Esra Tasali

Slow-wave sleep and the risk of type 2 diabetes in humans

There is convincing evidence that, in humans, discrete sleep stages are important for daytime brain function, but whether any particular sleep stage has functional significance for the rest of the body is not known. Deep non-rapid eye movement (NREM) sleep, also known as slow-wave sleep (SWS), is thought to be the most “restorative” sleep stage, but beneficial effects of SWS for physical well being have not been demonstrated. The initiation of SWS coincides with hormonal changes that affect glucose regulation, suggesting that SWS may be important for normal glucose tolerance. If this were so, selective suppression of SWS should adversely affect glucose homeostasis and increase the risk of type 2 diabetes. Here we show that, in young healthy adults, all-night selective suppression of SWS, without any change in total sleep time, results in marked decreases in insulin sensitivity without adequate compensatory increase in insulin release, leading to reduced glucose tolerance and increased diabetes risk. SWS suppression reduced delta spectral power, the dominant EEG frequency range in SWS, and left other EEG frequency bands unchanged. Importantly, the magnitude of the decrease in insulin sensitivity was strongly correlated with the magnitude of the reduction in SWS. These findings demonstrate a clear role for SWS in the maintenance of normal glucose homeostasis. Furthermore, our data suggest that reduced sleep quality with low levels of SWS, as occurs in aging and in many obese individuals, may contribute to increase the risk of type 2 diabetes.

Effects of poor and short sleep on glucose metabolism and obesity risk

The importance of sleep to hormones and glucose metabolism was first documented more than four decades ago. Since then, sleep curtailment has become an endemic behavior in modern society. In addition, the prevalence of sleep disorders, particularly obstructive sleep apnea (OSA), has increased. OSA is very common in endocrine and metabolic disorders, but often remains undiagnosed. This Review summarizes the laboratory and epidemiologic evidence that suggests how sleep loss, either behavioral or disease-related, and poor quality of sleep might promote the development of obesity and diabetes mellitus, and exacerbate existing endocrine conditions. Treatment of sleep disorders has the potential to improve glucose metabolism and energy balance. Screening for habitual sleep patterns and OSA might be critically important for patients with endocrine and metabolic disorders.

Metabolic consequences of sleep and sleep loss.

Reduced sleep duration and quality appear to be endemic in modern society. Curtailment of the bedtime period to minimum tolerability is thought to be efficient and harmless by many. It has been known for several decades that sleep is a major modulator of hormonal release, glucose regulation and cardiovascular function. In particular, slow wave sleep (SWS), thought to be the most restorative sleep stage, is associated with decreased heart rate, blood pressure, sympathetic nervous activity and cerebral glucose utilization, compared with wakefulness. During SWS, the anabolic growth hormone is released while the stress hormone cortisol is inhibited. In recent years, laboratory and epidemiologic evidence have converged to indicate that sleep loss may be a novel risk factor for obesity and type 2 diabetes. The increased risk of obesity is possibly linked to the effect of sleep loss on hormones that play a major role in the central control of appetite and energy expenditure, such as leptin and ghrelin. Reduced leptin and increased ghrelin levels correlate with increases in subjective hunger when individuals are sleep restricted rather than well rested. Given the evidence, sleep curtailment appears to be an important, yet modifiable, risk factor for the metabolic syndrome, diabetes and obesity. The marked decrease in average sleep duration in the last 50 years coinciding with the increased prevalence of obesity, together with the observed adverse effects of recurrent partial sleep deprivation on metabolism and hormonal processes, may have important implications for public health.

Obstructive Sleep Apnea and Type 2 Diabetes: Interacting Epidemics

Type 2 diabetes is a major public health concern with high morbidity, mortality, and health-care costs. Recent reports have indicated that the majority of patients with type 2 diabetes also have obstructive sleep apnea (OSA). There is compelling evidence that OSA is a significant risk factor for cardiovascular disease and mortality. Rapidly accumulating data from both epidemiologic and clinical studies suggest that OSA is also independently associated with alterations in glucose metabolism and places patients at an increased risk of the development of type 2 diabetes. Experimental studies in humans and animals have demonstrated that intermittent hypoxia and reduced sleep duration due to sleep fragmentation, as occur in OSA, exert adverse effects on glucose metabolism. Based on the current evidence, clinicians need to address the risk of OSA in patients with type 2 diabetes and, conversely, evaluate the presence of type 2 diabetes in patients with OSA. Clearly, there is a need for further research, using well-designed studies and long-term follow-up, to fully demonstrate a causal role for OSA in the development and severity of type 2 diabetes. In particular, future studies must carefully consider the confounding effects of central obesity in examining the link between OSA and alterations in glucose metabolism. The interactions among the rising epidemics of obesity, OSA, and type 2 diabetes are likely to be complex and involve multiple pathways. A better understanding of the relationship between OSA and type 2 diabetes may have important public health implications.

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

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

Impact of Sleep and Sleep Loss on Neuroendocrine and Metabolic Function

Background: Sleep exerts important modulatory effects on neuroendocrine function and glucose regulation. During the past few decades, sleep curtailment has become a very common behavior in industrialized countries. This trend toward shorter sleep times has occurred over the same time period as the dramatic increases in the prevalence of obesity and diabetes. Aims: This article will review rapidly accumulating laboratory and epidemiologic evidence indicating that chronic partial sleep loss could play a role in the current epidemics of obesity and diabetes. Conclusions: Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes. Epidemiologic findings in both children and adults are consistent with the laboratory data.

Obstructive Sleep Apnea and Metabolic Syndrome : Alterations in Glucose Metabolism and Inflammation

Metabolic syndrome (MS), the commonly used term for the clustering of obesity, insulin resistance, hypertension, and dyslipidemia, affects millions of people worldwide, and is associated with an increased risk of cardiovascular disease and type 2 diabetes. Recently, it has been suggested that obstructive sleep apnea (OSA), an increasingly prevalent condition, may contribute to the development of MS and diabetes. Despite substantial evidence from both clinical and population studies to suggest an independent link between OSA and metabolic abnormalities, the issue still remains controversial. Obesity, particularly visceral obesity, is an important factor in the assessment of adverse metabolic outcome in OSA. Further prospective and interventional studies, with adequate sample sizes and longer follow-up, rigorous control for adiposity, and, ideally, randomization and control for any therapeutic intervention, are clearly needed to address the direction of causality. There are multiple mechanistic pathways involved in the interaction between OSA, obesity, and metabolic derangements. Chronic intermittent hypoxia and sleep fragmentation with sleep loss in OSA are likely key triggers that initiate or contribute to the sustenance of inflammation as a prominent phenomenon, but their complex interplay remains to be elucidated. In summary, OSA may represent a novel risk factor for MS and diabetes, and thus clinicians should be encouraged to systematically evaluate the presence of metabolic abnormalities in OSA and vice versa.

Impaired insulin signaling in human adipocytes after experimental sleep restriction: a randomized, crossover study.

BACKGROUND Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown. OBJECTIVE To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance. DESIGN Randomized, 2-period, 2-condition, crossover clinical study. SETTING University of Chicago Clinical Resource Center. PARTICIPANTS Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m(2) (SD, 1.6). INTERVENTION Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity. MEASUREMENTS Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt-tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test. RESULTS The insulin concentration for the half-maximal pAkt-tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt-tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity. LIMITATION This was a single-center study with a small sample size. CONCLUSION Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues. PRIMARY FUNDING SOURCE National Institutes of Health.

Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society.

ABSTRACT Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine.

Pulmonary manifestations of Behçet's disease

Behcets disease is a chronic inflammatory disorder of unknown aetiology characterised by recurrent attacks. Although the triple symptom complex of oral and genital ulcerations with uveitis was reported by Hippocrates and other authors who attributed the symptom triad to major infections, Hulusi Behcet, a Turkish dermatologist, discarded the association with other illnesses and was the first to delineate the disease that now bears his name.1 Clinical manifestations additional to this triad were described later including involvement of the skin, joints, large vessels, lung, brain, gastrointestinal and genitourinary tracts (table 1).2-6It is now recognised as a multisystem disease with vasculitis as the main pathological finding.6-10 View this table: Table 1 Frequency of clinical manifestations in Behcets disease8 9 12 Since Behcets disease does not have pathognomonic symptoms or laboratory findings, the diagnosis is made on the basis of the criteria proposed by the International Study Group for Behcets disease in 1990 (table 2).11 According to the criteria, recurrent oral ulceration must be present and at least two of the following: recurrent genital ulceration, eye lesions, skin lesions, or a positive pathergy test (development of a papule or pustule following a needle prick to the skin, as in table 2). View this table: Table 2 International Study Group criteria for the diagnosis of Behcets disease11 Although Behcets disease has a worldwide distribution, most cases cluster along the ancient Silk Road which extends from far eastern Asia to the Mediterranean basin (table 3).12-18The highest prevalence rate was reported from Turkey as 80–370 per 100 000. The prevalence ranges from two to 30 cases per 100 000 in other Asian countries, with lower figures in Europe and the USA. The age of disease onset is usually in the second or third decade of life and the male to female ratio is reported to …