ, Goetzl L, Davey A, Foster GD: Objectively-measured sleep duration and hyperglycemia in pregnancy. Sleep Med 15:51–55, 2014 [PMC free article: PMC3947268] [PubMed: 24239498]

291.

Facco FL, Ouyang D, Grobman W, Strohl A, Gonzalez A, Espinoza A, Verzillo V, Zee P: Sleep apnea is associated with an increased risk of gestational diabetes (Abstract). Sleep 36(Suppl):A123, 2013

292.

Reutrakul S, Zaidi N, Wroblewski K, Kay HH, Ismail M, Ehrmann DA, Van Cauter E: Interactions between pregnancy, obstructive sleep apnea, and gestational diabetes mellitus. J Clin Endocrinol Metab 98:4195–4202, 2013 [PMC free article: PMC3790617] [PubMed: 23966237]

293.

Bisson M, Series F, Giguere Y, Pamidi S, Kimoff J, Weisnagel SJ, Marc I: Gestational diabetes mellitus and sleep-disordered breathing. Obstet Gynecol 123:634–641, 2014 [PubMed: 24499765]

294.

Luque-Fernandez MA, Bain PA, Gelaye B, Redline S, Williams MA: Sleep-disordered breathing and gestational diabetes mellitus: a meta-analysis of 9,795 participants enrolled in epidemiological observational studies. Diabetes Care 36:3353–3360, 2013 [PMC free article: PMC3781575] [PubMed: 24065843]

295.

Louis JM, Auckley D, Sokol RJ, Mercer BM: Maternal and neonatal morbidities associated with obstructive sleep apnea complicating pregnancy. Am J Obstet Gynecol 202:261.e1–261.e5, 2010 [PubMed: 20005507]

296.

Champagne K, Schwartzman K, Opatrny L, Barriga P, Morin L, Mallozzi A, Benjamin A, Kimoff RJ: Obstructive sleep apnoea and its association with gestational hypertension. Eur Respir J 33:559–565, 2009 [PubMed: 19213789]

297.

August EM, Salihu HM, Biroscak BJ, Rahman S, Bruder K, Whiteman VE: Systematic review on sleep disorders and obstetric outcomes: scope of current knowledge. Am J Perinatol 30:323–334, 2013 [PubMed: 22893551]

298.

Pamidi S, Pinto LM, Marc I, Benedetti A, Schwartzman K, Kimoff RJ: Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol 210:52.e1–52.e14, 2014 [PubMed: 23911687]

299.

O’Keeffe M, St-Onge MP: Sleep duration and disorders in pregnancy: implications for glucose metabolism and pregnancy outcomes. Int J Obes (Lond) 37:765–770, 2013 [PMC free article: PMC3836666] [PubMed: 22945608]

300.

Guilleminault C, Kreutzer M, Chang JL: Pregnancy, sleep disordered breathing and treatment with nasal continuous positive airway pressure. Sleep Med 5:43–51, 2004 [PubMed: 14725826]

301.

Huang W, Ramsey KM, Marcheva B, Bass J: Circadian rhythms, sleep, and metabolism. J Clin Invest 121:2133–2141, 2011 [PMC free article: PMC3104765] [PubMed: 21633182]

302.

Morris CJ, Yang JN, Scheer FA: The impact of the circadian timing system on cardiovascular and metabolic function. Prog Brain Res 199:337–358, 2012 [PMC free article: PMC3704149] [PubMed: 22877674]

303.

Marcheva B, Ramsey KM, Peek CB, Affinati A, Maury E, Bass J: Circadian clocks and metabolism. Handb Exp Pharmacol 217:127–155, 2013 [PMC free article: PMC4089089] [PubMed: 23604478]

304.

Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, Bass J: Obesity and metabolic syndrome in circadian Clock mutant mice. Science 308:1043–1045, 2005 [PMC free article: PMC3764501] [PubMed: 15845877]

305.

Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim A, Nelson RJ: Light at night increases body mass by shifting the time of food intake. Proc Natl Acad Sci U S A 107:18664–18669, 2010 [PMC free article: PMC2972983] [PubMed: 20937863]

306.

Bureau of Labor Statistics: Workers on Flexible and Shift Schedules in May 2004. Washington, DC: U.S. Department of Labor, Bureau of Labor Statistics, 2005

307.

Oyama I, Kubo T, Fujino Y, Kadowaki K, Kunimoto M, Shirane K, Tabata H, Sabanai K, Nakamura T, Matsuda S: Retrospective cohort study of the risk of impaired glucose tolerance among shift workers. Scand J Work Environ Health 38:337–342, 2012 [PubMed: 22508500]

308.

Suwazono Y, Uetani M, Oishi M, Tanaka K, Morimoto H, Sakata K: Calculation of the benchmark duration of shift work associated with the development of impaired glucose metabolism: a 14-year cohort study on 7104 male workers. Occup Environ Med 67:532–537, 2010 [PubMed: 20573848]

309.

Eriksson AK, van den Donk M, Hilding A, Ostenson CG: Work stress, sense of coherence, and risk of type 2 diabetes in a prospective study of middle-aged Swedish men and women. Diabetes Care 36:2683–2689, 2013 [PMC free article: PMC3747928] [PubMed: 23637356]

310.

Guo Y, Liu Y, Huang X, Rong Y, He M, Wang Y, Yuan J, Wu T, Chen W: The effects of shift work on sleeping quality, hypertension and diabetes in retired workers. PLOS ONE 8:e71107, 2013 [PMC free article: PMC3745433] [PubMed: 23976988]

311.

Monk TH, Buysse DJ: Exposure to shift work as a risk factor for diabetes. J Biol Rhythms 28:356–359, 2013 [PMC free article: PMC4001827] [PubMed: 24132061]

312.

Morikawa Y, Nakagawa H, Miura K, Soyama Y, Ishizaki M, Kido T, Naruse Y, Suwazono Y, Nogawa K: Shift work and the risk of diabetes mellitus among Japanese male factory workers. Scand J Work Environ Health 31:179–183, 2005 [PubMed: 15999569]

313.

Oberlinner C, Ott MG, Nasterlack M, Yong M, Messerer P, Zober A, Lang S: Medical program for shift workers—impacts on chronic disease and mortality outcomes. Scand J Work Environ Health 35:309–318, 2009 [PubMed: 19471844]

314.

Pan A, Schernhammer ES, Sun Q, Hu FB: Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women. PLOS Med 8:e1001141, 2011 [PMC free article: PMC3232220] [PubMed: 22162955]

315.

Suwazono Y, Sakata K, Okubo Y, Harada H, Oishi M, Kobayashi E, Uetani M, Kido T, Nogawa K: Long-term longitudinal study on the relationship between alternating shift work and the onset of diabetes mellitus in male Japanese workers. J Occup Environ Med 48:455–461, 2006 [PubMed: 16688001]

316.

Teratani T, Morimoto H, Sakata K, Oishi M, Tanaka K, Nakada S, Nogawa K, Suwazono Y: Dose-response relationship between tobacco or alcohol consumption and the development of diabetes mellitus in Japanese male workers. Drug Alcohol Depend 125:276–282, 2012 [PubMed: 22445622]

317.

Poulsen K, Cleal B, Clausen T, Andersen LL: Work, diabetes and obesity: a seven year follow-up study among Danish health care workers. PLOS ONE 9:e103425, 2014 [PMC free article: PMC4113351] [PubMed: 25068830]

318.

Vimalananda VG, Palmer JR, Gerlovin H, Wise LA, Rosenzweig JL, Rosenberg L, Ruiz Narvaez EA: Night-shift work and incident diabetes among African-American women. Diabetologia 58:699–706, 2015 [PMC free article: PMC4461435] [PubMed: 25586362]

319.

Morikawa Y, Miura K, Sasaki S, Yoshita K, Yoneyama S, Sakurai M, Ishizaki M, Kido T, Naruse Y, Suwazono Y, Higashiyama M, Nakagawa H: Evaluation of the effects of shift work on nutrient intake: a cross-sectional study. J Occup Health 50:270–278, 2008 [PubMed: 18408349]

320.

Lennernas M, Hambraeus L, Akerstedt T: Shift related dietary intake in day and shift workers. Appetite 25:253–265, 1995 [PubMed: 8746965]

321.

de Assis MA, Nahas MV, Bellisle F, Kupek E: Meals, snacks and food choices in Brazilian shift workers with high energy expenditure. J Hum Nutr Diet 16:283–289, 2003 [PubMed: 12859710]

322.

Gan Y, Yang C, Tong X, Sun H, Cong Y, Yin X, Li L, Cao S, Dong X, Gong Y, Shi O, Deng J, Bi H, Lu Z: Shift work and diabetes mellitus: a meta-analysis of observational studies. Occup Environ Med 72:72–78, 2015 [PubMed: 25030030]

323.

Anothaisintawee T, Reutrakul S, Van Cauter E, Thakkinstian A: Sleep disturbances compared to traditional risk factors for diabetes development: systematic review and meta-analysis. Sleep Med Rev 30:11–24, 2015 [PubMed: 26687279]

324.

Scheer FA, Hilton MF, Mantzoros CS, Shea SA: Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106:4453–4458, 2009 [PMC free article: PMC2657421] [PubMed: 19255424]

325.

Buxton OM, Cain SW, O’Connor SP, Porter JH, Duffy JF, Wang W, Czeisler CA, Shea SA: Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. Sci Transl Med 4:129ra43, 2012 [PMC free article: PMC3678519] [PubMed: 22496545]

326.

McHill AW, Melanson EL, Higgins J, Connick E, Moehlman TM, Stothard ER, Wright KP, Jr.: Impact of circadian misalignment on energy metabolism during simulated nightshift work. Proc Natl Acad Sci U S A 111:17302–17307, 2014 [PMC free article: PMC4260578] [PubMed: 25404342]

327.

Morris CJ, Yang JN, Garcia JI, Myers S, Bozzi I, Wang W, Buxton OM, Shea SA, Scheer FA: Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans. Proc Natl Acad Sci U S A 112:E2225–E2234, 2015 [PMC free article: PMC4418873] [PubMed: 25870289]

328.

Poole CJ, Wright AD, Nattrass M: Control of diabetes mellitus in shift workers. Br J Ind Med 49:513–515, 1992 [PMC free article: PMC1039274] [PubMed: 1637712]

329.

Chalernvanichakorn T, Sithisarankul P, Hiransuthikul N: Shift work and type 2 diabetic patients’ health. J Med Assoc Thai 91:1093–1096, 2008 [PubMed: 18839851]

330.

Young J, Waclawski E, Young JA, Spencer J: Control of type 1 diabetes mellitus and shift work. Occup Med (Lond) 63:70–72, 2013 [PubMed: 23024256]

331.

Zee PC, Attarian H, Videnovic A: Circadian rhythm abnormalities. Continuum (Minneap Minn) 19:132–147, 2013 [PMC free article: PMC3654533] [PubMed: 23385698]

332.

Kantermann T, Duboutay F, Haubruge D, Hampton S, Darling AL, Berry JL, Kerkhofs M, Boudjeltia KZ, Skene DJ: The direction of shift-work rotation impacts metabolic risk independent of chronotype and social jetlag—an exploratory pilot study. Chronobiol Int 31:1139–1145, 2014 [PubMed: 25187988]

333.

Wittmann M, Dinich J, Merrow M, Roenneberg T: Social jetlag: misalignment of biological and social time. Chronobiol Int 23:497–509, 2006 [PubMed: 16687322]

334.

Horne JA, Ostberg O: A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 4:97–110, 1976 [PubMed: 1027738]

335.

Roenneberg T, Kuehnle T, Juda M, Kantermann T, Allebrandt K, Gordijn M, Merrow M: Epidemiology of the human circadian clock. Sleep Med Rev 11:429–438, 2007 [PubMed: 17936039]

336.

Roenneberg T, Kuehnle T, Pramstaller PP, Ricken J, Havel M, Guth A, Merrow M: A marker for the end of adolescence. Curr Biol 14:R1038–R1039, 2004 [PubMed: 15620633]

337.

Merikanto I, Lahti T, Puolijoki H, Vanhala M, Peltonen M, Laatikainen T, Vartiainen E, Salomaa V, Kronholm E, Partonen T: Associations of chronotype and sleep with cardiovascular diseases and type 2 diabetes. Chronobiol Int 30:470–477, 2013 [PubMed: 23281716]

338.

Wong PM, Roecklein KA, Muldoon M, Manuck S: Later chronotype is associated with increased risk for the metabolic syndrome (Abstract). Sleep 36(Suppl):A285, 2013

339.

Finn L, Young EJ, Mignot E, Young T, Peppard PE: Associations of eveningness chronotype with adverse metabolic indications in the Wisconsin Sleep Cohort (Abstract). Sleep 36(Suppl):A188, 2013

340.

Garaulet M, Esteban Tardido A, Lee YC, Smith CE, Parnell LD, Ordovas JM: SIRT1 and CLOCK 3111T>C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity. Int J Obes (Lond) 36:1436–1441, 2012 [PMC free article: PMC4428942] [PubMed: 22310473]

341.

Scott EM, Carter AM, Grant PJ: Association between polymorphisms in the Clock gene, obesity and the metabolic syndrome in man. Int J Obes (Lond) 32:658–662, 2008 [PubMed: 18071340]

342.

Woon PY, Kaisaki PJ, Braganca J, Bihoreau MT, Levy JC, Farrall M, Gauguier D: Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proc Natl Acad Sci U S A 104:14412–14417, 2007 [PMC free article: PMC1958818] [PubMed: 17728404]

343.

Lucassen EA, Zhao X, Rother KI, Mattingly MS, Courville AB, de Jonge L, Csako G, Cizza G; Sleep Extension Study Group: Evening chronotype is associated with changes in eating behavior, more sleep apnea, and increased stress hormones in short sleeping obese individuals. PLOS ONE 8:e56519, 2013 [PMC free article: PMC3590198] [PubMed: 23483886]

344.

Reutrakul S, Hood MM, Crowley SJ, Morgan MK, Teodori M, Knutson KL, Van Cauter E: Chronotype is independently associated with glycemic control in type 2 diabetes. Diabetes Care 36:2523–2529, 2013 [PMC free article: PMC3747872] [PubMed: 23637357]

345.

Iwasaki M, Hirose T, Mita T, Sato F, Ito C, Yamamoto R, Someya Y, Yoshihara T, Tamura Y, Kanazawa A, Kawamori R, Fujitani Y, Watada H: Morningness-eveningness questionnaire score correlates with glycated hemoglobin in middle-aged male workers with type 2 diabetes mellitus. J Diabetes Investig 4:376–381, 2013 [PMC free article: PMC4020233] [PubMed: 24843683]

346.

Osonoi Y, Mita T, Osonoi T, Saito M, Tamasawa A, Nakayama S, Someya Y, Ishida H, Kanazawa A, Gosho M, Fujitani Y, Watada H: Morningness-eveningness questionnaire score and metabolic parameters in patients with type 2 diabetes mellitus. Chronobiol Int 31:1017–1023, 2014 [PubMed: 25102425]

347.

Brzezinski A: Melatonin in humans. N Engl J Med 336:186–195, 1997 [PubMed: 8988899]

348.

Waldhauser F, Dietzel M: Daily and annual rhythms in human melatonin secretion: role in puberty control. Ann N Y Acad Sci 453:205–214, 1985 [PubMed: 3865581]

349.

Crowley SJ: Assessment of circadian rhythms. In The Oxford Handbook of Infant, Child, and Adolescent Sleep and Behavior. Wolfson AR, Montgomery-Downs HE, Eds. New York, NY, Oxford University Press, 2013, p. 204–222

350.

Peschke E, Muhlbauer E: New evidence for a role of melatonin in glucose regulation. Best Pract Res Clin Endocrinol Metab 24:829–841, 2010 [PubMed: 21112029]

351.

Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT: Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol Cell Endocrinol 351:152–166, 2012 [PMC free article: PMC3288509] [PubMed: 22245784]

352.

McArthur AJ, Gillette MU, Prosser RA: Melatonin directly resets the rat suprachiasmatic circadian clock in vitro. Brain Res 565:158–161, 1991 [PubMed: 1773352]

353.

Ramracheya RD, Muller DS, Squires PE, Brereton H, Sugden D, Huang GC, Amiel SA, Jones PM, Persaud SJ: Function and expression of melatonin receptors on human pancreatic islets. J Pineal Res 44:273–279, 2008 [PubMed: 18194202]

354.

Cizza G, Requena M, Galli G, de Jonge L: Chronic sleep deprivation and seasonality: implications for the obesity epidemic. J Endocrinol Invest 34:793–800, 2011 [PMC free article: PMC3297412] [PubMed: 21720205]

355.

Sparso T, Bonnefond A, Andersson E, Bouatia-Naji N, Holmkvist J, Wegner L, Grarup N, Gjesing AP, Banasik K, Cavalcanti-Proenca C, Marchand M, Vaxillaire M, Charpentier G, Jarvelin MR, Tichet J, Balkau B, Marre M, Levy-Marchal C, Faerch K, Borch-Johnsen K, Jorgensen T, Madsbad S, Poulsen P, Vaag A, Dina C, Hansen T, Pedersen O, Froguel P: G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans. Diabetes 58:1450–1456, 2009 [PMC free article: PMC2682679] [PubMed: 19324940]

356.

Langenberg C, Pascoe L, Mari A, Tura A, Laakso M, Frayling TM, Barroso I, Loos RJ, Wareham NJ, Walker M; RISC Consortium: Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response. Diabetologia 52:1537–1542, 2009 [PMC free article: PMC2709880] [PubMed: 19455304]

357.

Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orru M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR: Variants in MTNR1B influence fasting glucose levels. Nat Genet 41:77–81, 2009 [PMC free article: PMC2682768] [PubMed: 19060907]

358.

Lyssenko V, Nagorny CL, Erdos MR, Wierup N, Jonsson A, Spegel P, Bugliani M, Saxena R, Fex M, Pulizzi N, Isomaa B, Tuomi T, Nilsson P, Kuusisto J, Tuomilehto J, Boehnke M, Altshuler D, Sundler F, Eriksson JG, Jackson AU, Laakso M, Marchetti P, Watanabe RM, Mulder H, Groop L: Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82–88, 2009 [PMC free article: PMC3725650] [PubMed: 19060908]

359.

Bonnefond A, Clement N, Fawcett K, Yengo L, Vaillant E, Guillaume JL, Dechaume A, Payne F, Roussel R, Czernichow S, Hercberg S, Hadjadj S, Balkau B, Marre M, Lantieri O, Langenberg C, Bouatia-Naji N; Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC), Charpentier G, Vaxillaire M, Rocheleau G, Wareham NJ, Sladek R, McCarthy MI, Dina C, Barroso I, Jockers R, Froguel P: Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 44:297–301, 2012 [PMC free article: PMC3773908] [PubMed: 22286214]

360.

McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP: Melatonin secretion and the incidence of type 2 diabetes. JAMA 309:1388–1396, 2013 [PMC free article: PMC3804914] [PubMed: 23549584]

361.

Diethelm K, Libuda L, Bolzenius K, Griefahn B, Buyken AE, Remer T: Longitudinal associations between endogenous melatonin production and reported sleep duration from childhood to early adulthood. Horm Res Paediatr 74:390–398, 2010 [PubMed: 20516653]

362.

Hernandez C, Abreu J, Abreu P, Castro A, Jimenez A: Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP. Eur Respir J 30:496–500, 2007 [PubMed: 17537771]

363.

Garfinkel D, Zorin M, Wainstein J, Matas Z, Laudon M, Zisapel N: Efficacy and safety of prolonged-release melatonin in insomnia patients with diabetes: a randomized, double-blind, crossover study. Diabetes Metab Syndr Obes 4:307–313, 2011 [PMC free article: PMC3160855] [PubMed: 21887103]

364.

Rubio-Sastre P, Scheer FA, Gomez-Abellan P, Madrid JA, Garaulet M: Acute melatonin administration in humans impairs glucose tolerance in both the morning and evening. Sleep 37:1715–1719, 2014 [PMC free article: PMC4173928] [PubMed: 25197811]

365.

Vasisht KP, Kessler LE, Booth JN, 3rd, Imperial JG, Penev PD: Differences in insulin secretion and sensitivity in short-sleep insomnia. Sleep 36:955–957, 2013 [PMC free article: PMC3649837] [PubMed: 23729940]

366.

Vgontzas AN, Liao D, Pejovic S, Calhoun S, Karataraki M, Basta M, Fernandez-Mendoza J, Bixler EO: Insomnia with short sleep duration and mortality: the Penn State cohort. Sleep 33:1159–1164, 2010 [PMC free article: PMC2938855] [PubMed: 20857861]

367.

Cespedes EM, Dudley KA, Sotres-Alvarez D, Zee PC, Daviglus ML, Shah NA, Talavera GA, Gallo LC, Mattei J, Qi Q, Ramos AR, Schneiderman N, Espinoza-Giacinto RA, Patel SR: Joint associations of insomnia and sleep duration with prevalent diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). J Diabetes 8:387–397, 2016 [PMC free article: PMC5021506] [PubMed: 25952169]

368.

Kim NH, Lee SK, Eun CR, Seo JA, Kim SG, Choi KM, Baik SH, Choi DS, Yun CH, Kim NH, Shin C: Short sleep duration combined with obstructive sleep apnea is associated with visceral obesity in Korean adults. Sleep 36:723–729, 2013 [PMC free article: PMC3624827] [PubMed: 23633755]

369.

Chin K, Oga T, Takahashi K, Takegami M, Nakayama-Ashida Y, Wakamura T, Sumi K, Nakamura T, Horita S, Oka Y, Minami I, Fukuhara S, Kadotani H: Associations between obstructive sleep apnea, metabolic syndrome, and sleep duration, as measured with an actigraph, in an urban male working population in Japan. Sleep 33:89–95, 2010 [PMC free article: PMC2802253] [PubMed: 20120625]

370.

Siwasaranond N, Nimitphong H, Saetung S, Chirakalwasan N, Ongphiphadhanakul B, Reutrakul S: Shorter sleep duration is associated with poorer glycemic control in type 2 diabetes patients with untreated sleep-disordered breathing. Sleep Breath 20:569–574, 2016 [PubMed: 26298194]

371.

Lajoie P, Aronson KJ, Day A, Tranmer J: A cross-sectional study of shift work, sleep quality and cardiometabolic risk in female hospital employees. BMJ Open 5:e007327, 2015 [PMC free article: PMC4360582] [PubMed: 25757950]

372.

Laudencka A, Klawe JJ, Tafil-Klawe M, Zlomanczuk P: Does night-shift work induce apnea events in obstructive sleep apnea patients? J Physiol Pharmacol 58(Suppl 5):345–347, 2007 [PubMed: 18204146]

373.

Paciorek M, Korczynski P, Bielicki P, Byskiniewicz K, Zielinski J, Chazan R: Obstructive sleep apnea in shift workers. Sleep Med 12:274–277, 2011 [PubMed: 21316298]

374.

Gottlieb DJ, Punjabi NM, Newman AB, Resnick HE, Redline S, Baldwin CM, Nieto FJ: Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med 165:863–867, 2005 [PubMed: 15851636]

375.

Rafalson L, Donahue RP, Stranges S, Lamonte MJ, Dmochowski J, Dorn J, Trevisan M: Short sleep duration is associated with the development of impaired fasting glucose: the Western New York Health Study. Ann Epidemiol 20:883–889, 2010 [PMC free article: PMC2962429] [PubMed: 20620078]

376.

Grandner MA, Chakravorty S, Perlis ML, Oliver L, Gurubhagavatula I: Habitual sleep duration associated with self-reported and objectively determined cardiometabolic risk factors. Sleep Med 15:42–50, 2014 [PMC free article: PMC3947242] [PubMed: 24333222]

377.

Jackson CL, Redline S, Kawachi I, Hu FB: Association between sleep duration and diabetes in black and white adults. Diabetes Care 36:3557–3565, 2013 [PMC free article: PMC3816913] [PubMed: 24026552]

378.

Liu Y, Wheaton AG, Chapman DP, Croft JB: Sleep duration and chronic diseases among U.S. adults age 45 years and older: evidence from the 2010 Behavioral Risk Factor Surveillance System. Sleep 36:1421–1427, 2013 [PMC free article: PMC3773191] [PubMed: 24082301]

379.

Zizi F, Pandey A, Murrray-Bachmann R, Vincent M, McFarlane S, Ogedegbe G, Jean-Louis G: Race/ethnicity, sleep duration, and diabetes mellitus: analysis of the National Health Interview Survey. Am J Med 125:162–167, 2012 [PMC free article: PMC3266551] [PubMed: 22269619]

380.

Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S: The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 328:1230–1235, 1993 [PubMed: 8464434]

381.

Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A: Effects of age on sleep apnea in men: I. prevalence and severity. Am J Respir Crit Care Med 157:144–148, 1998 [PubMed: 9445292]

382.

Bixler EO, Vgontzas AN, Lin HM, Ten Have T, Rein J, Vela-Bueno A, Kales A: Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 163:608–613, 2001 [PubMed: 11254512]

383.

Bearpark H, Elliott L, Grunstein R, Cullen S, Schneider H, Althaus W, Sullivan C: Snoring and sleep apnea. A population study in Australian men. Am J Respir Crit Care Med 151:1459–1465, 1995 [PubMed: 7735600]

384.

Udwadia ZF, Doshi AV, Lonkar SG, Singh CI: Prevalence of sleep-disordered breathing and sleep apnea in middle-aged urban Indian men. Am J Respir Crit Care Med 169:168–173, 2004 [PubMed: 14604837]

385.

Ip MS, Lam B, Lauder IJ, Tsang KW, Chung KF, Mok YW, Lam WK: A community study of sleep-disordered breathing in middle-aged Chinese men in Hong Kong. Chest 119:62–69, 2001 [PubMed: 11157585]

386.

Ip MS, Lam B, Tang LC, Lauder IJ, Ip TY, Lam WK: A community study of sleep-disordered breathing in middle-aged Chinese women in Hong Kong: prevalence and gender differences. Chest 125:127–134, 2004 [PubMed: 14718431]

387.

Kim J, In K, Kim J, You S, Kang K, Shim J, Lee S, Lee J, Lee S, Park C, Shin C: Prevalence of sleep-disordered breathing in middle-aged Korean men and women. Am J Respir Crit Care Med 170:1108–1113, 2004 [PubMed: 15347562]

388.

Tiihonen M, Partinen M, Narvanen S: The severity of obstructive sleep apnoea is associated with insulin resistance. J Sleep Res 2:56–61, 1993 [PubMed: 10607072]

389.

Strohl KP, Novak RD, Singer W, Cahan C, Boehm KD, Denko CW, Hoffstem VS: Insulin levels, blood pressure and sleep apnea. Sleep 17:614–618, 1994 [PubMed: 7846459]

390.

Davies RJ, Turner R, Crosby J, Stradling JR: Plasma insulin and lipid levels in untreated obstructive sleep apnoea and snoring; their comparison with matched controls and response to treatment. J Sleep Res 3:180–185, 1994 [PubMed: 10607124]

391.

Grunstein RR, Stenlof K, Hedner J, Sjostrom L: Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS) Study. Int J Obes Relat Metab Disord 19:410–418, 1995 [PubMed: 7550526]

392.

Stoohs RA, Facchini F, Guilleminault C: Insulin resistance and sleep-disordered breathing in healthy humans. Am J Respir Crit Care Med 154:170–174, 1996 [PubMed: 8680675]

393.

Ip MS, Lam KS, Ho C, Tsang KW, Lam W: Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 118:580–586, 2000 [PubMed: 10988175]

394.

Vgontzas AN, Papanicolaou DA, Bixler EO, Hopper K, Lotsikas A, Lin HM, Kales A, Chrousos GP: Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 85:1151–1158, 2000 [PubMed: 10720054]

395.

Elmasry A, Lindberg E, Berne C, Janson C, Gislason T, Awad Tageldin M, Boman G: Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med 249:153–161, 2001 [PubMed: 11240844]

396.

Ip MS, Lam B, Ng MM, Lam WK, Tsang KW, Lam KS: Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 165:670–676, 2002 [PubMed: 11874812]

397.

Manzella D, Parillo M, Razzino T, Gnasso P, Buonanno S, Gargiulo A, Caputi M, Paolisso G: Soluble leptin receptor and insulin resistance as determinant of sleep apnea. Int J Obes Relat Metab Disord 26:370–375, 2002 [PubMed: 11896492]

398.

Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL: Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 165:677–682, 2002 [PubMed: 11874813]

399.

Meslier N, Gagnadoux F, Giraud P, Person C, Ouksel H, Urban T, Racineux JL: Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome. Eur Respir J 22:156–160, 2003 [PubMed: 12882466]

400.

Tassone F, Lanfranco F, Gianotti L, Pivetti S, Navone F, Rossetto R, Grottoli S, Gai V, Ghigo E, Maccario M: Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables. Clin Endocrinol (Oxf) 59:374–379, 2003 [PubMed: 12919162]

401.

Barcelo A, Barbe F, Llompart E, Mayoralas LR, Ladaria A, Bosch M, Agusti AG: Effects of obesity on c-reactive protein level and metabolic disturbances in male patients with obstructive sleep apnea. Am J Med 117:118–121, 2004 [PubMed: 15234648]

402.

Makino S, Handa H, Suzukawa K, Fujiwara M, Nakamura M, Muraoka S, Takasago I, Tanaka Y, Hashimoto K, Sugimoto T: Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance. Clin Endocrinol (Oxf) 64:12–19, 2006 [PubMed: 16402923]

403.

Kapsimalis F, Varouchakis G, Manousaki A, Daskas S, Nikita D, Kryger M, Gourgoulianis K: Association of sleep apnea severity and obesity with insulin resistance, c-reactive protein, and leptin levels in male patients with obstructive sleep apnea. Lung 186:209–217, 2008 [PubMed: 18365276]

404.

Theorell-Haglow J, Berne C, Janson C, Lindberg E: Obstructive sleep apnoea is associated with decreased insulin sensitivity in females. Eur Respir J 31:1054–1060, 2008 [PubMed: 18184681]

405.

Tkacova R, Dorkova Z, Molcanyiova A, Radikova Z, Klimes I, Tkac I: Cardiovascular risk and insulin resistance in patients with obstructive sleep apnea. Med Sci Monit 14:CR438–CR444, 2008 [PubMed: 18758413]

406.

Punjabi NM, Beamer BA: Alterations in glucose disposal in sleep-disordered breathing. Am J Respir Crit Care Med 179:235–240, 2009 [PMC free article: PMC2633056] [PubMed: 19011148]

407.

Kelly A, Dougherty S, Cucchiara A, Marcus CL, Brooks LJ: Catecholamines, adiponectin, and insulin resistance as measured by HOMA in children with obstructive sleep apnea. Sleep 33:1185–1191, 2010 [PMC free article: PMC2938859] [PubMed: 20857865]

408.

Deboer MD, Mendoza JP, Liu L, Ford G, Yu PL, Gaston BM: Increased systemic inflammation overnight correlates with insulin resistance among children evaluated for obstructive sleep apnea. Sleep Breath 16:349–354, 2012 [PMC free article: PMC3253221] [PubMed: 21360253]

409.

Seicean S, Kirchner HL, Gottlieb DJ, Punjabi NM, Resnick H, Sanders M, Budhiraja R, Singer M, Redline S: Sleep-disordered breathing and impaired glucose metabolism in normal-weight and overweight/obese individuals: the Sleep Heart Health Study. Diabetes Care 31:1001–1006, 2008 [PubMed: 18268072]

410.

Tuomilehto H, Peltonen M, Partinen M, Seppa J, Saaristo T, Korpi-Hyovalti E, Oksa H, Puolijoki H, Saltevo J, Vanhala M, Tuomilehto J: Sleep duration is associated with an increased risk for the prevalence of type 2 diabetes in middle-aged women—the FIN-D2D survey. Sleep Med 9:221–227, 2008 [PubMed: 17644479]

411.

Al-Delaimy WK, Manson JE, Willett WC, Stampfer MJ, Hu FB: Snoring as a risk factor for type II diabetes mellitus: a prospective study. Am J Epidemiol 155:387–393, 2002 [PubMed: 11867347]

412.

Leineweber C, Kecklund G, Akerstedt T, Janszky I, Orth-Gomer K: Snoring and the metabolic syndrome in women. Sleep Med 4:531–536, 2003 [PubMed: 14607347]

413.

Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP: Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 25:735–741, 2004 [PubMed: 15120883]

414.

Dursunoglu N, Dursunoglu D, Ozkurt S, Kiter G, Evyapan F: Gender differences in global cardiovascular risk factors of obstructive sleep apnea patients. Tuberk Toraks 54:305–314, 2006 [PubMed: 17203415]

415.

Sasanabe R, Banno K, Otake K, Hasegawa R, Usui K, Morita M, Shiomi T: Metabolic syndrome in Japanese patients with obstructive sleep apnea syndrome. Hypertens Res 29:315–322, 2006 [PubMed: 16832151]

416.

Gruber A, Horwood F, Sithole J, Ali NJ, Idris I: Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc Diabetol 5:22, 2006 [PMC free article: PMC1636630] [PubMed: 17078884]

417.

Lam JC, Lam B, Lam CL, Fong D, Wang JK, Tse HF, Lam KS, Ip MS: Obstructive sleep apnea and the metabolic syndrome in community-based Chinese adults in Hong Kong. Respir Med 100:980–987, 2006 [PubMed: 16337115]

418.

Onat A, Hergenc G, Uyarel H, Yazici M, Tuncer M, Dogan Y, Can G, Rasche K: Obstructive sleep apnea syndrome is associated with metabolic syndrome rather than insulin resistance. Sleep Breath 11:23–30, 2007 [PubMed: 17061139]

419.

Peled N, Kassirer M, Shitrit D, Kogan Y, Shlomi D, Berliner AS, Kramer MR: The association of OSA with insulin resistance, inflammation and metabolic syndrome. Respir Med 101:1696–1701, 2007 [PubMed: 17466499]

420.

Kono M, Tatsumi K, Saibara T, Nakamura A, Tanabe N, Takiguchi Y, Kuriyama T: Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest 131:1387–1392, 2007 [PubMed: 17494788]

421.

Parish JM, Adam T, Facchiano L: Relationship of metabolic syndrome and obstructive sleep apnea. J Clin Sleep Med 3:467–472, 2007 [PMC free article: PMC1978322] [PubMed: 17803009]

422.

Katsumata K, Okada T, Miyao M, Katsumata Y: High incidence of sleep apnea syndrome in a male diabetic population. Diabetes Res Clin Pract 13:45–51, 1991 [PubMed: 1773713]

423.

Renko AK, Hiltunen L, Laakso M, Rajala U, Keinanen-Kiukaanniemi S: The relationship of glucose tolerance to sleep disorders and daytime sleepiness. Diabetes Res Clin Pract 67:84–91, 2005 [PubMed: 15620438]

424.

West SD, Nicoll DJ, Stradling JR: Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 61:945–950, 2006 [PMC free article: PMC2121154] [PubMed: 16928713]

425.

Juuti AK, Hiltunen L, Rajala U, Laakso M, Harkonen P, Hedberg P, Ruokonen A, Keinanen-Kiukaanniemi S, Laara E: Association of abnormal glucose tolerance with self-reported sleep apnea among a 57-year-old urban population in Northern Finland. Diabetes Res Clin Pract 80:477–482, 2008 [PubMed: 18353486]

426.

Venkateswaran S, Shankar P: The prevalence of syndrome Z (the interaction of obstructive sleep apnoea with the metabolic syndrome) in a teaching hospital in Singapore. Postgrad Med J 83:329–331, 2007 [PMC free article: PMC2600079] [PubMed: 17488863]

427.

Takama N, Kurabayashi M: Relationship between metabolic syndrome and sleep-disordered breathing in patients with cardiovascular disease—metabolic syndrome as a strong factor of nocturnal desaturation. Intern Med 47:709–715, 2008 [PubMed: 18421186]

428.

Mikuni E, Ohoshi T, Hayashi K, Miyamura K: Glucose intolerance in an employed population. Tohoku J Exp Med 141(Suppl):251–256, 1983 [PubMed: 6680494]

429.

Nagaya T, Yoshida H, Takahashi H, Kawai M: Markers of insulin resistance in day and shift workers aged 30–59 years. Int Arch Occup Environ Health 75:562–568, 2002 [PubMed: 12373318]

430.

Karlsson BH, Knutsson AK, Lindahl BO, Alfredsson LS: Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health 76:424–430, 2003 [PubMed: 12783235]

431.

Ika K, Suzuki E, Mitsuhashi T, Takao S, Doi H: Shift work and diabetes mellitus among male workers in Japan: does the intensity of shift work matter? Acta Med Okayama 67:25–33, 2013 [PubMed: 23439506]

CONVERSIONS

Conversions for A1c and glucose values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Drs. Reutrakul, Punjabi, and Van Cauter reported no conflicts of interest. Dr. Reutrakul received speaker honoraria from Sanofi, Novo Nordisk, and Medtronic, and is the recipient of investigator-initiated grant support from Merck. Dr. Punjabi has received research grant support from Philips Respironics and ResMed that is unrelated to the current work. Dr. Van Cauter has served as a consultant for Shire, Philips Respironics, Pfizer, and Vanda Pharmaceuticals, and is the recipient of investigator-initiated grant support from Shire, Merck, and AstraZeneca.

ACKNOWLEDGMENTS/FUNDING The authors acknowledge the contributions of Dr. Esra Tasali and Dr. Jan Polak for their comments on the first draft of this chapter. Large portions of this chapter were previously published by the New York Academy of Sciences (NYAS), and permission to reproduce the material was obtained from the Editor at NYAS. Dr. Reutrakul was supported by research grants from Merck. Dr. Van Cauter was supported by grants from Merck, AstraZeneca, and Shire.