Abstract
Background Resting heart rate has been shown to predict risk of cardiovascular disease; its association with diabetes remains unclear, particularly in non-Western populations.
Methods We evaluated the association between resting heart rate and risk of type 2 diabetes in the Shanghai Women’s Health Study, a population-based prospective cohort study. The analysis included 47 571 Chinese women with no prior history of diabetes, cancer, cardiovascular disease or thyroid dysfunction at the time when resting heart rate was measured. Incident diabetes was ascertained through biennial in-person interviews.
Results During a mean follow-up of 4.9 years, 849 women developed type 2 diabetes. For heart rate categories of ≤68, 69–72, 73–76, 77–80 and >80 beats/min, the incidence rates of diabetes per 1000 person-years were 2.91, 3.31, 3.71, 4.16 and 5.34, respectively. The multivariable-adjusted hazard ratios (HRs) [95% confidence intervals (CIs)] for diabetes across increasing heart rate categories were 1, 1.21 (0.99–1.47), 1.30 (1.05–1.62), 1.37 (1.12–1.69) and 1.60 (1.28–2.00), respectively. Further analyses of the joint effects of heart rate with body mass index (BMI), waist–hip ratio (WHR) and blood pressure (BP) showed increased risk of diabetes with increasing heart rate in all categories of BMI, WHR or BP. The combinations of the highest heart rate category with highest BMI, WHR or BP category were associated with the highest HRs, ranging from 4.81 to 6.34.
Conclusions A high resting heart rate is independently associated with an increased risk of type 2 diabetes in women. The combinations of high heart rate with high BMI, WHR or BP level are associated with a substantially increased risk.
Keywords: Resting heart rate, type 2 diabetes, women
Introduction
Many epidemiological studies have shown that resting heart rate independently predicts cardiovascular events and mortality in the general population and in those with various cardiovascular diseases.1–4 Relatively few studies, however, have evaluated the association between resting heart rate and risk of type 2 diabetes, particularly in non-Western populations. Furthermore, previous studies have focussed exclusively on resting heart rate measured in office settings.5,6 Resting heart rate can be affected by a variety of environmental stimuli, including the ‘white coat’ effect.7 Out-of-office measurement of resting heart rate may be preferable in epidemiologic studies, as it is more likely to reflect the true usual resting heart rate.
Some Asian populations, including Chinese, have been found to be particularly susceptible to insulin resistance and type 2 diabetes, despite having a low rate of obesity.8,9 Identifying factors that may predict risk of type 2 diabetes is an important step toward improved understanding and prevention of this major disease in high-risk populations. We prospectively evaluated the association between resting heart rate measured at home and risk of type 2 diabetes in a large cohort of Chinese women enrolled in the Shanghai Women’s Health Study (SWHS). We also examined joint effects of heart rate with body mass index (BMI), waist–hip ratio (WHR) and blood pressure (BP) on diabetes risk.
Methods
The SWHS is a population-based, prospective cohort study of adult Chinese women. Details of the study design and methods have been described previously.10 Briefly, all eligible women 40–70 years of age and living in seven typical urban communities of Shanghai were invited to participate in the study. Between December 1996 and May 2000, a total of 74 942 women enrolled in the study and completed the baseline survey (participation rate: 92.7%). The baseline survey was conducted at participants’ homes by trained interviewers who were retired medical professionals. Structured questionnaires were used during the survey to obtain information on demographics, lifestyle habits, medical history, medication use and other characteristics. Total physical activity was assessed using a validated physical activity questionnaire that captured information on regular exercise participation, walking and cycling for transportation and other reasons, and household activities.11 Estimates of physical activity levels were calculated as metabolic equivalent (MET)-hours/day. Participants were also measured for weight, height and circumferences of the waist and hips following a standard protocol.12 The study was approved by the Institutional Review Boards of all institutes involved, and written, informed consent was obtained from all participants.
Measurement of heart rate and BP
During the first follow-up home visit (2000–02), 68 412 living cohort members completed heart rate and BP measurements in addition to an in-person interview. Measurements were performed uniformly according to standard protocols. Participants were asked to sit and relax. After at least a 5-min rest, heart rate was measured by pulse palpation over a 30-s period, and BP was measured using the auscultatory method with a conventional mercury sphygmomanometer. Two BP measurements were taken at a 30-s interval.
Outcome ascertainment
Incident type 2 diabetes was identified through in-person follow-up interviews that were conducted approximately every 2 years. During the interviews, each participant was asked whether, since last interview, she had been diagnosed with diabetes by a physician. For each positive response, information was obtained on symptoms, diagnostic tests, the date of first diagnosis and the use of oral hypoglycaemic medications and insulin. The diagnosis of diabetes was considered to be confirmed if the participant reported having at least one of the following: (i) classic symptoms of hyperglycaemia plus elevated glucose levels [fasting blood glucose concentration ≥7.0 mmol/l or 2-h blood glucose value during an oral glucose tolerance test (OGTT) ≥11.1 mmol/l]; (ii) elevated glucose levels (fasting blood glucose ≥7.0 mmol/l or 2-h blood glucose during OGTT ≥11.1 mmol/l) on at least two separate occasions; or (iii) use of oral hypoglycaemic agents or insulin. The diagnostic criteria are in line with the American Diabetes Association guidelines.13
Statistical analysis
Since resting heart rate was measured during the first follow-up interview, we used the date of the first follow-up as the baseline for the present analysis. We excluded women with previously diagnosed diabetes, cancer, cardiovascular disease, cardiac arrhythmias, or thyroid dysfunction at the first follow-up interview. We also excluded women who reported use of antihypertensive medications, as some forms of antihypertensive medication can affect heart rate. After these exclusions, 47 571 women remained for the analysis. Participants were classified into five categories according to quintile cut-points of resting heart rate, with the lowest heart rate category serving as the reference category. Cox proportional hazards models were used, with age as the time scale, to estimate hazard ratios (HRs) of incident diabetes associated with resting heart rate and their 95% confidence intervals (CIs), and to adjust for potential confounders. Entry time was defined as age at the first follow-up interview, when resting heart rate was taken. Exit time was defined as age at the diagnosis of diabetes that occurred after the first follow-up interview, death or censoring. Covariates included age (continuous), education level (four categories), occupation (three categories), annual family income (four categories), cigarette smoking (yes or no), alcohol consumption (yes or no), BMI (quintiles), WHR (quintiles), overall physical activity level (quintiles) and systolic BP (continuous). Additional adjustment for dietary factors, including intakes of fat, vegetables, fruits, glycaemic load and sodium, did not appreciably alter the risk estimates, and these variables were not included in the final models. Tests for linear trend in risk across heart rate categories were performed by using the median value for each heart rate category and modelling them as continuous variables. We also conducted analyses stratified by age. Finally, we conducted analyses of the joint effects of heart rate with BMI, WHR and BP on diabetes risk. P values for multiplicative interaction were derived by using the likelihood ratio test for nested models with and without interaction terms. Statistical analyses were performed by using SAS statistical software (version 9.1; SAS Institute Inc., Cary, NC, USA). All statistical tests were based on two-sided probability.
Results
The mean age [standard deviation (SD)] of the study population at baseline was 53.5 years (8.7). The mean resting heart rate was 73.6 (SD = 7.0). Very few women ever smoked cigarettes or drank alcohol. Table 1 presents selected characteristics of the study population according to five resting heart rate categories. Compared with women with lower resting heart rate, women with higher heart rate appeared to have lower levels of education, occupational status and family income. They tended to have higher levels of BMI, WHR and BP. In addition, they were more likely to have ever smoked cigarettes. Resting heart rate did not appear to be related to age, overall physical activity or alcohol consumption. The proportions of women with prevalent diabetes at baseline across five increasing heart rate categories were 3.91, 3.88, 3.83, 4.99 and 6.02%, respectively.
Table 1.
Characteristics of study participants according to five categories of resting heart ratea
| Resting heart rate categories, beats/min |
||||||
|---|---|---|---|---|---|---|
| Characteristic | ≤68 (n = 12 613) | 69–72 (n = 13 060) | 73–76 (n = 8110) | 77–80 (n = 8620) | >80 (n = 5168) | P for trend |
| Age (years), mean | 54.0 | 53.1 | 53.3 | 53.4 | 54.1 | 0.41 |
| Education level | <0.0001 | |||||
| Elementary school or less | 18.7 | 16.1 | 16.8 | 17.8 | 20.5 | |
| Middle school | 39.0 | 41.4 | 41.6 | 41.5 | 39.1 | |
| High school | 29.1 | 29.6 | 28.9 | 28.9 | 28.7 | |
| College or more | 13.2 | 12.9 | 12.7 | 11.7 | 11.7 | |
| Occupation | 0.0004 | |||||
| Manufacturing and agricultural workers | 50.6 | 50.9 | 51.1 | 52.3 | 52.4 | |
| Clerical and service workers | 20.8 | 21.5 | 21.0 | 21.0 | 21.2 | |
| Professionals, technicians, administrators | 28.7 | 27.6 | 27.8 | 26.7 | 26.4 | |
| Annual family income (yuan) | <0.0001 | |||||
| <10 000 | 15.7 | 15.1 | 14.9 | 15.8 | 17.4 | |
| 10 000–19 999 | 37.8 | 37.9 | 39.6 | 40.1 | 39.3 | |
| 20 000–29 999 | 28.3 | 29.6 | 28.6 | 27.9 | 26.7 | |
| ≥30 000 | 18.2 | 17.3 | 16.9 | 16.1 | 16.6 | |
| Ever smoked cigarettes | 2.2 | 2.4 | 2.7 | 2.6 | 3.3 | 0.0001 |
| Ever drank alcohol | 2.3 | 2.4 | 2.4 | 2.5 | 2.4 | 0.44 |
| BMI (kg/m2), mean | 23.5 | 23.5 | 23.6 | 23.7 | 23.9 | <0.0001 |
| WHR, mean | 0.80 | 0.80 | 0.81 | 0.81 | 0.81 | <0.0001 |
| Physical activity (MET-h/day), mean | 15.4 | 15.5 | 15.5 | 15.4 | 15.3 | 0.26 |
| Systolic BP (mmHg), mean | 118.7 | 118.4 | 118.8 | 119.7 | 121.9 | <0.0001 |
| Diastolic BP (mmHg), mean | 75.8 | 76.0 | 76.5 | 77.0 | 78.1 | <0.0001 |
aUnless otherwise indicated, data are given as percentage of subjects.
During a mean of 4.9 years of follow-up, 849 incident cases of type 2 diabetes were documented. For five increasing heart rate categories, the incidence rates of type 2 diabetes per 1000 person-years were 2.91, 3.31, 3.71, 4.16 and 5.34, respectively. Table 2 summarizes the HRs and 95% CIs of type 2 diabetes according to five resting heart rate categories. In both analyses adjusted for age only and analyses adjusted for various potential confounders, including socio-demographic factors, BMI, WHR, physical activity, smoking, alcohol consumption and BP, resting heart rate was positively associated with risk of type 2 diabetes in a dose–response fashion (P for trend <0.0001). The multivariable-adjusted HRs for type 2 diabetes across five increasing categories of resting heart rate were 1 (reference), 1.21 (0.99–1.47), 1.30 (1.05–1.62), 1.37 (1.12–1.69) and 1.60 (1.28–2.00), respectively. When resting heart rate was analysed as a continuous variable, for each 1-SD increase (seven beats/min) in heart rate, the risk for type 2 diabetes increased by 17% (HR, 1.17; 95% CI, 1.10–1.24). This positive association persisted in sensitivity analyses that excluded early years of follow-up after heart rate was taken. For each 1-SD increase in heart rate, the adjusted HRs were 1.16 (95% CI, 1.08–1.24) and 1.11 (1.02–1.21) after excluding first 1 and 2 years of follow-up, respectively. The HRs (95% CIs) across five increasing heart rate categories were 1 (reference), 1.10 (0.88–1.37), 1.24 (0.98–1.57), 1.27 (1.01–1.59) and 1.53 (1.20–1.96), respectively, after excluding first year of follow-up. Further stratified analyses showed that the magnitude of the association appeared to be greater in women ≤55 years than in women >55 years (Table 2). The P-value for multiplicative interaction was 0.56.
Table 2.
HRs of type 2 diabetes according to five categories of resting heart rate
| Resting heart rate categories, beats/min | ||||||
|---|---|---|---|---|---|---|
| ≤68 | 69–72 | 73–76 | 77–80 | >80 | P for trend | |
| All subjects | ||||||
| Number of subjects | 12 613 | 13 060 | 8110 | 8620 | 5168 | |
| Number of cases | 180 | 212 | 147 | 176 | 134 | |
| Age-adjusted HR | 1.00 | 1.19 (0.98–1.46) | 1.32 (1.06–1.65) | 1.48 (1.21–1.83) | 1.83 (1.47–2.29) | <0.0001 |
| Multivariate HRa | 1.00 | 1.21 (0.99–1.47) | 1.30 (1.05–1.62) | 1.37 (1.12–1.69) | 1.60 (1.28–2.00) | <0.0001 |
| Age ≤55 years | ||||||
| Number of subjects | 7815 | 8656 | 5271 | 5592 | 3196 | |
| Number of cases | 64 | 97 | 74 | 77 | 57 | |
| Multivariate HRa | 1.00 | 1.37 (1.00–1.88) | 1.63 (1.16–2.27) | 1.51 (1.08–2.10) | 1.82 (1.27–2.61) | 0.0007 |
| Age >55 years | ||||||
| Number of subjects | 4798 | 4404 | 2839 | 3028 | 1972 | |
| Number of cases | 116 | 115 | 73 | 99 | 77 | |
| Multivariate HRa | 1.00 | 1.12 (0.87–1.45) | 1.09 (0.81–1.46) | 1.29 (0.99–1.69) | 1.47 (1.10–1.96) | 0.007 |
aAdjusted for age, education, occupation, family income, cigarette smoking, alcohol consumption, BMI,
WHR, physical activity and systolic BP.
Table 3 presents the joint effects of resting heart rate with BMI, WHR and BP on diabetes risk. Within each category of BMI, WHR or BP, resting heart rate was positively associated with risk of diabetes; likewise, diabetes risk increased with increasing levels of BMI, WHR or BP across all heart rate categories. Women in both the highest category of heart rate and the highest category of BMI, WHR or BP had the highest HRs for type 2 diabetes. The P-values for multiplicative interaction between heart rate and BMI, WHR or BP were 0.21, 0.37 and 0.84, respectively.
Table 3.
Joint effects of resting heart rate with BMI, WHR and BP on the risk of type 2 diabetes
| Resting heart rate, beats per minute | |||
|---|---|---|---|
| ≤70 | 71–80 | >80 | |
| BMI (kg/m2) | |||
| Tertile 1 (≤22.0) | |||
| Number of subjects | 5347 | 8960 | 1619 |
| Number of cases | 22 | 57 | 16 |
| Multivariate HRa | 1.00 (reference) | 1.54 (0.94–2.52) | 2.09 (1.10–3.99) |
| Tertile 2 (22.1–24.7) | |||
| Number of subjects | 5162 | 8927 | 1633 |
| Number of cases | 45 | 133 | 22 |
| Multivariate HRa | 1.40 (0.84–2.34) | 2.44 (1.55–3.84) | 2.03 (1.12–3.67) |
| Tertile 3 (>24.7) | |||
| Number of subjects | 5103 | 8904 | 1916 |
| Number of cases | 149 | 309 | 96 |
| Multivariate HRa | 3.14 (1.99–4.96) | 3.86 (2.48–6.00) | 5.10 (3.18–8.19) |
| WHR | |||
| Tertile 1 (≤0.78) | |||
| Number of subjects | 5285 | 9022 | 1596 |
| Number of cases | 16 | 57 | 8 |
| Multivariate HR* | 1.00 (reference) | 2.05 (1.18–3.57) | 1.52 (0.65–3.54) |
| Tertile 2 (0.79–0.82) | |||
| Number of subjects | 5318 | 8944 | 1676 |
| Number of cases | 62 | 135 | 38 |
| Multivariate HR* | 2.56 (1.47–4.45) | 3.38 (2.01–5.69) | 4.85 (2.70–8.71) |
| Tertile 3 (>0.82) | |||
| Number of subjects | 5009 | 8825 | 1896 |
| Number of cases | 138 | 307 | 88 |
| Multivariate HR* | 4.02 (2.38–6.80) | 5.31 (3.19–8.84) | 6.34 (3.69–10.89) |
| BP (mmHg) | |||
| Normal (SBP < 120 and DBP < 80) | |||
| Number of subjects | 6732 | 10870 | 1777 |
| Number of cases | 33 | 75 | 12 |
| Multivariate HRa | 1.00 (reference) | 1.37 (0.91–2.06) | 1.26 (0.65–2.44) |
| Prehypertension (SBP: 120–139 or DBP: 80–89) | |||
| Number of subjects | 5838 | 11 023 | 2167 |
| Number of cases | 89 | 231 | 63 |
| Multivariate HRa | 2.03 (1.36–3.03) | 2.82 (1.95–4.07) | 3.69 (2.41–5.63) |
| Hypertension (SBP ≥ 140 or DBP ≥ 90) | |||
| Number of subjects | 3042 | 4898 | 1224 |
| Number of cases | 94 | 193 | 59 |
| Multivariate HRa | 3.03 (2.03–4.54) | 3.93 (2.70–5.72) | 4.81 (3.12–7.40) |
SBP, Systolic BP; DBP, Diastolic BP.
Variables were not included in the model when used for joint analysis.
aAdjusted for age, education, occupation, family income, cigarette smoking, alcohol consumption, BMI, WHR, physical activity and systolic BP.
We assessed the proportional hazards assumption by including interaction terms between exposure and log time and found no evidence of violation of the assumption.
Discussion
In this large, population-based cohort study of apparently healthy Chinese women, high resting heart rate was associated with a moderate increase in the risk of type 2 diabetes. This positive association persisted even after accounting for levels of BMI, WHR, BP and physical activity and other potential confounders. Analyses of the joint effects further revealed that the increased risk of type 2 diabetes associated with increasing heart rate existed across all categories of BMI, WHR or BP. The combinations of high heart rate and high BMI, WHR or BP level were associated with a substantially increased risk of developing type 2 diabetes.
Resting heart rate provides an overall index of autonomic tone.14 An elevation in resting heart rate may reflect an imbalance in the autonomic nervous system favouring sympathetic activation.14 Enhanced sympathetic activity has been linked to reduced insulin sensitivity, high BP, obesity, sub-clinical inflammation and the metabolic syndrome, conditions that are all associated with the development of type 2 diabetes.15–19 These observations support the biological plausibility of a positive association between resting heart rate and diabetes risk.
The findings of our study based on resting heart rate measured at home are generally in agreement with the results of previous studies, in which heart rate was measured in office settings.5,6,20 In a recent analysis from the Chicago Heart Association Detection Project in Industry Study, resting heart rate in middle age was positively associated with diabetes diagnosis and diabetes mortality in older age.5 Likewise, a positive association between resting heart rate and incident diabetes was also observed in the Atherosclerosis Risk in the Communities (ARIC) Study and a post hoc analysis of the Diabetes Prevention Program.6,20 However, unlike our study, the positive association between heart rate and diabetes was not consistently observed across various age or BMI subgroups in previous studies.5 In addition to resting heart rate, other measures of autonomic function, including heart rate variability and heart rate recovery after exercise, were also linked to the risk of diabetes in the ARIC study and the Coronary Artery Risk Development in Young Adults (CARDIA) Study.6,21 In the CARDIA study, the association between heart rate recovery and diabetes risk was observed in individuals with low physical fitness but not those with high fitness. Overall, these findings are consistent with the notion that autonomic nervous system dysfunction may not only be the consequence of diabetes but also a potential contributor to the disease.
BMI, WHR and BP are strong predictors of type 2 diabetes and significant correlates of resting heart rate.22,23 Our study has shown, for the first time, that women in both the highest category of BMI, WHR or BP level and highest category of resting heart rate are at the greatest risk for type 2 diabetes. This finding suggests that a simple measure of heart rate, along with measures of BMI, WHR or BP, may provide enhanced assessment of diabetes risk. Women with elevated levels of BMI, WHR or BP, as well as elevated resting heart rate may need more frequent surveillance of blood glucose levels and more aggressive intervention.
Several limitations of our study need to be considered when interpreting the results. Because of the observational nature of the study, we cannot conclude that the observed association between resting heart rate and diabetes risk is a causal one. The average follow-up time of 4.9 years in our study is relatively short, raising concern about the effect of sub-clinical or undiagnosed diabetes. We have conducted sensitivity analyses excluding early follow-up and found no material change in the risk estimates. However, because of the lack of baseline glucose measurements, we were unable to evaluate whether the association between heart rate and diabetes risk could be explained by baseline glucose levels. Although we have adjusted for a range of potential confounding variables, including socio-economic status, BMI, WHR, BP, physical activity and other lifestyle factors, we cannot rule out the possibility of residual confounding due to unmeasured or inaccurately measured covariates. One such concern is related to the lack of a direct measure of physical fitness, which is known to be associated with resting heart rate and diabetes risk.5 We have assessed the potential confounding effect of total physical activity and found that adjustment for physical activity did not alter the risk estimates considerably, suggesting that the observed association between resting heart rate and diabetes is unlikely to be fully explained by the potential confounding effect of physical fitness. Another limitation of the study is that diabetes was assessed through in-person interviews and this could lead to some misclassification in outcome ascertainment. Because of the prospective design and because that study interviewers were unaware of study hypothesis, the outcome misclassification would likely be non-differential and thus would tend to result in an underestimate of the associations.
Despite the limitations, our study suggests that resting heart rate, a simple, easily accessible measure of autonomic tone, independently predicts the risk of type 2 diabetes in middle-aged and elderly Chinese women. The combinations of high heart rate with high BMI, WHR or BP level are associated with a substantially increased risk.
Funding
National Institutes of Health (R01CA70867 and R01HL079123); National Institutes of Health-sponsored Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) Program at Vanderbilt University (2K12HD043483-06) to X.Z. The funding bodies had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest: None declared.
KEY MESSAGES.
Resting heart rate, a simple, easily accessible measure of autonomic tone, independently predicts the risk of type 2 diabetes in middle-aged and elderly Chinese women.
The combinations of high resting heart rate with high BMI, WHR or BP level are associated with a substantially increased risk of type 2 diabetes.
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