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 increased risk for diabetes, CVD 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 said in an interview.

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 BP. 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.

“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 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.

At baseline, 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 said in an interview. “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 also 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.”

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] suggest 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.”

Increasing CV risks

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.

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. 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 said in an interview. “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 CVD,” 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 at 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 said. “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 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

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

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

There currently is no proven manipulation of the internal body clock that reduces the risk for CVD, 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.

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.

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. 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 of novel targeted therapeutic approaches to counter the adverse health effects of night work and are likely applicable to other sleep and circadian disruptions as well.

– Frank A.J.L. Scheer, PhD

Associate Director, Medical Chronobiology Program

Brigham and Women’s Hospital

Disclosure: Dr. Scheer reports no relevant financial disclosures.

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.

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 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 for 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

Assistant Professor, Department of Chemical Physiology

The Scripps Research Institute, La Jolla, Calif.

Disclosure: Dr. Lamia reports no relevant financial disclosures.