Endocrine effects of sleep loss go beyond exhaustion

For far too many adults, the idea of a good night’s sleep is just that — an idea.

According to a 2008 poll from the National Sleep Foundation, the average American is sleeping 6 hours and 40 minutes on workdays, and an average of 7 hours and 25 minutes on other days. The numbers are a far cry from the average of 8 hours and 40 minutes per night adults reported sleeping in the 1960s, and the health consequences of those lost hours can be dramatic, even life-threatening.

Photo by Jean Lachat for the University of Chicago Medicine

Sleep disturbances are common in endocrine disorders, particularly in metabolic disorders. Sleep restriction, or poor quality sleep, is now widely recognized as a risk factor for both obesity and type 2 diabetes. Untreated sleep disorders can exacerbate both diseases.

“The endocrine system is almost like a microcosm of all aspects of sleep loss,” M. Safwan Badr, MD, a professor and chief of the division of pulmonary, critical care and sleep medicine at Wayne State University School of Medicine in Detroit, told Endocrine Today. “I don’t think people are focusing enough on all the adverse consequences of sleep loss, insufficient sleep, sleep deficiency — whatever term we use — on the endocrine system, cardiovascular system, on blood pressure, cognition and mortality. And they’re all, to some extent, probably connected.”

Badr devised a creative way to drive home the importance of sleep. Patients, he said, seemed to understand the role of a healthy diet and exercise in good health, whereas sleep was not taken seriously.

He decided to treat sleep like a prescribed drug.

“In the days when we actually had prescription pads, I would write a prescription for 8 hours of sleep, times 2 weeks, and then come and talk to me,” said Badr, also a past president of the American Academy of Sleep Medicine. “This is how important it is. If I write you a prescription for an antibiotic, you grab it. And I’m telling you this is cheap, and you need to do it.”

A diabetes risk factor

Sleep disturbances come in several forms, according to Eve Van Cauter, PhD, professor of medicine and director of the Sleep, Metabolism and Health Center at the University of Chicago. With behavioral sleep curtailment, a person will fight the urge to sleep to do other things, Van Cauter said. For some, circadian rhythm disturbance will occur when a person engages in behavior that ignores the biological clock, including shift work. For others, obstructive sleep apnea — often a byproduct of obesity — makes achieving quality sleep difficult.

The consequences of chronic sleep curtailment can go far beyond feeling tired. In the past decade, researchers have examined glucose regulation after participants with normal glucose tolerance experienced insufficient sleep in a laboratory setting. Across multiple studies, Van Cauter said, the results have been similar.

“There have been a number of different renditions [of sleep restriction studies] ... and the studies have been consistent that in less than a week of sleep restriction — which is typical of the contemporary adult — there is a large decrease in insulin sensitivity,” Van Cauter told Endocrine Today. “And the beta cell, instead of being able to compensate by producing more insulin, is not compensating. Therefore, the risk of diabetes is increasing.”

In a 2015 meta-analysis of prospective observational sleep studies appearing in Diabetes Care, Chandra L. Jackson, PhD, a research associate with the Clinical and Translational Science Center at Harvard Catalyst and the Harvard T. H. Chan School of Public Health, and colleagues assessed the dose-response relationship between sleep duration and type 2 diabetes risk.

Researchers analyzed data from 18,443 incident cases of type 2 diabetes among 482,502 participants with follow-up periods ranging from 2.5 to 16 years, and found a U-shaped relationship between sleep duration and type 2 diabetes, with the lowest risk associated with 7 to 8 hours of sleep per day. Researchers found the pooled relative risk for type 2 diabetes was 1.09 (95% CI, 1.04-1.15) for each hour of sleep lost among individuals who slept less than 7 hours per day, when compared with participants sleeping 7 hours per day. Researchers also found a link between type 2 diabetes and long sleep: The pooled relative risk was 1.14 (95% CI, 1.03-1.26) for each additional hour of sleep among individuals with longer sleep duration.

“Disruptions in a person’s circadian rhythm, such as shift work when one eats during the night, is especially bad for metabolic health,” Jackson told Endocrine Today. “The body typically releases hormones across the 24-hour period. Weight gain and problems with glucose and insulin metabolism may result when one eats at times when hormones have not been primed to optimally respond to food.”

Sleep time and obesity risk

Studies that examined levels of leptin and ghrelin following sleep restriction revealed a strong link between sleep curtailment and appetite regulation, Van Cauter said. Participants in multiple studies, after 4 or 5 nights of normal sleep, would be subjected to 1 or 2 nights of restricted sleep. Under short sleep conditions, leptin levels decrease, whereas hormones that control hunger, such as ghrelin, increase.

In a 2004 study conducted by Shahrad Taheri, MD, of Weill Cornell Medical College in Qatar, and colleagues, researchers analyzed data from 1,024 volunteers participating in the Wisconsin Sleep Cohort Study, a population-based longitudinal study of sleep disorders. Participants underwent overnight polysomnography for 1 night in a sleep laboratory, with participants setting their own sleep and wake times, and completed questionnaires and 6-day sleep diaries regarding their sleep habits. After 1 night of sleep in the laboratory, researchers evaluated serum leptin and ghrelin, adiponectin, insulin and glucose levels. The study, according to researchers, was the first to demonstrate a correlation between peripheral hormone levels and both self-reported and polysomnographically determined sleep amounts in a general population sample.

After adjustment for BMI, age and sex, researchers found that a decrease from 8 to 5 hours in average nightly sleep was associated with a predicted 15.5% decrease in leptin and a 14.9% increase in ghrelin. In addition, researchers found that less than 7.7 hours of habitual sleep duration was associated with increased BMI.

A decade later, additional studies further strengthen the link between sleep and appetite, though the exact impact of sleep loss on leptin and ghrelin specifically remain an issue of debate. In a 2014 study appearing in The Journal of Clinical Endocrinology & Metabolism, Van Cauter and colleagues analyzed the adverse effects of sleep restriction on various hormone levels. Thirteen participants were randomly assigned to 2 nights of 10 hours in bed vs. 2 nights of 4 hours in bed. Researchers sampled blood in 20-minute intervals from 9 a.m. to midnight to measure ACTH and total cortisol, collected saliva every 20 minutes from 2 p.m. to midnight to measure free cortisol and assessed perceived stress, hunger and appetite at hourly intervals with validated scales.

Sleep restriction was associated with a 19% increase in overall ATCH, as well as a 21% increase in overall total cortisol that was correlated with an increase in appetite, compared with participants assigned to 10 hours in bed.

A 2014 study in the International Journal of Obesity also explored the effect of sleep restriction on brain responses to food. Marie-Pierre St. Onge, PhD, FAHA, of the College of Physicians and Surgeons at Columbia University, and colleagues analyzed data from 25 normal-weight participants who typically slept 7 to 9 hours per night, randomly assigned to either 5 nights of either 4 or 9 hours in bed. Researchers performed functional MRI in a fasted state, presenting healthy and unhealthy food stimuli and objects in a block design, to measure responses to unhealthy and healthy food stimuli after each sleep period.

Researchers found that, after a period of restricted sleep, viewing the unhealthy foods led to greater activation in the superior and middle temporal gyri, middle and superior frontal gyri, left inferior parietal lobule, orbitofrontal cortex, and right insula when compared with healthy foods. Food intake during restricted sleep also increased, according to researchers.

“Acute sleep deprivation tends to tip the hormonal balance toward weight gain,” Eric Olson, MD, director of the Mayo Clinic’s Sleep Medicine Specialty Council and co-director of the Mayo Clinic Center for Sleep Medicine, told Endocrine Today. “Ghrelin increases, and you get this craving for high-calorie food.”

Participants in similar studies, Badr said, typically self-reported feeling more hungry and reported craving or eating carbohydrate-rich foods, including salty snacks, starchy foods and sweets.

“After a night of sleep deprivation ... you’re not going to wake up and go, ‘Boy, I’m really craving some celery,’” Badr said. “After a night of sleep deprivation, we crave doughnuts, muffins.”

Restricted sleep also interferes with high-level cognitive functions, Jackson said, which can influence decision making regarding healthful eating.

“Insufficient sleep influences the brain’s responses to food cues,” Jackson said. “Sleep-deprived people have been shown to have higher activation of their brain’s reward centers when viewing high-calorie foods compared with individuals who are not sleep deprived.”

Recent studies have also examined whether staying awake longer burns more energy — that some may overeat when sleep deprived in response to a need for more energy to sustain the cost of extended wakefulness.

“The studies have been done carefully ... and have shown that, yes indeed, extending wakefulness has an energy cost, but the energy cost is small, about 15 to 20 calories per hour,” Van Cauter said. “So, if you sleep 4 ½ hours instead of 7 ½ hours, that is burning roughly 50 to 60 calories, which is a small portion of a cookie. So, the stimulation of hunger and appetite far exceeds the energy demands of the extended wakefulness.”

Obesity and obstructive sleep apnea — a greater risk

Restricted sleep is a risk factor for obesity, but obesity, in turn, can further affect quality of sleep, increasing the risk for developing comorbid conditions, such as type 2 diabetes.

“The main impact may be through obesity increasing risk for obstructive sleep apnea, a condition of repetitive breathing pauses during sleep due to intermittent narrowing of the upper airway,” Olson said. “Obesity is the most important risk factor for this condition. Other conditions precipitated by obesity may, in turn, disrupt sleep. For example, arthropathy of the knees may cause pain that disrupts sleep.”

“My personal opinion — not demonstrated, not published — is that today, in the population of obese diabetics, the majority of people became diabetic because they had obstructive sleep apnea,” Van Cauter said. “And it’s a major risk factor in the population where today, two out of three people are overweight or obese. This enormous increase in the prevalence of diabetes is driven by the epidemic of obesity, but within the epidemic of obesity, the real toxic aspect is obstructive sleep apnea.”

Sleep and clinical practice

More research continues to reveal the important role sleep plays in overall health. At the same time, sleep has become less of a priority among patients. Clinicians, experts say, are not doing enough to address the problem.

“Americans have reduced their time in bed by an hour and a half to 2 hours in order to watch TV,” Van Cauter said. “We live in this 24-hour society, and people have chosen to disregard sleep. That is because having enough sleep is not [considered one] of the pillars of health. Doctors talk about diet, they talk about exercise. They don’t talk about sleep, because they don’t know about sleep.”

Although between 50 million and 70 million adults are believed to have sleep or wakefulness disorders, many clinicians, including endocrinologists, have had limited education in sleep medicine, Jackson said. Clinicians are also challenged by the short time available with patients to address sleep issues, especially when a patient has competing health concerns.

In addition, electronic health records typically fail to ask key questions that gauge sleep health.

“This gets to one of my pet peeves in this business, which is, if you look at the typical physician intake [form]... it has a whole lot of things in it that I consider ... not common things,” Badr said. “I saw one that had [a question] about galactorrhea. How often do I see galactorrhea? But it does not have a word about sleep.

“The starting point is asking the question, and it may be as simple as, ‘How is your sleep?’ ‘How many hours of sleep do you get?’” Badr said. “We need to embed questions like these in all the electronic medical records templates. It has to be part of a standard review.”

Importance of healthy sleep habits

Getting good, quality sleep is associated with a reduced risk for obesity, diabetes, hypertension, heart disease, stroke and cancer, as well as a reduced risk for mental health conditions, including depression and dementia, Jackson said.

“In one study, we found a relationship between poor sleep quality, reduced quality of life and depression,” Taheri said. “Asking about sleep duration and patterns provides a good insight into a patient’s lifestyle. Regular sleep habits will have long-term benefits for a patient’s health and well-being.”

The benefits of good sleep have been shown to restore memory, improve the mood and improve functionality, according to Harneet Walia, MD, FAASM, of the center for sleep disorders at Cleveland Clinic. Getting more sleep may also have metabolic benefits, including improving glucose regulation, although more studies are needed to know for certain, Walia said.

“Sleep should definitely be one of the priority symptoms that [clinicians] should be assessing for,” Walia told Endocrine Today. “They should assess the amount of sleep that a person is obtaining, the sleep habits, the sleep-wake patterns, and they should be cognizant of how to counsel patients on good sleep hygiene and the adequate amount of sleep.”

Clinicians should also discuss ways to create healthy sleep habits with their patients, Olson said. Some of those steps, like creating a pleasant, comfortable place to sleep, limiting total time for sleep to 8 hours per day and avoiding watching the clock if unable to fall asleep, can seem like simple changes. Other steps — regular exercise and minimizing the intake of caffeine, alcohol and tobacco — are behavioral changes that are often more difficult to achieve.

“We need behavioral and public health research to identify the best ways to change individual sleep health behaviors and improve sleep across communities, especially those that are most at risk,” Susan Redline, MD, MPH, a professor of sleep medicine at Harvard Medical School and senior physician in the division of sleep and circadian disorders at Brigham and Women’s Hospital in Boston, told Endocrine Today. “We need to better understand the neuroendocrine signals that are responsible for eating behaviors after sleep deprivation.”

More research is also needed to better understand how the patterns of sleep across the life span, including in early childhood, may influence obesity and diabetes risk, Redline said. – by Regina Schaffer

• References:
• Araghi MH, et al. Sleep. 2013;doi:10.5665/sleep.3216.
• Beebe DW, et al. Sleep. 2013;doi:10.5665/sleep.2704.
• Cain SW, et al. Scand J Work Environ Health. 2015;doi:10.5271/sjweh.3486.
• Guyon A, et al. J Clin Endocrinol Metab. 2014;doi:10.1210/jc.2013-4254.
• Jung CM, et al. J Physiol. 2011;doi:10.1113/jphysiol.2010.197517.
• Sariarslan HA, et al. Neurosciences (Riyadh). 2015;doi:10.17712/nsj.2015.3.20150157.
• Spiegel K, et al. Lancet. 1999;354:1435-1439.
• St. Onge MP, et al. Int J Obes (Lond). 2104;doi:10.1038/ijo.2013.114.
• Taheri S, et al. PLoS Med. 2004;1:e62.
• Yaggi HK, et al. Diabetes Care. 2006;29:657-661.

• For more information:
• M. Safwan Badr, MD, can be reached at 3990 John R St., Detroit, MI 48201; email: sbadr@dmc.org.
• Chandra L. Jackson, PhD, can be reached at 10 Shattuck St., Boston, MA 02115; email: chandra_jackson@hms.harvard.edu.
• Eric Olson, MD, can be reached at 200 First Street SW, Rochester, MN 55905; email: olson.eric@mayo.edu.
• Susan Redline, MD, MPH, can be reached at 75 Francis St., Boston, MA 02115; email: sredline1@rics.bwh.harvard.edu.
• Shahrad Taheri, MBBS, PhD, can be reached at email: szt2004@qatar-med.cornell.edu.
• Eve Van Cauter, PhD, 5841 S. Maryland Ave., Chicago, IL 60637; email: evcauter@medicine.bsd.uchicago.edu.
• Harneet Walia, MD, FAASM, can be reached at 11203 Stokes Blvd., Cleveland, OH, 44104; email: waliah@ccf.org.

Disclosures: Badr, Jackson, Olson, Redline, Taheri and Walia report no relevant financial disclosures. Van Cauter reports receiving funding from Philips Respironics.

Can a sleep debt be repaid?

Chronic sleep loss takes a toll, but some evidence suggests that with enough recovery sleep, the debt can be repaid.

When adults were subjected to a harsh “jet lag” protocol in which they basically lived 28-hour long days for 3 weeks, sleeping only 5.6 hours per 24-hour period, insulin sensitivity was significantly impaired but had normalized after 9 days of recovery sleep. Long-time shift workers showed signs of cognitive aging equaling 6.5 extra years of age, but their cognitive functions were indistinguishable from never-shift workers 5 years or more after quitting shift work. Individuals who reported sleep problems at age 50 had a 50% increased risk of developing Alzheimer’s disease over the next 40 years, but the risk was especially pronounced for those who reported still having sleep problems at age 70, suggesting that improving sleep during this time period can counteract long-term negative effects of sleep problems.

When extended periods of sleep are not possible, it is even more important to try to make those few hours of sleep as high in quality as possible. This includes keeping a regular sleep-wake schedule, exercising in moderate amounts, being exposed to natural bright light during the day (but avoiding it late at night) and avoiding sleep-disruptive substances, such as caffeine, alcohol and nicotine. Evidence suggests that exercise can improve sleep by increasing the amount of restorative slow-wave sleep. Even though a nap does not equal the amount of sleep lost during the night, it can substantially improve the retention of recently learned memories, restore vigor and reduce the inflammation that goes along with sleep loss.

Sleep that is “mistimed,” ie, occurring during the day, is less efficient and typically shorter in duration than nighttime sleep, the time during which the biological clock has programmed sleep to occur. Indeed, daytime sleep seems to worsen metabolism and inflammation more than a shorter amount of “properly timed” nighttime sleep. Importantly, one may be able to prevent some sleep debt by sleeping more prior to subsequent sleep loss, as this can mitigate at least some effects of sleep loss and make recovery faster afterwards.

Given enough time to sleep as much as we need, it seems we may be able to repay at least some of the effects of extended sleep loss. The question is when to find the time needed to do this. Losing 2 hours of sleep each work day, year after year, can amount to thousands of hours of lost sleep. Yet only a few of those hours can be recovered every weekend. Nevertheless, the extent to which the body and mind can seemingly often be restored after a single night of good sleep is remarkable. Full recovery may take significantly longer periods of adequate sleep, and our performance may be impaired during this time even though we are not aware of it.

Jonathan Cedernaes, MD, PhD, is a researcher in the Department of Neuroscience at Uppsala University Sweden. Disclosure: Cedernaes reports no relevant financial disclosures.

Perhaps, but staying out of debt is difficult.

Short sleep duration, particularly on workdays, is a ubiquitous phenomenon in today’s society. To compensate, adults often try to get “catch-up sleep” on weekends. However, what ends up happening is somewhat later bedtimes on nights before free/non-work days and much later wake times on free days than workdays. This behavior has been well documented and described as “social jetlag”: the discrepancy in sleep timing between workdays and free days. For some, the time difference can be quite striking, as high as 2 to 3 hours, which is akin to westward travel by two to three time zones on Friday nights and return east on Monday morning.

Social jetlag results from an attempt to pay back, over 2 days, a sleep debt incurred during the 5-day workweek. Yet, this behavior, which should be expected to counteract the negative effects of short sleep duration on obesity and cardiometabolic risk, is in itself associated with adverse health effects. In fact, studies have shown that increasing social jetlag is associated with increased BMI and fat mass and higher odds of obesity and metabolic syndrome. In those who have obesity and metabolic syndrome, social jetlag increases the risk of having elevated C-reactive protein, a marker of chronic inflammation, and increased HbA1c. In healthy individuals, social jetlag of at least 2 hours is associated with higher cortisol levels and resting heart rate, lower physical activity levels and shorter sleep duration than social jetlag of 1 hour or less.

Studies show that recovery sleep can reverse the adverse health effects of acute, severe sleep restriction. However, little is known about recurring mild sleep restriction, and there are no studies to date to show whether recuperating sleep on weekends can cancel the adverse effects of 5 of 7 days of mild sleep restriction. Given that epidemiologic studies of social jetlag show that shifting sleep timing back and forth during long periods of time is related to a worse metabolic profile, it is likely that 2 nights of longer weekend sleep may not be sufficient, over the long term, in reducing the risk for diabetes and cardiovascular disease. Therefore, chronic short sleep may very well be just as detrimental as “yo-yo” sleeping, resulting in social jetlag, at least from a metabolic standpoint. Other effects on mood, cognition and work safety, to name a few, have not been considered herein. However, again here one can argue that sleep inertia occurs while repaying a sleep debt, and one must push through this initial stage to reap benefits — if only to get back into short sleep after a couple of days, the benefits are unlikely to be prominent.

Should a sleep debt be paid? Absolutely! But only if you don’t fall back into debt week after week. For it is well known that a consistent sleep schedule, of at least 7 hours of sleep per night, is associated with the lowest risk of chronic disorders and best health outcomes.

Marie-Pierre St-Onge, PhD, FAHA, is an assistant professor of medicine at Columbia University College of Physicians and Surgeons. Disclosure: St-Onge reports no relevant financial disclosures.