Chronobiology International, 2014; 31(10): 1146–1151 ! Informa Healthcare USA, Inc. ISSN: 0742-0528 print / 1525-6073 online DOI: 10.3109/07420528.2014.957308
ORIGINAL ARTICLE
Shift work and diabetes – A systematic review Anders Knutsson1 and Anders Kempe2 Department of Health Sciences, Mid Sweden University, Sundsvall, Sweden and 2Health Centre of So¨ra˚ker, Timra˚, Sweden
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1
Diabetes mellitus is a chronic disease, which has an increasing trend all over the world. Type 2 diabetes constitutes 90% of all diabetes. It is associated with weight gain and insulin resistance. Research during recent years has suggested that shift work could be a risk factor of type 2 diabetes. Since shift work is becoming more common, it could contribute to the increasing trend of diabetes. In this systematic review, we have studied the potential association between shift work and type 2 diabetes. We have also reviewed studies on control of diabetes in relation to shift work. Keywords: Circadian disruption, diabetes control, nightwork, shiftwork, work schedules
INTRODUCTION The prevalence of shift work has increased during the last decades in Europe. According to the most recent investigation of the work force in Europe, 17% had shift work and 10% night work (European Foundation for the Improvement of Living and Working Conditions, 2010). Shift work is often defined as work beyond normal day work. The prevalence of work in weekends in Europe is 53%. On call duties is also common. The health consequences of shift work are increased risk of sleep disorders, fatigue, accidents, cardiovascular disease, and cancer (Wang et al., 2011). Shift work has also been suggested to be a risk factor of type 2 diabetes (Wang et al., 2011). Diabetes is a metabolic disturbance that leads to increased concentration of sugar in the blood. Type 2 diabetes, which usually becomes manifest at ages above 40, is due to insulin resistance. Type 2 diabetes constitutes 90% of all diabetes (World Health Organization, 1999). The prevalence of diabetes in ages 20–79 years in Europe is 6–7% (International Diabetes Federation, 2013), and the trend is increasing. The prevalence is increasing with age, and the disease is more common in men than in women. There is also a socioeconomic gradient, with higher prevalence in lower socioeconomic groups (Agardh et al., 2004). Established risk factors for type 2 diabetes are age, obesity, family history, smoking and physical inactivity.
Another issue is how diabetes should be managed in the workplace, particularly with regard to working hours. What is the impact of shift work on the glucose– insulin metabolism? Is the risk of hypoglycaemia increased in shift workers? This study was aimed to carry out a systematic review on the association between shift work and diabetes. We have also sought studies dealing with problems of blood sugar control in people who work shifts.
METHODS A systematic literature search was performed in Pubmed, Noishtic2, and Science Direct until 1 Nov 2012. The search strategy included the following terms: night work, nightwork, shift work, shiftwork, circadian, diurnal, diabetes, diabetic, hypoglycaemia, hypoglycaemia, guidelines, and control. Only articles in English and Scandinavian languages were included. Referent lists of the retrieved articles were searched manually. For information about national guidelines, we scrutinised guidelines from Sweden, Norway, USA, Canada, England, Scotland and EU (American Diabetes Association, 2012; Meltzer et al., 1998; Royal College of Physicians, 2009; Scottish Intercollegiate Guidelines Network, 2010). None of these guidelines contain information about issues related to shift work and diabetes.
Submitted February 18, 2014, Returned for revision April 24, 2014, Accepted July 14, 2014
Correspondence: Dr. Anders Knutsson, Department of Health Sciences, Mid Sweden University, Sundsvall, Sweden. E-mail: [email protected]
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Shift work and diabetes For evidence grading the modified Royal College of General Practitioners (RCGP) three-star system was used (Wang et al., 2011): Strong evidence – provided by generally consistent findings in multiple, high quality scientific studies; Moderate evidence – provided by generally consistent findings in fewer, smaller, or lower quality scientific studies; Limited or contradictory evidence – provided by one scientific study or inconsistent findings in multiple scientific studies; No scientific evidence – based on clinical studies, theoretical considerations and/or clinical consensus.
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RESULTS The search on the association between shift work and type 2 diabetes generated 181 references (Figure 1). After exclusion of 172 records due to irrelevant exposure or outcome based upon abstract screening, nine full text articles were scrutinised. Two of these were crosssectional studies, and seven cohort studies. We excluded the cross-sectional studies. One study was excluded due to inadequate participants. The subjects were diagnosed with impaired fasting glucose and/or impaired glucose tolerance at baseline (Toshihiro et al., 2008). Two studies from USA had overlapping populations (Kroenke et al., 2007; Pan et al., 2011). Therefore, only the more recent publication with the larger study population was included. The remaining five articles were included in the final assessment. All studies were epidemiological cohort studies. Of those, three were carried out in Japan, one in the USA, and one in Sweden. All studies demonstrated increased risk of diabetes in shift workers, but in some studies the results were not statistically significant (Table 1). Kawakami et al. (1999) studied male workers in an electrical company. The cohort was followed during
8 years. Cox regressions showed an increased but insignificant increased risk among shift workers compared with day workers (Hazard ratio 1.67, 95% CI 0.57– 4.90). Diabetes was diagnosed in annual screening procedures. Fasting plasma glucose was checked for those who had glucosurea and those who had plasma glucose level equal or above 110 mg/dl (¼6.1 mmol/l) were tested with oral glucose tolerance test. The Cox regression model included the following a number of potential confounding variables, e.g. age, years of education, occupation, overtime, job strain, social support, body mass index (BMI), alcohol consumption, smoking, physical inactivity, and family history of diabetes. Years of exposure to shift work is not reported. In a Swedish study of male workers in pulp and paper manufacturing plants, a cohort consisted of 2354 shift workers and 3088 day workers was followed (Karlsson et al., 2005). The cohort was open, and the mortality was monitored from 1952 to 2001. The standardised relative rate (SRR) for diabetes mortality was 0.57 for those with 55 years of shift work, 0.99 for 5–9 years, 1.09 for 10–19 years, 1.54 for 20–29 years, and 1.22 for 30 years. The SRR for all shift workers versus all day workers was 1.24 (95% CI 0.91–1.70). When the length of follow-up was restricted to 68 years, or a maximum of 4 years after termination of employment, the SRR increased to 2.29 (95% CI 0.97–5.40). For the exposure categories 10–19 years, 20–29 years or 30 years, the SRRs for shift workers were 1.41 (95% CI 0.18–11.30), 1.92 (95% CI 0.5– 7.32), and 2.85 (95% CI 1.15–7.08). The analysis was adjusted for age. The population included only bluecollar workers. Exposure to shift and day work was based on company records. The shift schedule included night shifts. The results were not adjusted for smoking, but when the relative risk (RR) of lung cancer was compared between shift and day workers there was no indication that smoking was more prevalent in shift workers.
181 records identified through database searching
Search term control OR hypoglycemia OR hypoglycaemia added 44 records excluded due to irrelevant exposure or outcome based upon abstract screening
1 record excluded due to inadequate control condition
181 records screened 172 records excluded due to irrelevant exposure or outcome based upon abstract screening
47 records screened
3 full text articles assessed for eligibility
2 studies included
9 full text articles assessed for eligibility 2 records excluded due to study design, 1 study due to inadequate participants, 1 study due to overlapping 5 studies included
FIGURE 1. Outline of the systematic selection process. !
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TABLE 1. Characteristics of studies on the association between shift work and type 2 diabetes.
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Study
Baseline sample
Age at baseline
Working hours
Kawakami et al., Male workers at an 1999, Japan electrical company 1015 shift, 1179 day
18–60
Rotating shift/day
Karlsson et al., Male paper mill 2005, Sweden workers 2354 shift, 3088 day
14–60
Rotating 3-shift
Morikawa et al., Male employees at a 2005, Japan sash and zipper factory 720 shift 2140 day
29–46
Suwazono et al., Male employees 2006, Japan in steel industries 2426 shift, 3203 day Pan et al., Female nurses, 2011, USA NHS I and II 107 733 shift, 69 451 day
Type 2 diabetes OGTT
Follow-up length
Risk estimate HR ¼ 1.67 (CI 0.59–4.90) Multivariate adj.
8 years
Type 1 and Employed6 mo SRR ¼ 1.24 Type 2 diabetes 1940–1998 (CI 0.91–1.70) mortality Mortality 1952–2001 Two-shift Type 2 diabetes 8 years RR ¼ 1.33–2.11 in Three-shift Day HbA1c6.1% Different subgroup comparisons multivariate adj.
Mean age: Rotating Shift 37.7 (SD 8.8) night-shift Day 35.1 (SD 9.9) Mean age: 53.7 NHS I 34.3 NHS II
Diabetes criteria
Rotating night-shift
Type 2 diabetes HbA1c6.0%
10 years
OR ¼ 1.35 (CI 1.05–1.75) multivariate adj.
Type 2 diabetes Self-reported
18–20 years
HR per 5 years of shift work ¼ 1.05 (CI 1.04–1.06) multivariate adj.
CI, confidence interval; HR, hazard ratio; NHS I, Nurses’ Health Study I; NHS II, Nurses’ health study II; OGTT, oral glucose tolerance test; OR, odds ratio; RR, relative risk; SRR, standardised relative rate.
Morikawa et al. (2005) carried out a study of male factory workers in Japan (N ¼ 2860). Those with diabetes at baseline were excluded. The cohort was followed from 1994 to 2001 with annual examinations. Diabetes was diagnosed based on determination of HbA1c (6.1 mmol/l). Work schedules were classified into fixed-daytime, two-shift, and three-shift. Three-shift included night shifts. Two-shift included day shift and evening shift, but not night shift. The work was divided into blue-collar and white-collar. White-collar workers did not have shift work, only day work. The results showed that blue-collar two-shift workers had the highest incidence of diabetes (6.84/1000 person-years), and white-collar workers the lowest (3.34/1000 person-years) with three-shift and fixed-day shift workers were in between (5.32 and 4.43/1000 person-years, respectively). The RR of two-shift workers compared with fixed day-time workers was 1.73 (95% CI 0.85–3.52), and between threeshift workers and fixed day-time workers 1.33 (95% CI 0.74–2.36). When comparing two-shift workers and white-collar workers, the RR was 2.01 (95% CI 0.88–2.97). The Cox regression model included adjustment for age, BMI, family history, smoking, alcohol drinking, and physical inactivity. In a Japanese study on male workers in a steel company, alternating shift workers (night shifts included) were followed for 10 years. The comparison group consisted of day workers. The results demonstrated an increased risk of type 2 diabetes in shift
workers compared with day workers (OR 1.35, 95% CI 1.05–1.75) (Suwazono et al., 2006). Workers who were diagnosed with diabetes before baseline were excluded. During follow-up, yearly examinations was done. Outcome was diabetes where diagnosis was determined by hospital physician or by HbA1c values 6.0%. Negative lifestyle was more prevalent in shift workers, but the results were adjusted for alcohol intake, smoking, physical inactivity, and BMI. Data on total exposure time for shift work were not available. Pan et al. (2011) pooled data from Nurses’ Health Study I and II and analysed the association between night-shift work and risk of type 2 diabetes (N ¼ 177 184). The cohort was followed 18–20 years. The results showed that shift work was associated with risk of diabetes type 2. The hazard ratio for women with 1–2, 3–9, 10–19, and 20 years of nightshift work were 1.04 (95% CI 0.99–1.10), 1.24 (95% CI 1.24–1.30), 1.55 (95% CI 1.45–1.66), 1.78 (95% CI 1.61–1.96) in the age-adjusted model. Further adjustment for age, alcohol consumption, physical activity, smoking, race, menopausal status, hormone use, family history, diabetes dietary score, and BMI resulted in the hazard ratios 1.03 (95% CI 0.98–1.08), 1.06 (95% CI 1.01–1.11), 1.10 (95% CI 1.02–1.18), and 1.24 (1.13–1.37). Thus, this study showed that the association between shift work and diabetes type 2 was significant even after adjustment for BMI. The analysis also demonstrated a clear trend between years of exposure to shift work and diabetes. Chronobiology International
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Shift work and diabetes The search on the association between shift work and diabetes started with the data set previously described (181 references). A new search with the terms ‘‘control OR hypoglycaemia OR hypoglycaemia’’ yielded 47 records. After exclusion of 44 records due to inadequate participants or study design, three records remained. One study was excluded due to inadequate control condition. We found no studies that dealt with hypoglycaemia during shift work. The final assessment was based on the remaining two articles. In a study from Thailand, 240 patients with diabetes type 2 were included in the study – 120 were shift workers, and 120 day workers (Chalernvanichakom et al., 2008). The patients filled out a questionnaire with questions about demographic data, working conditions, mental health and stress. Relevant information from the patient’s medical records were retrieved, e.g. BMI, blood pressure and fasting blood glucose during the last 6 months. Average fasting blood glucose during the last 6 months 7.22 mmol/l was defined as good glycaemic control. The results showed that the proportion of patients who had good glycaemic control was lower among shift workers than day workers (16% versus 28%, p ¼ 0.02). Symptoms of hypoglycaemia were more common in shift workers (43% versus 27%, p ¼ 0.01). Young et al. (2013) included patients aged 16–65 with type 1 diabetes from two hospitals in Scotland. The patients were sent a questionnaire covering demographics, duration of diabetes, employment, and work schedule. The HbA1c results were obtained from records. Only employed participants were included (N ¼ 231). The number of shift workers was 67, among those 47 had night shifts. The results showed that shift work was significantly associated with higher HbA1c. Multivariate regression analysis showed that shift work was a significant predictor on control of diabetes.
DISCUSSION In the five identified cohort studies on the association between shift work and type 2 diabetes, all demonstrated increased risk of diabetes in shift workers compared with day workers. The search for studies on glycaemic control in relation to shift work yielded two studies, and both demonstrated deteriorating glycaemic control associated with shift work. Three studies from Japan used data from yearly screening programmes and based on the diagnosis of diabetes on OGGT and/or HbA1c values. In the study by Morikawa et al. (2005) the blue-collar plant workers were engaged in three well defined work schedules. One group had fixed day-time work, one two-shift without nights, and one rotating three-shift with nights. However, the exposure to the different work schedules was based only on information at baseline. Therefore, it is probable that some employees classified as day workers also had experienced shift work. It is also possible that some shift workers had very short careers !
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as shift workers. The results were adjusted for age, BMI, family history, smoking, habitual drinking, and physical exercise. Also in the study by Kawakami et al. (1999) shift work status was determined from baseline data only. The study subjects came from the same company. The work schedules included day work or shift work, and shift work included schedules with or without nights. It would have been valuable if shift system with night was reported as a separate group. The results were adjusted for age, education, occupation, overtime, job strain, social support, BMI, alcohol, smoking, physical activity and family history of diabetes. The study by Suwazono et al. (2006) used data from the annual health examinations to define exposure to shift work. The results showed that those who had shift schedules, which included night work, had increased risk for the development of diabetes compared with day workers. The authors used pooled logistic regression which made it possible to adjust for the covariates that were updated at each annual examination. Among covariates were age, mean blood pressure, alcohol, smoking, exercise and total cholesterol. In the study by Pan et al. (2011) diabetes was determined based on questionnaire information. Selfreported information is regarded as less valid than measurements of blood variables. However, the definition of cases and a check of validity in a sample of the population indicates good quality of data. A case of diabetes was considered confirmed if at least one of the following was reported: (1) classic symptoms plus fasting plasma glucose of 7.8 mmol/l; or random plasma glucose of 11.1 mmol/l; (2) at least two elevated plasma glucose concentrations on different occasions and/or a concentration of 11.1 mmol/l after 2 h of OGGT; (3) treatment with hypoglycaemic medication. Ninety-eight percent of a subsample was verified through medical records. The variable on shift- and day work was based on a question about how many years in total they had worked rotating night shifts, defined as at least three nights/month in addition to days and evenings in that month. The information was updated several times during follow-up. The information on duration was collapsed into five groups: never, 1–2 years, 3–9 years, 10–19 years, and 20 years. A problem with this exposure variable is that subjects who have experienced shift work without night shift could be classified as day workers. Also, permanent night work was classified as day work. This weakens the work-time variable. The authors conclude that ‘‘rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight’’. The final, multivariate model was adjusted for age, alcohol, physical activity, smoking, race, menopausal status, hormone use, oral contraceptives, family history, aspirin, total calorie intake, diabetes dietary score, and BMI. The strength of the study is the large population size.
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The study by Karlsson et al. (2005) is the only mortality study among the six studies included. Diabetes was considered as cause of death if it was indicated as primary or contributory cause of death. Exposure to day- and shift- work was obtained from company files. The overall risk of type 1 or type 2 diabetes during follow-up was 1.24, which is not statistically significant. However, there was a significantly increasing trend, with the following risk estimates in the different exposure groups: 55 years, 0.57; 5– 510 years, 0.99; 10– 520 years, 1.09; 20– 530 years, 1.54, and 30 years, 1.22. A weakness of the study was that no adjustments were made for other confounders except for age. Important potential confounding variables are age, BMI, family history, smoking and physical inactivity. Three studies adjusted for all these variables (Kawakami et al., 1999; Morikawa et al., 2005; Pan et al., 2011). In the study by Suwazono et al. (2006), the results were adjusted for age, BMI, smoking and exercise, but not for family history. In the study by Karlsson et al. (2005) adjustment was made only for age. A proxy variable was used to assess if smoking behaviour differed between day and shift workers. Shift work often requires the employee to work at different hours. Eating and sleeping at different times affects how well persons with diabetes can deep blood glucose levels at normal levels. In a study in Thailand, Chalernvanichakom et al. (2008) demonstrated that good glycaemic control was less common in shift workers than in day workers. Age, duration of diabetes and proportion of patients treated with oral hypoglycaemic agent did not differ between groups, but the shift workers worked more hours per week and had shorter sleeping time than day workers. The study does not report how shift work was defined, and adjustment for confounding variables was not reported. Young et al. (2013) studied patients in Scotland with type 1 diabetes who attended two hospitals annually and aged between 16 and 65. Shift work was defined as work scheduled outside standard day-time hours. Night work was defined as 3 h work between 11 p.m. and 6 a.m. Results of multivariate logistic regression analysis showed that shift work was associated with control of diabetes. The model is not described, the odds ratio and confidence interval is not reported. Poor glycaemic control is not defined. In addition the participant rate was low (22%). Additional data supporting a connection between shift work and diabetes are studies showing association between shift work and metabolic syndrome (Karlsson et al., 2003; Lin et al., 2009). The metabolic syndrome is a condition closely related to type 2 diabetes. Toshihiro et al. (2008) studied the effect of shift work on 128 male workers with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). IFG and IGT are risk factors for diabetes type 2. The participants were followed in 3.2 years. The results showed that 28%
were diagnosed with diabetes during follow-up, 32% recovered, and 41% remained in a state of IFG or IGT. Night work was associated with a hazard ratio of 5.48 (95% CI 1.8–16.5). In an experiment on humans the subjects were exposed to a 28 h light-dark cycle, which resulted in circadian misalignment. When subjects ate and slept out of phase from their habitual times, plasma glucose increased despite increased insulin. Three of the eight subjects showed post-prandial glucose responses in the range of a prediabetic state (Scheer et al., 2009). Animal experiments have demonstrated that disruption of clock genes leads to diabetes (Marcheva et al., 2010; Shi et al., 2013). Different pathways linking shift work to diabetes have been suggested. Experimental studies on animals and humans have shown that circadian misalignment can induce disturbance in the glucose/insulin regulating system (Scheer et al., 2009; Shi et al., 2013). Shift work is associated with increased risk of circadian disruption (Roden et al., 1993). Another pathway could be sleep problem. Sleep problems are more common in shift workers than in day workers and sleep deprivation is a risk factor for diabetes (Avas et al., 2003). Stress is also a potential mechanism that could explain increased risk of diabetes among shift workers (Eriksson et al., 2013; Harma, 2006). The major limitation of this review is the low number of studies. Another issue is low methodological quality in some studies. One cohort study has insufficient confounding control (Karlsson et al., 2005). The other cohort studies have acceptable quality. Both studies on glycaemic control have quality problems. The epidemiological studies together with the experimental studies on humans and animals strengthen the evidence of an association between shift work and type 2 diabetes. However, publication bias and unmeasured confounding cannot be excluded. Our literature review has shown consistent association between shift work and type 2 diabetes. The association is also supported by experiments on animals and humans. However, due to the scarcity of epidemiological studies the strength of the evidence is moderate.
CONCLUSIONS There is moderate evidence on an association between shift work and type 2 diabetes. The literature on blood sugar control when working shift work is limited. In current national guidelines on diabetes, there is lack of information about how to get good glycaemic control when working shift work.
DECLARATION OF INTEREST The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article. Chronobiology International
Shift work and diabetes
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REFERENCES Agardh EE, Ahlbom A, Andersson T, et al. (2004). Explanations of socioeconomic differences in excess risk of type 2 diabetes in Swedish men and women. Diabetes Care. 27: 716–21. American Diabetes Association. (2012). Diabetes and employment. Diabetes Care. 35:S94–98. Avas NI, White DP, Al-Delaimy WK, et al. (2003). A prospective study of self-reported sleep duration and incident diabetes in women. Diabetes Care. 26:380–4. Chalernvanichakom T, Sithisarankul P, Hiransuthikul N. (2008). Shift work and type 2 diabetic patients’ health. J Med Assoc Thai. 91:1093–6. ¨ stenson CG. (2013). Eriksson AK, van den Donk M, Hilding A, O Work stress, sense of coherence and risk of type 2 diabetes in a prospective study of middle-aged Swedish men and women. Diabetes Care. 36:2683–9. Eurofound (2012). Fifth European Working Conditions Survey. Luxembourg:Publications Office of the European Union. Harma M. (2006). Workhours in relation to work stress, recovery and health. Scand J Work Environ Health. 32:502–14. International Diabetes Federation. (2013). Diabetes Atlas, 6th edition. Available from: http://www.idf.org/diabetesatlas [last accessed 30 Apr 2013]. Karlsson B, Alfredsson L, Knutsson A, et al. (2005). Total mortality and cause-specific mortality of Swedish shift- and dayworkers in the pulp and paper industry in 1952–2001. Scand J Work Environ Health. 31:30–5. Karlsson B, Knutsson A, Lindahl BO, et al. (2003). Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health. 76: 424–30. Kawakami N, Araki S, Takatsuka N, et al. (1999). Overtime, psychosocial working conditions, and occurrence of noninsulin dependent diabetes mellitus in Japanese men. J Epidemiol Commun Health. 53:359–63. Kroenke CH, Spiegelman D, Manson J, et al. (2007). Work characteristics and incidence of type 2 diabetes in women. Am J Epidemiol. 165:175–83. Lin YC, Hsiao TJ, Chen PC. (2009). Persistent rotating shift-work exposure accelerates development of metabolic syndrome among middle-aged female employees: A five-year follow-up. Chronobiol Int. 26:740–55.
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Marcheva B, Ramsey KM, Burh ED, et al. (2010). Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 466:627–31. Meltzer S, Leiter L, Daneman D, et al. (1998). Clinical practice guidelines for the management of diabetes in Canada. CMAJ. 159:S1–29. Morikawa Y, Nakagawa H, Miura K, et al. (2005). Shift work and the risk of diabetes mellitus among Japanese male factory workers. Scand J Work Environ Health. 31:179–83. Pan A, Schernhammer E, Sun Q, et al. (2011). Rotating night shift work and risk of type 2 diabetes: Two prospective cohort studies in women. PlosMed. 8:e1001141. Roden M, Koller M, Pirich K, Vierhapper H, et al. (1993). The circadian melatonin and cortisol secretion pattern in permanent night shift workers. Am J Physiol. 265:R261–7. Royal College of Physicians. (2009). Type 2 diabetes. National clinical guide for management in primary and secondary care. Available from: http://guidance.nice.org.uk/CG66/Guidance/ pdf/English [last accessed 1 Oct 2012]. Scheer FA, Hilton MF, Mantzoros CS, et al. (2009). Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci USA. 106:4453–8. Scottish Intercollegiate Guidelines Network. (2010). Management of diabetes. A national clinical guideline. Available from: http:// www.sign.ac.uk/pdf/sign116.pdf [last accessed 1 Oct 2012]. Shi S, Ansari T, McGuiness O, et al. (2013). Circadian disruption leads to insulin resisstance and obesity. Curr Biol. 23:372–81. Suwazono Y, Sakata K, Okubo Y, et al. (2006). Long-term longitudinal study on the relationship between alternating shift work and the onset of diabetes mellitus in male Japanese workers. J Occup Environ Med. 48:455–61. Toshihiro M, Saito K, Takikawa S, et al. (2008). Psychosocial factors are independent risk factors for the development of type 2 diabetes in Japanese workers with impaired fasting glucose and/or impaired glucose tolerance. Diabet Med. 25:1211–17. Wang XS, Armstrong MEG, Cairns BJ, et al. (2011). Shift work and chronic disease: The epidemiological evidence. Occup Med. 61: 78–89. World Health Organization, WHO. (1999). Diabetes. Available from: http://www.who.int/diabetes/en/ 20121001 [last accessed 1 Oct 2012]. Young J, Waclawski E, Young JA, et al. (2013). Control of type 1 diabetes mellitus and shift work. Occup Med (Lond). 63:70–2.
ORIGINAL ARTICLE
Shift work and diabetes – A systematic review Anders Knutsson1 and Anders Kempe2 Department of Health Sciences, Mid Sweden University, Sundsvall, Sweden and 2Health Centre of So¨ra˚ker, Timra˚, Sweden
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1
Diabetes mellitus is a chronic disease, which has an increasing trend all over the world. Type 2 diabetes constitutes 90% of all diabetes. It is associated with weight gain and insulin resistance. Research during recent years has suggested that shift work could be a risk factor of type 2 diabetes. Since shift work is becoming more common, it could contribute to the increasing trend of diabetes. In this systematic review, we have studied the potential association between shift work and type 2 diabetes. We have also reviewed studies on control of diabetes in relation to shift work. Keywords: Circadian disruption, diabetes control, nightwork, shiftwork, work schedules
INTRODUCTION The prevalence of shift work has increased during the last decades in Europe. According to the most recent investigation of the work force in Europe, 17% had shift work and 10% night work (European Foundation for the Improvement of Living and Working Conditions, 2010). Shift work is often defined as work beyond normal day work. The prevalence of work in weekends in Europe is 53%. On call duties is also common. The health consequences of shift work are increased risk of sleep disorders, fatigue, accidents, cardiovascular disease, and cancer (Wang et al., 2011). Shift work has also been suggested to be a risk factor of type 2 diabetes (Wang et al., 2011). Diabetes is a metabolic disturbance that leads to increased concentration of sugar in the blood. Type 2 diabetes, which usually becomes manifest at ages above 40, is due to insulin resistance. Type 2 diabetes constitutes 90% of all diabetes (World Health Organization, 1999). The prevalence of diabetes in ages 20–79 years in Europe is 6–7% (International Diabetes Federation, 2013), and the trend is increasing. The prevalence is increasing with age, and the disease is more common in men than in women. There is also a socioeconomic gradient, with higher prevalence in lower socioeconomic groups (Agardh et al., 2004). Established risk factors for type 2 diabetes are age, obesity, family history, smoking and physical inactivity.
Another issue is how diabetes should be managed in the workplace, particularly with regard to working hours. What is the impact of shift work on the glucose– insulin metabolism? Is the risk of hypoglycaemia increased in shift workers? This study was aimed to carry out a systematic review on the association between shift work and diabetes. We have also sought studies dealing with problems of blood sugar control in people who work shifts.
METHODS A systematic literature search was performed in Pubmed, Noishtic2, and Science Direct until 1 Nov 2012. The search strategy included the following terms: night work, nightwork, shift work, shiftwork, circadian, diurnal, diabetes, diabetic, hypoglycaemia, hypoglycaemia, guidelines, and control. Only articles in English and Scandinavian languages were included. Referent lists of the retrieved articles were searched manually. For information about national guidelines, we scrutinised guidelines from Sweden, Norway, USA, Canada, England, Scotland and EU (American Diabetes Association, 2012; Meltzer et al., 1998; Royal College of Physicians, 2009; Scottish Intercollegiate Guidelines Network, 2010). None of these guidelines contain information about issues related to shift work and diabetes.
Submitted February 18, 2014, Returned for revision April 24, 2014, Accepted July 14, 2014
Correspondence: Dr. Anders Knutsson, Department of Health Sciences, Mid Sweden University, Sundsvall, Sweden. E-mail: [email protected]
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Shift work and diabetes For evidence grading the modified Royal College of General Practitioners (RCGP) three-star system was used (Wang et al., 2011): Strong evidence – provided by generally consistent findings in multiple, high quality scientific studies; Moderate evidence – provided by generally consistent findings in fewer, smaller, or lower quality scientific studies; Limited or contradictory evidence – provided by one scientific study or inconsistent findings in multiple scientific studies; No scientific evidence – based on clinical studies, theoretical considerations and/or clinical consensus.
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RESULTS The search on the association between shift work and type 2 diabetes generated 181 references (Figure 1). After exclusion of 172 records due to irrelevant exposure or outcome based upon abstract screening, nine full text articles were scrutinised. Two of these were crosssectional studies, and seven cohort studies. We excluded the cross-sectional studies. One study was excluded due to inadequate participants. The subjects were diagnosed with impaired fasting glucose and/or impaired glucose tolerance at baseline (Toshihiro et al., 2008). Two studies from USA had overlapping populations (Kroenke et al., 2007; Pan et al., 2011). Therefore, only the more recent publication with the larger study population was included. The remaining five articles were included in the final assessment. All studies were epidemiological cohort studies. Of those, three were carried out in Japan, one in the USA, and one in Sweden. All studies demonstrated increased risk of diabetes in shift workers, but in some studies the results were not statistically significant (Table 1). Kawakami et al. (1999) studied male workers in an electrical company. The cohort was followed during
8 years. Cox regressions showed an increased but insignificant increased risk among shift workers compared with day workers (Hazard ratio 1.67, 95% CI 0.57– 4.90). Diabetes was diagnosed in annual screening procedures. Fasting plasma glucose was checked for those who had glucosurea and those who had plasma glucose level equal or above 110 mg/dl (¼6.1 mmol/l) were tested with oral glucose tolerance test. The Cox regression model included the following a number of potential confounding variables, e.g. age, years of education, occupation, overtime, job strain, social support, body mass index (BMI), alcohol consumption, smoking, physical inactivity, and family history of diabetes. Years of exposure to shift work is not reported. In a Swedish study of male workers in pulp and paper manufacturing plants, a cohort consisted of 2354 shift workers and 3088 day workers was followed (Karlsson et al., 2005). The cohort was open, and the mortality was monitored from 1952 to 2001. The standardised relative rate (SRR) for diabetes mortality was 0.57 for those with 55 years of shift work, 0.99 for 5–9 years, 1.09 for 10–19 years, 1.54 for 20–29 years, and 1.22 for 30 years. The SRR for all shift workers versus all day workers was 1.24 (95% CI 0.91–1.70). When the length of follow-up was restricted to 68 years, or a maximum of 4 years after termination of employment, the SRR increased to 2.29 (95% CI 0.97–5.40). For the exposure categories 10–19 years, 20–29 years or 30 years, the SRRs for shift workers were 1.41 (95% CI 0.18–11.30), 1.92 (95% CI 0.5– 7.32), and 2.85 (95% CI 1.15–7.08). The analysis was adjusted for age. The population included only bluecollar workers. Exposure to shift and day work was based on company records. The shift schedule included night shifts. The results were not adjusted for smoking, but when the relative risk (RR) of lung cancer was compared between shift and day workers there was no indication that smoking was more prevalent in shift workers.
181 records identified through database searching
Search term control OR hypoglycemia OR hypoglycaemia added 44 records excluded due to irrelevant exposure or outcome based upon abstract screening
1 record excluded due to inadequate control condition
181 records screened 172 records excluded due to irrelevant exposure or outcome based upon abstract screening
47 records screened
3 full text articles assessed for eligibility
2 studies included
9 full text articles assessed for eligibility 2 records excluded due to study design, 1 study due to inadequate participants, 1 study due to overlapping 5 studies included
FIGURE 1. Outline of the systematic selection process. !
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TABLE 1. Characteristics of studies on the association between shift work and type 2 diabetes.
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Study
Baseline sample
Age at baseline
Working hours
Kawakami et al., Male workers at an 1999, Japan electrical company 1015 shift, 1179 day
18–60
Rotating shift/day
Karlsson et al., Male paper mill 2005, Sweden workers 2354 shift, 3088 day
14–60
Rotating 3-shift
Morikawa et al., Male employees at a 2005, Japan sash and zipper factory 720 shift 2140 day
29–46
Suwazono et al., Male employees 2006, Japan in steel industries 2426 shift, 3203 day Pan et al., Female nurses, 2011, USA NHS I and II 107 733 shift, 69 451 day
Type 2 diabetes OGTT
Follow-up length
Risk estimate HR ¼ 1.67 (CI 0.59–4.90) Multivariate adj.
8 years
Type 1 and Employed6 mo SRR ¼ 1.24 Type 2 diabetes 1940–1998 (CI 0.91–1.70) mortality Mortality 1952–2001 Two-shift Type 2 diabetes 8 years RR ¼ 1.33–2.11 in Three-shift Day HbA1c6.1% Different subgroup comparisons multivariate adj.
Mean age: Rotating Shift 37.7 (SD 8.8) night-shift Day 35.1 (SD 9.9) Mean age: 53.7 NHS I 34.3 NHS II
Diabetes criteria
Rotating night-shift
Type 2 diabetes HbA1c6.0%
10 years
OR ¼ 1.35 (CI 1.05–1.75) multivariate adj.
Type 2 diabetes Self-reported
18–20 years
HR per 5 years of shift work ¼ 1.05 (CI 1.04–1.06) multivariate adj.
CI, confidence interval; HR, hazard ratio; NHS I, Nurses’ Health Study I; NHS II, Nurses’ health study II; OGTT, oral glucose tolerance test; OR, odds ratio; RR, relative risk; SRR, standardised relative rate.
Morikawa et al. (2005) carried out a study of male factory workers in Japan (N ¼ 2860). Those with diabetes at baseline were excluded. The cohort was followed from 1994 to 2001 with annual examinations. Diabetes was diagnosed based on determination of HbA1c (6.1 mmol/l). Work schedules were classified into fixed-daytime, two-shift, and three-shift. Three-shift included night shifts. Two-shift included day shift and evening shift, but not night shift. The work was divided into blue-collar and white-collar. White-collar workers did not have shift work, only day work. The results showed that blue-collar two-shift workers had the highest incidence of diabetes (6.84/1000 person-years), and white-collar workers the lowest (3.34/1000 person-years) with three-shift and fixed-day shift workers were in between (5.32 and 4.43/1000 person-years, respectively). The RR of two-shift workers compared with fixed day-time workers was 1.73 (95% CI 0.85–3.52), and between threeshift workers and fixed day-time workers 1.33 (95% CI 0.74–2.36). When comparing two-shift workers and white-collar workers, the RR was 2.01 (95% CI 0.88–2.97). The Cox regression model included adjustment for age, BMI, family history, smoking, alcohol drinking, and physical inactivity. In a Japanese study on male workers in a steel company, alternating shift workers (night shifts included) were followed for 10 years. The comparison group consisted of day workers. The results demonstrated an increased risk of type 2 diabetes in shift
workers compared with day workers (OR 1.35, 95% CI 1.05–1.75) (Suwazono et al., 2006). Workers who were diagnosed with diabetes before baseline were excluded. During follow-up, yearly examinations was done. Outcome was diabetes where diagnosis was determined by hospital physician or by HbA1c values 6.0%. Negative lifestyle was more prevalent in shift workers, but the results were adjusted for alcohol intake, smoking, physical inactivity, and BMI. Data on total exposure time for shift work were not available. Pan et al. (2011) pooled data from Nurses’ Health Study I and II and analysed the association between night-shift work and risk of type 2 diabetes (N ¼ 177 184). The cohort was followed 18–20 years. The results showed that shift work was associated with risk of diabetes type 2. The hazard ratio for women with 1–2, 3–9, 10–19, and 20 years of nightshift work were 1.04 (95% CI 0.99–1.10), 1.24 (95% CI 1.24–1.30), 1.55 (95% CI 1.45–1.66), 1.78 (95% CI 1.61–1.96) in the age-adjusted model. Further adjustment for age, alcohol consumption, physical activity, smoking, race, menopausal status, hormone use, family history, diabetes dietary score, and BMI resulted in the hazard ratios 1.03 (95% CI 0.98–1.08), 1.06 (95% CI 1.01–1.11), 1.10 (95% CI 1.02–1.18), and 1.24 (1.13–1.37). Thus, this study showed that the association between shift work and diabetes type 2 was significant even after adjustment for BMI. The analysis also demonstrated a clear trend between years of exposure to shift work and diabetes. Chronobiology International
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Shift work and diabetes The search on the association between shift work and diabetes started with the data set previously described (181 references). A new search with the terms ‘‘control OR hypoglycaemia OR hypoglycaemia’’ yielded 47 records. After exclusion of 44 records due to inadequate participants or study design, three records remained. One study was excluded due to inadequate control condition. We found no studies that dealt with hypoglycaemia during shift work. The final assessment was based on the remaining two articles. In a study from Thailand, 240 patients with diabetes type 2 were included in the study – 120 were shift workers, and 120 day workers (Chalernvanichakom et al., 2008). The patients filled out a questionnaire with questions about demographic data, working conditions, mental health and stress. Relevant information from the patient’s medical records were retrieved, e.g. BMI, blood pressure and fasting blood glucose during the last 6 months. Average fasting blood glucose during the last 6 months 7.22 mmol/l was defined as good glycaemic control. The results showed that the proportion of patients who had good glycaemic control was lower among shift workers than day workers (16% versus 28%, p ¼ 0.02). Symptoms of hypoglycaemia were more common in shift workers (43% versus 27%, p ¼ 0.01). Young et al. (2013) included patients aged 16–65 with type 1 diabetes from two hospitals in Scotland. The patients were sent a questionnaire covering demographics, duration of diabetes, employment, and work schedule. The HbA1c results were obtained from records. Only employed participants were included (N ¼ 231). The number of shift workers was 67, among those 47 had night shifts. The results showed that shift work was significantly associated with higher HbA1c. Multivariate regression analysis showed that shift work was a significant predictor on control of diabetes.
DISCUSSION In the five identified cohort studies on the association between shift work and type 2 diabetes, all demonstrated increased risk of diabetes in shift workers compared with day workers. The search for studies on glycaemic control in relation to shift work yielded two studies, and both demonstrated deteriorating glycaemic control associated with shift work. Three studies from Japan used data from yearly screening programmes and based on the diagnosis of diabetes on OGGT and/or HbA1c values. In the study by Morikawa et al. (2005) the blue-collar plant workers were engaged in three well defined work schedules. One group had fixed day-time work, one two-shift without nights, and one rotating three-shift with nights. However, the exposure to the different work schedules was based only on information at baseline. Therefore, it is probable that some employees classified as day workers also had experienced shift work. It is also possible that some shift workers had very short careers !
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as shift workers. The results were adjusted for age, BMI, family history, smoking, habitual drinking, and physical exercise. Also in the study by Kawakami et al. (1999) shift work status was determined from baseline data only. The study subjects came from the same company. The work schedules included day work or shift work, and shift work included schedules with or without nights. It would have been valuable if shift system with night was reported as a separate group. The results were adjusted for age, education, occupation, overtime, job strain, social support, BMI, alcohol, smoking, physical activity and family history of diabetes. The study by Suwazono et al. (2006) used data from the annual health examinations to define exposure to shift work. The results showed that those who had shift schedules, which included night work, had increased risk for the development of diabetes compared with day workers. The authors used pooled logistic regression which made it possible to adjust for the covariates that were updated at each annual examination. Among covariates were age, mean blood pressure, alcohol, smoking, exercise and total cholesterol. In the study by Pan et al. (2011) diabetes was determined based on questionnaire information. Selfreported information is regarded as less valid than measurements of blood variables. However, the definition of cases and a check of validity in a sample of the population indicates good quality of data. A case of diabetes was considered confirmed if at least one of the following was reported: (1) classic symptoms plus fasting plasma glucose of 7.8 mmol/l; or random plasma glucose of 11.1 mmol/l; (2) at least two elevated plasma glucose concentrations on different occasions and/or a concentration of 11.1 mmol/l after 2 h of OGGT; (3) treatment with hypoglycaemic medication. Ninety-eight percent of a subsample was verified through medical records. The variable on shift- and day work was based on a question about how many years in total they had worked rotating night shifts, defined as at least three nights/month in addition to days and evenings in that month. The information was updated several times during follow-up. The information on duration was collapsed into five groups: never, 1–2 years, 3–9 years, 10–19 years, and 20 years. A problem with this exposure variable is that subjects who have experienced shift work without night shift could be classified as day workers. Also, permanent night work was classified as day work. This weakens the work-time variable. The authors conclude that ‘‘rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight’’. The final, multivariate model was adjusted for age, alcohol, physical activity, smoking, race, menopausal status, hormone use, oral contraceptives, family history, aspirin, total calorie intake, diabetes dietary score, and BMI. The strength of the study is the large population size.
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The study by Karlsson et al. (2005) is the only mortality study among the six studies included. Diabetes was considered as cause of death if it was indicated as primary or contributory cause of death. Exposure to day- and shift- work was obtained from company files. The overall risk of type 1 or type 2 diabetes during follow-up was 1.24, which is not statistically significant. However, there was a significantly increasing trend, with the following risk estimates in the different exposure groups: 55 years, 0.57; 5– 510 years, 0.99; 10– 520 years, 1.09; 20– 530 years, 1.54, and 30 years, 1.22. A weakness of the study was that no adjustments were made for other confounders except for age. Important potential confounding variables are age, BMI, family history, smoking and physical inactivity. Three studies adjusted for all these variables (Kawakami et al., 1999; Morikawa et al., 2005; Pan et al., 2011). In the study by Suwazono et al. (2006), the results were adjusted for age, BMI, smoking and exercise, but not for family history. In the study by Karlsson et al. (2005) adjustment was made only for age. A proxy variable was used to assess if smoking behaviour differed between day and shift workers. Shift work often requires the employee to work at different hours. Eating and sleeping at different times affects how well persons with diabetes can deep blood glucose levels at normal levels. In a study in Thailand, Chalernvanichakom et al. (2008) demonstrated that good glycaemic control was less common in shift workers than in day workers. Age, duration of diabetes and proportion of patients treated with oral hypoglycaemic agent did not differ between groups, but the shift workers worked more hours per week and had shorter sleeping time than day workers. The study does not report how shift work was defined, and adjustment for confounding variables was not reported. Young et al. (2013) studied patients in Scotland with type 1 diabetes who attended two hospitals annually and aged between 16 and 65. Shift work was defined as work scheduled outside standard day-time hours. Night work was defined as 3 h work between 11 p.m. and 6 a.m. Results of multivariate logistic regression analysis showed that shift work was associated with control of diabetes. The model is not described, the odds ratio and confidence interval is not reported. Poor glycaemic control is not defined. In addition the participant rate was low (22%). Additional data supporting a connection between shift work and diabetes are studies showing association between shift work and metabolic syndrome (Karlsson et al., 2003; Lin et al., 2009). The metabolic syndrome is a condition closely related to type 2 diabetes. Toshihiro et al. (2008) studied the effect of shift work on 128 male workers with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). IFG and IGT are risk factors for diabetes type 2. The participants were followed in 3.2 years. The results showed that 28%
were diagnosed with diabetes during follow-up, 32% recovered, and 41% remained in a state of IFG or IGT. Night work was associated with a hazard ratio of 5.48 (95% CI 1.8–16.5). In an experiment on humans the subjects were exposed to a 28 h light-dark cycle, which resulted in circadian misalignment. When subjects ate and slept out of phase from their habitual times, plasma glucose increased despite increased insulin. Three of the eight subjects showed post-prandial glucose responses in the range of a prediabetic state (Scheer et al., 2009). Animal experiments have demonstrated that disruption of clock genes leads to diabetes (Marcheva et al., 2010; Shi et al., 2013). Different pathways linking shift work to diabetes have been suggested. Experimental studies on animals and humans have shown that circadian misalignment can induce disturbance in the glucose/insulin regulating system (Scheer et al., 2009; Shi et al., 2013). Shift work is associated with increased risk of circadian disruption (Roden et al., 1993). Another pathway could be sleep problem. Sleep problems are more common in shift workers than in day workers and sleep deprivation is a risk factor for diabetes (Avas et al., 2003). Stress is also a potential mechanism that could explain increased risk of diabetes among shift workers (Eriksson et al., 2013; Harma, 2006). The major limitation of this review is the low number of studies. Another issue is low methodological quality in some studies. One cohort study has insufficient confounding control (Karlsson et al., 2005). The other cohort studies have acceptable quality. Both studies on glycaemic control have quality problems. The epidemiological studies together with the experimental studies on humans and animals strengthen the evidence of an association between shift work and type 2 diabetes. However, publication bias and unmeasured confounding cannot be excluded. Our literature review has shown consistent association between shift work and type 2 diabetes. The association is also supported by experiments on animals and humans. However, due to the scarcity of epidemiological studies the strength of the evidence is moderate.
CONCLUSIONS There is moderate evidence on an association between shift work and type 2 diabetes. The literature on blood sugar control when working shift work is limited. In current national guidelines on diabetes, there is lack of information about how to get good glycaemic control when working shift work.
DECLARATION OF INTEREST The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article. Chronobiology International
Shift work and diabetes
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