Cover Story

Shift work disrupts circadian rhythms, increases health risks in women

For many years, researchers have described the negative effect that shift work has on health.

Most of the literature has focused on the link between circadian rhythm disruptions and an increased risk for diabetes, cardiovascular disease and metabolic syndrome in men. Until now, the data on this association in women have been limited. Recent research, however, shows that women who work shifts are also at risk for this trio of health problems.

Shift work interrupts the body’s normal circadian rhythms, said David J. Earnest, PhD, a professor in the department of neuroscience and experimental therapeutics and Center for Biological Clocks Research at Texas A&M Health Science Center. Circadian rhythms are important for normal health because they provide internal synchronization between the body and the environment, Earnest told Endocrine Today.

Jeyaraj_Darwin

Darwin Jeyaraj, MD, MRCP, of Case Western Reserve University, said his research has linked circadian rhythms to risk for ventricular arrhythmias.
Reprinted with permission from: Darwin Jeyaraj, MD, MRCP

Rotating shifts are especially challenging because they keep the circadian rhythms in a constant state of flux, Earnest said. Normally, it takes about a week for the body to adjust to new working hours. On a rotating shift, a person will typically work a few day shifts, a few night shifts and then a few graveyard shifts, leaving the body no opportunity to adjust.

Eva Schernhammer, MD, DrPH, associate professor of medicine at Harvard Medical School, likened it to jet lag. “When you fly from America to Europe, you have jet lag, and it takes about 5 to 7 days for the body to adjust to the new time,” she said. “Rotating shift workers are in a constant jet lag because they never reach the point where after 5 to 7 days they adjust. We believe that this is the worst-case scenario.”

There are consequences to this constant shifting. “[It] creates an internal disorganization that has pathological consequences,” Earnest said. “We’ve known for a long period of time that circadian rhythms may play a role in CVD.”

Circadian rhythm disruptions also lead to dysregulation of glucose metabolism and blood pressure. In the long run, that can lead to increased insulin resistance, hypoglycemia and, eventually, to type 2 diabetes, said Frank B. Hu, MD, PhD, professor of medicine at Harvard Medical School and professor of nutrition and epidemiology at Harvard School of Public Health.

“In the short term, people can adapt to the disruption of the circadian rhythm, but if the person is exposed to chronic sleep deprivation and disruption of the circadian rhythm, that can lead to increased risk for chronic disease such as diabetes, hypertension and even CVD,” Hu said.

Much of this information comes from studies conducted in men, although women comprise a significant portion of the shift work force (26.7%), according to the Bureau of Labor Statistics (BLS).

“A lot of research has been done with male factory workers,” said Joan E. Tranmer, RN, PhD, associate professor in the School of Nursing, Community Health and Epidemiology at Queen’s University in Kingston, Ontario, Canada. “We know that women are different than men. We have to explore what the pathways are and what to consider when we look at this problem for women.”

Nurses’ Health Study data

Hu and colleagues have begun collecting data on the health implications of shift work in women as part of the Nurses’ Health Study (NHS). They followed women in the NHS I (1998-2008) and the NHS II (1989-2007) who did not have diabetes, CVD and cancer at baseline. There were 69,269 women aged 42 to 67 years in NHS I and 107,915 women aged 25 to 42 years in NHS II.

Earnest_David
David J. Earnest

At baseline, the researchers asked the participants how long they had worked rotating night shifts, which they defined as working at least 3 nights per month besides days and evenings in that month. In NHS II, they updated this information every 2 to 4 years.

During the 18 to 20 years of follow-up, 6,165 women in NHS I and 3,961 women in NHS II developed incident type 2 diabetes. After adjusting for diabetes risk factors, duration of shift work was associated with an increased risk for type 2 diabetes in both cohorts.

“We found a pretty strong relationship between rotating shift work and the subsequent risk for type 2 diabetes,” Hu told Endocrine Today. “And it appears that the longer the duration, the higher the risk. Compared with women who didn’t do shift work, those who did shift work for 10 to 19 years, their risk for developing diabetes increased by 40%; those who did shift work for 20 or more years, their risk for developing diabetes increased by 58%.”

Women who worked shift work for a shorter duration, for example, 3 to 9 years, had a 20% increased risk. “This is a pretty clear dose-response relationship between duration of shift work and increased risk for diabetes,” Hu said.

Effect mediated by weight gain

The researchers examined how weight gain influenced the relationship between shift work and diabetes. “We found that about two-thirds of the effect is mediated through weight gain and/or obesity,” Hu said. “That is the most important mechanism for analyzing this relationship. Women who do shift work tend to gain more weight than those who don’t do shift work.”

Hu_FrankB
Frank B. Hu

There are some reasons for this weight gain, Hu said. First, the shift workers had less-healthy dietary habits compared with nonshift workers. “They ate more calories, ate more snack foods and ate fewer fruits and vegetables,” Hu said. Second, they were more likely to have disrupted sleep patterns, with a greater likelihood of insomnia or sleep deprivation, which can increase appetite hormones and increase insulin resistance.

“[These findings] suggests that we need to pay particular attention to diabetes screening, detection and prevention in this high-risk group,” Hu said. “Of course, health education, eating a healthy diet, increasing physical activity and also balancing sleep with work are all important health messages, not only for the general public, but also more relevant for people who are engaged in shift work.”

Hu’s colleagues are currently in the process of recruiting a younger generation of nurses for the NHS III. Their goal is to enroll 100,000 nurses for this new study.

“It’s important for us to study the younger generation because the exposures to diet and lifestyle are different for the current generation than the older generation,” Hu said. “This is an important research direction for the future.”

fastfacts 

Cardiovascular risks

Besides diabetes risk, shift work also appears to affect heart health in women. Results of Tranmer’s cross-sectional study of 227 women aged 22 to 66 years (mean age, 46 years) showed that women who work rotating shifts at hospitals are at increased risk for CVD.

Participants included nurses, laboratory and equipment technicians, as well as administrative employees who worked at two hospitals in southeastern Ontario.

Tranmer_JoanE
Joan E. Tranmer

The researchers examined the women’s possible risk factors relevant to metabolic syndrome, which include abdominal obesity, high BP, elevated blood glucose, elevated triglycerides and low levels of HDL cholesterol. The women also completed a work history and lifestyle questionnaire.

Results showed that 17% of women in the trial had at least three indicators of CV risk. “[That is] one in five of a middle-aged population,” Tranmer told Endocrine Today. “And the most prevalent were obesity and hypertension.”

Sixty percent of women were overweight or obese, and 37% had hypertension, she said.

Age and a long duration of shift work influenced risk, Tranmer said. Women aged older than 45 years were more likely to have metabolic syndrome. Women who had a history of shift work longer than 6 years had twice the risk for metabolic syndrome indicators.

Currently, Tranmer is trying to determine which potential pathways link shift work to increased CVD risk by examining detailed measures related to potential circadian rhythm disruptions, such as melatonin and cortisol levels. She is also studying behavioral pathways, such as the levels of physical activity and stress.

“We’re trying to tease out what is it about shift work that may put women at increased risk for cardiovascular disease,” Tranmer said. “If we can start teasing some of that out, then we would be better positioned to maybe do some more health promotion strategies.”

Search for answers continues

Research continues on exactly how circadian rhythms influence health. Researchers have found that a novel genetic factor, Krüppel-like factor 15 (KLF15), links the circadian rhythm to vulnerability in ventricular arrhythmias in mice and regulates cardiac electrical activity. Results of this animal study, led by Darwin Jeyaraj, MD, MRCP, assistant professor of medicine, Case Western Reserve University, showed that too little or too much KLF15 causes a disruption in the heart’s electrical cycle, which significantly increases the susceptibility to arrhythmias.

“Increased predilection for sudden cardiac death has been known for a few decades in the general population,” said Jeyaraj, who is also a cardiologist at Harrington Heart and Vascular Institute at University Hospitals Case Medical Center. “In certain hereditary syndromes, an increased nocturnal occurrence of death has been known for a long time. However, causes for such time-dependent occurrence of this fatal disorder were not known. Our study identified a potential link between circadian rhythms and susceptibility to ventricular arrhythmias.”

These results may lead to new diagnostic tools and treatments. “We routinely use ambulatory continuous ECG measurements in clinical cardiology to diagnose arrhythmic disorders,” Jeyaraj told Endocrine Today. “Future studies are necessary in at-risk subjects or families to detect if abnormal 24-hour variations occur in the rhythmic variation in ECG parameters. Next, pharmacological modulation of the clock components, in particular KLF15 that we identified, is another option. However, because these factors regulate many critical cellular processes, this will be challenging.”

Potential remedies

Several potential solutions exist for the problems caused by shift work and the accompanying circadian rhythm disruptions; however, all of them require much more research, Schernhammer said.

“It’s an illusion to think that we could ever get rid of night work,” she said. “Clearly, we have to find some solutions that can allow society to continue working night shift.”

Limiting the amount of night work might be effective. “Because duration of night work seems to matter, maybe every individual should maybe only work 5 years — I’m just randomly giving a number — of rotating night shifts,” Schernhammer said.

Supplements such as melatonin may be useful, but they have not been studied well enough yet, she said.

Nutritional changes might also be an effective way to offset the circadian rhythm disruptions, Earnest said.

“We are trying to find a way to use specific nutrients, like glucose, protein and fatty acids in which we can think about developing therapeutics to say, for example, when someone is on a shift work cycle. … We can go in and recommend that they should be taking certain types of nutrients at specific times during their cycle,” he said.

“We might be able to compensate for some of the problems associated with shift work simply with dietary patterns, in which we get specific about what we take in as far as nutrients and when we take them in,” Earnest said. – by Colleen Owens

 For more information:

  • Arendt J. Chronobiol Int. 2012;29:379-394.
  • Barker A. Diabetes. 2011;60:1805-1812.
  • Buxton OM. Sci Transl Med. 2012;4:129ra43.
  • Damiola F. Genes Dev. 2000;14:2950-2961.
  • Dupuis J. Nat Genet. 2010;42:105-116.
  • Hu FB. Circulation. 2011;123:961-970.
  • Hu C. PLoS One. 2010;5:e15542.
  • Jeyaraj D. Cell Metab. 2012;15:311-323.
  • Jeyaraj D. Nature. 2012;483:96-99.
  • Lamia KA. Nature. 2011;480:552-556.
  • Lamia KA. Proc Natl Acad Sci. 2008;105:15172-15177.
  • Liu C. Nature. 2007;447:477-481.
  • Marcheva B. Nature. 2010;466:627-631.
  • Morgan L. J Endocrinol. 1998;157:443-451.
  • Pan A. PLoS Med. 2011;8:e1001141.
  • Sadacca LA. Diabetologia. 2011;54:120-124.
  • Tranmer JE. Abstract 022. Presented at: Canadian Cardiovascular Congress 2011; Oct. 24-26; Vancouver.
  • Salgado-Delgado R. Endocrinology. 2010;151:1019-1029.
  • Scheer F. PLoS One. 2011;6:e24549.
  • Scheer F. Proc Natl Acad Sci U S A. 2010;107:20541-20546.
  • Scheer F. Proc Natl Acad Sci U S A. 2009;106:4453-4458.
  • Shea SA. Circ Res. 2011;108:980-984.
  • Smith MR. J Biol Rhythms. 2009;24:161-172.
  • Spiegel K. Nat Rev Endocrinol. 2009;5:253-261.
  • Van Cauter E. Am J Physiol. 1994;266:E953-E963.
  • Wolff G. Med Sci Sports Exerc. 2012. [Published online ahead of print, March 28]
  • Yamazaki S. Science. 2000;288:682-5.
  • Zhang EE. Nat Med. 2010;16:1152-1156.

    Disclosures:

    • Drs. Earnest, Hu, Jeyaraj and Schernhammer report no relevant financial disclosures. Dr. Tranmer’s research is supported by by the Ontario Women’s Health Council and the Canadian Institutes of Health Research.

    POINT/COUNTER
    Can the internal body clock be manipulated to reduce the growing risk for CVD, diabetes and metabolic syndrome among shift workers?

    POINT

    It may be possible some day.

    Lamia_Katja
    Katja Lamia

    Epidemiologic studies have demonstrated a clear correlation between circadian disruption and increased susceptibility to metabolic disease. Recent advances in understanding the molecular regulation of metabolic function by mammalian circadian clocks suggests that it may someday be possible to manipulate clock function in order to reduce the adverse effects of shift work on human health.

    A recent study (Solt LA. Nature. 2012;doi:10.1038/nature11030) supporting this idea introduced synthetic compounds that modulate circadian rhythms and reduce fat mass and cholesterol in mice. However, the ability to perform such manipulations reliably and safely will require a more detailed understanding of the molecular connections between clocks and metabolic physiology than we currently have. This is especially important due to the likelihood that circadian clocks have wide-ranging roles in physiology, and altering their function will probably impact many physiological systems.

    Circadian rhythms were first recognized in the 19th century and have been described in a wide variety of organisms, from daily movements of plant leaves to human sleep-wake cycles. In mammals, circadian behavior is driven by the suprachiasmatic nucleus (SCN), a small area of the hypothalamus that receives light signals from the retinas. More recently, circadian clocks have been discovered in virtually all mammalian organ systems and play important roles in metabolic physiology, in particular in the daytime-dependent secretion of glucose from the liver and of insulin from pancreatic beta cells. Circadian clocks in peripheral organs such as the liver and the pancreas seem to optimize the timing of various physiological processes in anticipation of predictable daily changes in metabolic demand, such as fluctuations in food intake.

    Genetic experiments have identified a handful of transcription factors that are required for circadian rhythms in mammals (CLOCK, BMAL1, NPAS2, CRY1-2, PER1-3, REVERB-alpha and REVERB-beta). Several of those factors directly regulate metabolism. For example, mice harboring genetic disruption of CLOCK, BMAL1, CRY1, CRY2, REVERB-alpha or REVERB-beta display altered glucose and/or lipid homeostasis. In addition, a variant allele of the CRY2 gene is associated with increased risk of elevated blood glucose in several different human populations. These alterations in blood glucose probably reflect perturbations of several different molecular pathways. For example, CRY1 and CRY2 can modulate glucose production in the liver by repressing BMAL1-mediated transcription of the glucose transporter glut2, CREB-mediated transcription of glucose 6-phosphatase (g6pc) and phosphoenolpyruvate carboxykinase (pck1) and/or GR-driven transcription of pck1. The ability of CRY1 and CRY2 to modulate gene expression through multiple transcription factor pathways likely contributes to the ability of circadian clocks to coordinate a variety of physiological processes with daily rhythms in the external environment. This apparent promiscuity also presents a challenge for the development of pharmacological strategies to manipulate these pathways for therapeutic benefit.

    Katja Lamia, PhD, is an assistant professor, department of chemical physiology, The Scripps Research Institute in La Jolla, Calif.

    Disclosure: Dr. Lamia reports no relevant financial disclosures.

     

    COUNTER

    Currently, no proven manipulation reduces risk.

    Scheer_Frank
    Frank A. J. L. Scheer

    The short answer is that there currently is no proven manipulation of the internal body clock that reduces the risk for cardiovascular disease, diabetes and metabolic syndrome among shift workers, although intensive research is being conducted in this area. Development of effective and practical countermeasures requires the understanding of the basic underlying mechanisms. The understanding of these mechanisms is still in its infancy but is expanding rapidly. A comprehensive overview is beyond the scope of this brief response, but below is a selection of broad concepts regarding the development of promising countermeasures.

    The human circadian system regulates metabolism and cardiovascular function and has been proposed to optimally regulate their function across the rest/activity cycle. Disruption of this normal alignment between the endogenous circadian system — or body clock — and the behavioral sleep/wake cycle appears to play a key role in these adverse effects of night work on cardiovascular and metabolic function, as supported by laboratory studies. Therefore, realignment between the body clock cycle and the behavioral cycle would appear to be the most logical countermeasure against the adverse effects of night work.

    However, rapid realignment of the central circadian clock is a challenge because of the relatively small phase shifts of a couple of hours per day that can be achieved by even the most potent zeitgeber (time cue): retinal light exposure. This inertia prevents the rapid shifting between different work schedules (as with rotating shifts) and between night work and time off (also in permanent night workers), during which most night workers typically revert to sleeping at night to be with friends and family during the day. The adjustment to the night shift is further impeded by the daylight exposure during the morning commute home after a night shift, which counters the readjustment of the clock to night work. By giving light at night and having people wear dark glasses in the morning, attempts have been made to facilitate the phase adjustment of the circadian system, but there is no data yet on effects on cardiometabolic risk. Another approach would be for night workers to keep their inverted sleep/wake cycle also during their days off. Despite that this been reported for isolated work locations such as oil rigs and Antarctic bases, this may not be feasible for most night workers who want to spend time with their friends and family.

    In addition to the central circadian clock, located in the hypothalamic suprachiasmatic nucleus (SCN), peripheral circadian clocks are present in most organs and tissues, such as heart, liver, lungs and adipose tissue. These peripheral oscillators are normally closely entrained, or synchronized, with the SCN. However, during night work, they may become uncoupled from each other and from the SCN, causing internal desynchrony, which has been observed in animal experimental models. Thus, realigning the different circadian oscillators among themselves and with the SCN may be important to the success of a countermeasure. Recent studies also show the close connection of circadian clock genes with metabolic regulation, such that disruption of clock genes may directly cause metabolic changes. Because the peripheral clocks of different organ systems are differentially sensitive to different behavioral and chemical signals, eg, liver sensitive to food and muscle to exercise, this may require a combination of specific and targeted interventions, in addition to light.

    Instead of trying to manipulate the body clock, another approach is to manipulate part of the behavioral cycle that is misaligned relative to the circadian clock. For example, animal experimental work suggests that manipulating the time of feeding to occur at an appropriate circadian phase, even if the sleep/wake cycle is mistimed, can prevent some of the adverse metabolic effects of simulated shift work in rodents. This seems to be a promising approach. However, at this time, there exist no controlled human data.

    Another approach would be to not correct the circadian misalignment in shift workers, but to alleviate the disruption and shortening of (daytime) sleep that night workers experience, which is a secondary effect of circadian misalignment. Even in a dark and quiet bedroom, daytime sleep is disrupted because the endogenous circadian system sends out its wake promoting signals at that time. That improving sleep might have beneficial cardiometabolic effects is suggested by the adverse effects of experimental sleep restriction and the association of adverse cardiometabolic outcomes with self-reported short sleep. Whether or not hypnotics can reduce the risk for cardiometabolic disease in night workers requires further study.

    In summary, future studies are urgently needed to determine which subcomponents of the circadian system (SCN and different peripheral oscillators), which aspects of the behavioral cycle (including cycles of sleep/wake, fasting/feeding and dark/light), and their interaction are most important to target with the goal to impede and/or reverse the adverse health effects in night workers. Such advances in fundamental knowledge are expected to help in the development novel targeted therapeutic approaches to counter the adverse health effects of night work and are likely applicable as well to other sleep and circadian disruptions.

    Frank A. J. L. Scheer, PhD, is an associate director of the Medical Chronobiology Program, Brigham and Women’s Hospital, Boston; assistant professor of medicine, Harvard Medical School.

    Disclosure: Dr. Scheer reports no relevant financial disclosures.

    For many years, researchers have described the negative effect that shift work has on health.

    Most of the literature has focused on the link between circadian rhythm disruptions and an increased risk for diabetes, cardiovascular disease and metabolic syndrome in men. Until now, the data on this association in women have been limited. Recent research, however, shows that women who work shifts are also at risk for this trio of health problems.

    Shift work interrupts the body’s normal circadian rhythms, said David J. Earnest, PhD, a professor in the department of neuroscience and experimental therapeutics and Center for Biological Clocks Research at Texas A&M Health Science Center. Circadian rhythms are important for normal health because they provide internal synchronization between the body and the environment, Earnest told Endocrine Today.

    Jeyaraj_Darwin

    Darwin Jeyaraj, MD, MRCP, of Case Western Reserve University, said his research has linked circadian rhythms to risk for ventricular arrhythmias.
    Reprinted with permission from: Darwin Jeyaraj, MD, MRCP

    Rotating shifts are especially challenging because they keep the circadian rhythms in a constant state of flux, Earnest said. Normally, it takes about a week for the body to adjust to new working hours. On a rotating shift, a person will typically work a few day shifts, a few night shifts and then a few graveyard shifts, leaving the body no opportunity to adjust.

    Eva Schernhammer, MD, DrPH, associate professor of medicine at Harvard Medical School, likened it to jet lag. “When you fly from America to Europe, you have jet lag, and it takes about 5 to 7 days for the body to adjust to the new time,” she said. “Rotating shift workers are in a constant jet lag because they never reach the point where after 5 to 7 days they adjust. We believe that this is the worst-case scenario.”

    There are consequences to this constant shifting. “[It] creates an internal disorganization that has pathological consequences,” Earnest said. “We’ve known for a long period of time that circadian rhythms may play a role in CVD.”

    Circadian rhythm disruptions also lead to dysregulation of glucose metabolism and blood pressure. In the long run, that can lead to increased insulin resistance, hypoglycemia and, eventually, to type 2 diabetes, said Frank B. Hu, MD, PhD, professor of medicine at Harvard Medical School and professor of nutrition and epidemiology at Harvard School of Public Health.

    “In the short term, people can adapt to the disruption of the circadian rhythm, but if the person is exposed to chronic sleep deprivation and disruption of the circadian rhythm, that can lead to increased risk for chronic disease such as diabetes, hypertension and even CVD,” Hu said.

    Much of this information comes from studies conducted in men, although women comprise a significant portion of the shift work force (26.7%), according to the Bureau of Labor Statistics (BLS).

    “A lot of research has been done with male factory workers,” said Joan E. Tranmer, RN, PhD, associate professor in the School of Nursing, Community Health and Epidemiology at Queen’s University in Kingston, Ontario, Canada. “We know that women are different than men. We have to explore what the pathways are and what to consider when we look at this problem for women.”

    Nurses’ Health Study data

    Hu and colleagues have begun collecting data on the health implications of shift work in women as part of the Nurses’ Health Study (NHS). They followed women in the NHS I (1998-2008) and the NHS II (1989-2007) who did not have diabetes, CVD and cancer at baseline. There were 69,269 women aged 42 to 67 years in NHS I and 107,915 women aged 25 to 42 years in NHS II.

    Earnest_David
    David J. Earnest

    At baseline, the researchers asked the participants how long they had worked rotating night shifts, which they defined as working at least 3 nights per month besides days and evenings in that month. In NHS II, they updated this information every 2 to 4 years.

    During the 18 to 20 years of follow-up, 6,165 women in NHS I and 3,961 women in NHS II developed incident type 2 diabetes. After adjusting for diabetes risk factors, duration of shift work was associated with an increased risk for type 2 diabetes in both cohorts.

    “We found a pretty strong relationship between rotating shift work and the subsequent risk for type 2 diabetes,” Hu told Endocrine Today. “And it appears that the longer the duration, the higher the risk. Compared with women who didn’t do shift work, those who did shift work for 10 to 19 years, their risk for developing diabetes increased by 40%; those who did shift work for 20 or more years, their risk for developing diabetes increased by 58%.”

    Women who worked shift work for a shorter duration, for example, 3 to 9 years, had a 20% increased risk. “This is a pretty clear dose-response relationship between duration of shift work and increased risk for diabetes,” Hu said.

    Effect mediated by weight gain

    The researchers examined how weight gain influenced the relationship between shift work and diabetes. “We found that about two-thirds of the effect is mediated through weight gain and/or obesity,” Hu said. “That is the most important mechanism for analyzing this relationship. Women who do shift work tend to gain more weight than those who don’t do shift work.”

    Hu_FrankB
    Frank B. Hu

    There are some reasons for this weight gain, Hu said. First, the shift workers had less-healthy dietary habits compared with nonshift workers. “They ate more calories, ate more snack foods and ate fewer fruits and vegetables,” Hu said. Second, they were more likely to have disrupted sleep patterns, with a greater likelihood of insomnia or sleep deprivation, which can increase appetite hormones and increase insulin resistance.

    “[These findings] suggests that we need to pay particular attention to diabetes screening, detection and prevention in this high-risk group,” Hu said. “Of course, health education, eating a healthy diet, increasing physical activity and also balancing sleep with work are all important health messages, not only for the general public, but also more relevant for people who are engaged in shift work.”

    Hu’s colleagues are currently in the process of recruiting a younger generation of nurses for the NHS III. Their goal is to enroll 100,000 nurses for this new study.

    “It’s important for us to study the younger generation because the exposures to diet and lifestyle are different for the current generation than the older generation,” Hu said. “This is an important research direction for the future.”

    fastfacts 

    Cardiovascular risks

    Besides diabetes risk, shift work also appears to affect heart health in women. Results of Tranmer’s cross-sectional study of 227 women aged 22 to 66 years (mean age, 46 years) showed that women who work rotating shifts at hospitals are at increased risk for CVD.

    Participants included nurses, laboratory and equipment technicians, as well as administrative employees who worked at two hospitals in southeastern Ontario.

    Tranmer_JoanE
    Joan E. Tranmer

    The researchers examined the women’s possible risk factors relevant to metabolic syndrome, which include abdominal obesity, high BP, elevated blood glucose, elevated triglycerides and low levels of HDL cholesterol. The women also completed a work history and lifestyle questionnaire.

    Results showed that 17% of women in the trial had at least three indicators of CV risk. “[That is] one in five of a middle-aged population,” Tranmer told Endocrine Today. “And the most prevalent were obesity and hypertension.”

    Sixty percent of women were overweight or obese, and 37% had hypertension, she said.

    Age and a long duration of shift work influenced risk, Tranmer said. Women aged older than 45 years were more likely to have metabolic syndrome. Women who had a history of shift work longer than 6 years had twice the risk for metabolic syndrome indicators.

    Currently, Tranmer is trying to determine which potential pathways link shift work to increased CVD risk by examining detailed measures related to potential circadian rhythm disruptions, such as melatonin and cortisol levels. She is also studying behavioral pathways, such as the levels of physical activity and stress.

    “We’re trying to tease out what is it about shift work that may put women at increased risk for cardiovascular disease,” Tranmer said. “If we can start teasing some of that out, then we would be better positioned to maybe do some more health promotion strategies.”

    Search for answers continues

    Research continues on exactly how circadian rhythms influence health. Researchers have found that a novel genetic factor, Krüppel-like factor 15 (KLF15), links the circadian rhythm to vulnerability in ventricular arrhythmias in mice and regulates cardiac electrical activity. Results of this animal study, led by Darwin Jeyaraj, MD, MRCP, assistant professor of medicine, Case Western Reserve University, showed that too little or too much KLF15 causes a disruption in the heart’s electrical cycle, which significantly increases the susceptibility to arrhythmias.

    “Increased predilection for sudden cardiac death has been known for a few decades in the general population,” said Jeyaraj, who is also a cardiologist at Harrington Heart and Vascular Institute at University Hospitals Case Medical Center. “In certain hereditary syndromes, an increased nocturnal occurrence of death has been known for a long time. However, causes for such time-dependent occurrence of this fatal disorder were not known. Our study identified a potential link between circadian rhythms and susceptibility to ventricular arrhythmias.”

    These results may lead to new diagnostic tools and treatments. “We routinely use ambulatory continuous ECG measurements in clinical cardiology to diagnose arrhythmic disorders,” Jeyaraj told Endocrine Today. “Future studies are necessary in at-risk subjects or families to detect if abnormal 24-hour variations occur in the rhythmic variation in ECG parameters. Next, pharmacological modulation of the clock components, in particular KLF15 that we identified, is another option. However, because these factors regulate many critical cellular processes, this will be challenging.”

    Potential remedies

    Several potential solutions exist for the problems caused by shift work and the accompanying circadian rhythm disruptions; however, all of them require much more research, Schernhammer said.

    “It’s an illusion to think that we could ever get rid of night work,” she said. “Clearly, we have to find some solutions that can allow society to continue working night shift.”

    Limiting the amount of night work might be effective. “Because duration of night work seems to matter, maybe every individual should maybe only work 5 years — I’m just randomly giving a number — of rotating night shifts,” Schernhammer said.

    Supplements such as melatonin may be useful, but they have not been studied well enough yet, she said.

    Nutritional changes might also be an effective way to offset the circadian rhythm disruptions, Earnest said.

    “We are trying to find a way to use specific nutrients, like glucose, protein and fatty acids in which we can think about developing therapeutics to say, for example, when someone is on a shift work cycle. … We can go in and recommend that they should be taking certain types of nutrients at specific times during their cycle,” he said.

    “We might be able to compensate for some of the problems associated with shift work simply with dietary patterns, in which we get specific about what we take in as far as nutrients and when we take them in,” Earnest said. – by Colleen Owens

     For more information:

    • Arendt J. Chronobiol Int. 2012;29:379-394.
    • Barker A. Diabetes. 2011;60:1805-1812.
    • Buxton OM. Sci Transl Med. 2012;4:129ra43.
    • Damiola F. Genes Dev. 2000;14:2950-2961.
    • Dupuis J. Nat Genet. 2010;42:105-116.
    • Hu FB. Circulation. 2011;123:961-970.
    • Hu C. PLoS One. 2010;5:e15542.
    • Jeyaraj D. Cell Metab. 2012;15:311-323.
    • Jeyaraj D. Nature. 2012;483:96-99.
    • Lamia KA. Nature. 2011;480:552-556.
    • Lamia KA. Proc Natl Acad Sci. 2008;105:15172-15177.
    • Liu C. Nature. 2007;447:477-481.
    • Marcheva B. Nature. 2010;466:627-631.
    • Morgan L. J Endocrinol. 1998;157:443-451.
    • Pan A. PLoS Med. 2011;8:e1001141.
    • Sadacca LA. Diabetologia. 2011;54:120-124.
    • Tranmer JE. Abstract 022. Presented at: Canadian Cardiovascular Congress 2011; Oct. 24-26; Vancouver.
    • Salgado-Delgado R. Endocrinology. 2010;151:1019-1029.
    • Scheer F. PLoS One. 2011;6:e24549.
    • Scheer F. Proc Natl Acad Sci U S A. 2010;107:20541-20546.
    • Scheer F. Proc Natl Acad Sci U S A. 2009;106:4453-4458.
    • Shea SA. Circ Res. 2011;108:980-984.
    • Smith MR. J Biol Rhythms. 2009;24:161-172.
    • Spiegel K. Nat Rev Endocrinol. 2009;5:253-261.
    • Van Cauter E. Am J Physiol. 1994;266:E953-E963.
    • Wolff G. Med Sci Sports Exerc. 2012. [Published online ahead of print, March 28]
    • Yamazaki S. Science. 2000;288:682-5.
    • Zhang EE. Nat Med. 2010;16:1152-1156.

      Disclosures:

      • Drs. Earnest, Hu, Jeyaraj and Schernhammer report no relevant financial disclosures. Dr. Tranmer’s research is supported by by the Ontario Women’s Health Council and the Canadian Institutes of Health Research.

      POINT/COUNTER
      Can the internal body clock be manipulated to reduce the growing risk for CVD, diabetes and metabolic syndrome among shift workers?

      POINT

      It may be possible some day.

      Lamia_Katja
      Katja Lamia

      Epidemiologic studies have demonstrated a clear correlation between circadian disruption and increased susceptibility to metabolic disease. Recent advances in understanding the molecular regulation of metabolic function by mammalian circadian clocks suggests that it may someday be possible to manipulate clock function in order to reduce the adverse effects of shift work on human health.

      A recent study (Solt LA. Nature. 2012;doi:10.1038/nature11030) supporting this idea introduced synthetic compounds that modulate circadian rhythms and reduce fat mass and cholesterol in mice. However, the ability to perform such manipulations reliably and safely will require a more detailed understanding of the molecular connections between clocks and metabolic physiology than we currently have. This is especially important due to the likelihood that circadian clocks have wide-ranging roles in physiology, and altering their function will probably impact many physiological systems.

      Circadian rhythms were first recognized in the 19th century and have been described in a wide variety of organisms, from daily movements of plant leaves to human sleep-wake cycles. In mammals, circadian behavior is driven by the suprachiasmatic nucleus (SCN), a small area of the hypothalamus that receives light signals from the retinas. More recently, circadian clocks have been discovered in virtually all mammalian organ systems and play important roles in metabolic physiology, in particular in the daytime-dependent secretion of glucose from the liver and of insulin from pancreatic beta cells. Circadian clocks in peripheral organs such as the liver and the pancreas seem to optimize the timing of various physiological processes in anticipation of predictable daily changes in metabolic demand, such as fluctuations in food intake.

      Genetic experiments have identified a handful of transcription factors that are required for circadian rhythms in mammals (CLOCK, BMAL1, NPAS2, CRY1-2, PER1-3, REVERB-alpha and REVERB-beta). Several of those factors directly regulate metabolism. For example, mice harboring genetic disruption of CLOCK, BMAL1, CRY1, CRY2, REVERB-alpha or REVERB-beta display altered glucose and/or lipid homeostasis. In addition, a variant allele of the CRY2 gene is associated with increased risk of elevated blood glucose in several different human populations. These alterations in blood glucose probably reflect perturbations of several different molecular pathways. For example, CRY1 and CRY2 can modulate glucose production in the liver by repressing BMAL1-mediated transcription of the glucose transporter glut2, CREB-mediated transcription of glucose 6-phosphatase (g6pc) and phosphoenolpyruvate carboxykinase (pck1) and/or GR-driven transcription of pck1. The ability of CRY1 and CRY2 to modulate gene expression through multiple transcription factor pathways likely contributes to the ability of circadian clocks to coordinate a variety of physiological processes with daily rhythms in the external environment. This apparent promiscuity also presents a challenge for the development of pharmacological strategies to manipulate these pathways for therapeutic benefit.

      Katja Lamia, PhD, is an assistant professor, department of chemical physiology, The Scripps Research Institute in La Jolla, Calif.

      Disclosure: Dr. Lamia reports no relevant financial disclosures.

       

      COUNTER

      Currently, no proven manipulation reduces risk.

      Scheer_Frank
      Frank A. J. L. Scheer

      The short answer is that there currently is no proven manipulation of the internal body clock that reduces the risk for cardiovascular disease, diabetes and metabolic syndrome among shift workers, although intensive research is being conducted in this area. Development of effective and practical countermeasures requires the understanding of the basic underlying mechanisms. The understanding of these mechanisms is still in its infancy but is expanding rapidly. A comprehensive overview is beyond the scope of this brief response, but below is a selection of broad concepts regarding the development of promising countermeasures.

      The human circadian system regulates metabolism and cardiovascular function and has been proposed to optimally regulate their function across the rest/activity cycle. Disruption of this normal alignment between the endogenous circadian system — or body clock — and the behavioral sleep/wake cycle appears to play a key role in these adverse effects of night work on cardiovascular and metabolic function, as supported by laboratory studies. Therefore, realignment between the body clock cycle and the behavioral cycle would appear to be the most logical countermeasure against the adverse effects of night work.

      However, rapid realignment of the central circadian clock is a challenge because of the relatively small phase shifts of a couple of hours per day that can be achieved by even the most potent zeitgeber (time cue): retinal light exposure. This inertia prevents the rapid shifting between different work schedules (as with rotating shifts) and between night work and time off (also in permanent night workers), during which most night workers typically revert to sleeping at night to be with friends and family during the day. The adjustment to the night shift is further impeded by the daylight exposure during the morning commute home after a night shift, which counters the readjustment of the clock to night work. By giving light at night and having people wear dark glasses in the morning, attempts have been made to facilitate the phase adjustment of the circadian system, but there is no data yet on effects on cardiometabolic risk. Another approach would be for night workers to keep their inverted sleep/wake cycle also during their days off. Despite that this been reported for isolated work locations such as oil rigs and Antarctic bases, this may not be feasible for most night workers who want to spend time with their friends and family.

      In addition to the central circadian clock, located in the hypothalamic suprachiasmatic nucleus (SCN), peripheral circadian clocks are present in most organs and tissues, such as heart, liver, lungs and adipose tissue. These peripheral oscillators are normally closely entrained, or synchronized, with the SCN. However, during night work, they may become uncoupled from each other and from the SCN, causing internal desynchrony, which has been observed in animal experimental models. Thus, realigning the different circadian oscillators among themselves and with the SCN may be important to the success of a countermeasure. Recent studies also show the close connection of circadian clock genes with metabolic regulation, such that disruption of clock genes may directly cause metabolic changes. Because the peripheral clocks of different organ systems are differentially sensitive to different behavioral and chemical signals, eg, liver sensitive to food and muscle to exercise, this may require a combination of specific and targeted interventions, in addition to light.

      Instead of trying to manipulate the body clock, another approach is to manipulate part of the behavioral cycle that is misaligned relative to the circadian clock. For example, animal experimental work suggests that manipulating the time of feeding to occur at an appropriate circadian phase, even if the sleep/wake cycle is mistimed, can prevent some of the adverse metabolic effects of simulated shift work in rodents. This seems to be a promising approach. However, at this time, there exist no controlled human data.

      Another approach would be to not correct the circadian misalignment in shift workers, but to alleviate the disruption and shortening of (daytime) sleep that night workers experience, which is a secondary effect of circadian misalignment. Even in a dark and quiet bedroom, daytime sleep is disrupted because the endogenous circadian system sends out its wake promoting signals at that time. That improving sleep might have beneficial cardiometabolic effects is suggested by the adverse effects of experimental sleep restriction and the association of adverse cardiometabolic outcomes with self-reported short sleep. Whether or not hypnotics can reduce the risk for cardiometabolic disease in night workers requires further study.

      In summary, future studies are urgently needed to determine which subcomponents of the circadian system (SCN and different peripheral oscillators), which aspects of the behavioral cycle (including cycles of sleep/wake, fasting/feeding and dark/light), and their interaction are most important to target with the goal to impede and/or reverse the adverse health effects in night workers. Such advances in fundamental knowledge are expected to help in the development novel targeted therapeutic approaches to counter the adverse health effects of night work and are likely applicable as well to other sleep and circadian disruptions.

      Frank A. J. L. Scheer, PhD, is an associate director of the Medical Chronobiology Program, Brigham and Women’s Hospital, Boston; assistant professor of medicine, Harvard Medical School.

      Disclosure: Dr. Scheer reports no relevant financial disclosures.