|Ahead of print publication
Response of proinflammatory cytokine, tumor necrosis factor-alpha to moderate physical activity in nondiabetic hypertensives and type 2 diabetic hypertensives
Barkha Gupta1, Sonali Sharma1, Sudhir Bhandari2, Sonal Bhardwaj1, Asrar Ahmed3
1 Department of Biochemistry, RUHS College of Medical Sciences and Associated Groups of Hospitals, Jaipur, Rajasthan, India
2 Department of Internal Medicine, SMS Medical College and Associated Group of Hospitals, Jaipur, Rajasthan, India
3 Department of General Medicine, RUHS College of Medical Sciences and Associated Groups of Hospitals, Jaipur, Rajasthan, India
|Date of Submission||04-Feb-2021|
|Date of Decision||25-Mar-2021|
|Date of Acceptance||31-Mar-2021|
Department of Biochemistry, RUHS College of Medical Sciences and Associated Groups of Hospitals, Sector 11, Kumbha Marg, Pratap Nagar, Jaipur - 302 033, Rajasthan
Source of Support: None, Conflict of Interest: None
Introduction: Hypertension is a multifactorial disease and is a major risk factor for cardiovascular disease, particularly in patients of diabetes mellitus. Management of hypertension is one of the critical components of comprehensive clinical management of diabetics. Aim: The aim of this study is to evaluate the effect of physical activity on systemic inflammation in patients with hypertension and type 2 diabetes mellitus in patients with hypertension. Methods: A total of 100 participants of either gender aged 40–69 years of Stage 2 essential hypertension were included in the study and assigned to 12 weeks of moderate physical activity (walking 10,000 steps/day). These study participants were further divided into two groups: type 2 diabetic (n =66) and nondiabetic (n = 34) hypertensives. Anthropometric parameters were noted and biochemical variables estimated at baseline and postintervention and evaluated statistically. Results: Twelve weeks of walking resulted in improved levels of inflammatory cytokine tumor necrosis factor-alpha (TNF-α). Systolic and diastolic blood pressure (BP) were reduced from 168.98 ± 3.76 to 154.29 ± 7.48 mmHg and from 103.38 ± 2.46s to 89.08 ± 3.62 mmHg, respectively. Body weight and body mass index were reduced from 69.8 ± 7.09 to 68.3 ± 6.53 kg and 23.21 ± 3.35 to 22.70 ± 3.16 kg/m2, respectively. A significant decrease in glycated hemoglobin (Group 1: 8.36% ± 1.83% vs. 7.74% ± 1.82%; Group 2: 5.56% ± 0.4% vs. 5.09% ± 0.19%) was found. A significant reduction in TNF-α levels in hypertensives with diabetes and a significant (P < 0.0001) decrease in nondiabetic hypertensive participants (Group 1: 1.38 ± 0.701 vs. 1.068 ± 0.657 pg/ml; Group 2: 1.341 ± 0.749 vs. 0.894 ± 0.601 pg/ml, respectively; pre vs. post P < 0.0001) were observed, respectively. Conclusion: Regular moderate physical activity induces anti-inflammatory state in hypertensives by reducing levels of proinflammatory marker TNF-α. It also resulted in good glycemic control and improvement in BP and has health beneficial effects.
Keywords: Diabetes, hypertension, inflammation, physical activity, tumor necrosis factor-alpha
|How to cite this URL:|
Gupta B, Sharma S, Bhandari S, Bhardwaj S, Ahmed A. Response of proinflammatory cytokine, tumor necrosis factor-alpha to moderate physical activity in nondiabetic hypertensives and type 2 diabetic hypertensives. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Jun 13]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=315947
| Introduction|| |
Hypertension is regarded as a multifactorial disease with a modest contribution of genetic factors and strongly affected by environmental factors. Hypertension is twice as frequent in patients with diabetes compared to those who do not have diabetes and is a major risk factor for cardiovascular disease (CVD) and particularly diabetes mellitus. Therefore, management of hypertension is one of the critical components of comprehensive clinical management of diabetics.
Frequent coexistence of hypertension and diabetes mellitus in individual results due to sharing of pathophysiology related to obesity and insulin resistance by both the conditions. Hypertension and diabetes are interconnected closely as these diseases have similar risk factors, viz., endothelial dysfunction, vascular inflammation, arterial remodeling, atherosclerosis, dyslipidemia, and obesity. Several studies have reported that inflammatory cytokines participate in the genesis of hypertension.,
Inflammatory response contributes to type 2 diabetes mellitus (T2DM) occurrences by causing insulin resistance and in turn intensifies in the presence of hyperglycemia, promoting long-term complications of diabetes mellitus. Insulin resistance is often exhibited by hypertensives, and they are at greater risk of developing diabetes as compared to normotensive individuals.
Inflammatory cytokines are soluble mediators that influence many inflammatory functions. These have an important role in the pathology of cardiovascular disorders and T2DM. The source of inflammatory cytokines interleukin 1 beta (IL-1b), IL-6, and tumor necrosis factor-alpha (TNF-α) can be muscle cells, adipocytes, brain, endothelial cells, and many of other cells. Proinflammatory cytokines are IL-6 and TNF-α that mediate process of inflammation and healing. TNF-α is a multifunctional and a pleiotropic stimulator of cellular responses. The inhibition of TNF-α in humans showed blood pressure (BP) reduction. Type 2 diabetes, particularly when poorly controlled, involves disease of the innate immune system and manifests as chronic low-grade inflammation.,
Increased levels of TNF-α and IL-6 are among predictors of an increased risk to develop lifestyle diseases, such as hypertension, coronary artery disease, and diabetes mellitus. Exercises of moderate nature reduce the incidence of CVDs. TNF-α inhibition has been discussed as a potential strategy to improve vascular function.
Studies on response of inflammatory marker TNF-α to exercise in hypertensives are scarce, and there is an inconsistency in the findings of effect of exercise on inflammatory cytokines in hypertensive diabetics. Given the implication of diabetes mellitus, it is crucial to identify the lifestyle measures in regard to BP goals, glycemic control, and inflammation in the hypertensive diabetic population.
Thus, this study was designed primarily to evaluate the effect of physical activity on systemic inflammation in hypertensive patients and secondarily to assess the effect on diabetic hypertensive patients having raised glycated hemoglobin (HbA1c) levels.
| Methods|| |
This was a single-arm pre- and post-clinical interventional study. A total of 100 participants of either gender aged 40–69 years of Stage 2 essential hypertension were enrolled in this pilot study by nonprobability convenience sampling method. The study was conducted in 2017–2018. Institutional ethics committee approval was taken (approval letter no RUHS-CMS/Ethics Comm./2017/123, dated August 29, 2017). Before the study, all eligible patients were briefed about the study, and written informed consent was taken of all enrolled participants.
Participants of Stage 2 essential hypertension which was defined as per the JNC 8 guidelines; participants on prescribed treatment of antihypertensive medicines; those having sedentary lifestyle (<3000 steps/day); and those possessing smartphone with pedometer step count application for record.
Participants with type 1 diabetes mellitus and nephropathy (proteinuria); those with CVD (coronary artery disease, peripheral arterial disease, and stroke); heavy alcoholics with history of habitual smoking; and pregnant and lactating women.
These hypertensive study participants were further divided into two groups, viz., Group 1 (Type 2 diabetic, n = 66) and Group 2 (nondiabetic, n = 34) as per clinical history and as per the ADA guidelines.
The participants engaged in physical activity program comprising walking 10,000 footsteps per day for 12 weeks. The exercise intervention was supervised on pedometer/pedometer smartphone application, and participants were motivated to not to change their physical activity levels for the duration of the study. Follow-up was monitored fortnightly during the 12-week intervention period. All the participants were asked to maintain their usual dietary habits and prescribed medicines for diabetes and hypertension.
Systolic BP (SBP) and diastolic BP (DBP) were defined as average of 3 times readings obtained while supine position after a minimum 5 min rest. Radial pulse was also recorded. Standard protocols with participants wearing light clothing without shoes were used to measure body weight and height. Body mass index (BMI) was calculated. Waist and hip circumferences were measured. All subjects were introduced about standard lifestyle measures. At baseline, participants were interviewed for demographic information, lifestyle information, socioeconomic status, personal and family history, and recorded in a pro forma. Height, weight, waist-hip ratio (WHR), BMI, and BP were measured at baseline.
BP was measured by mercury sphygmomanometer. Blood samples were withdrawn after 12-h fasting. HbA1c and TNF-α levels were estimated in all participants at baseline and after intervention. Serum concentrations of TNF-α were assessed by ELISA technique at baseline and reassessed after 12 weeks of physical activity, i.e., postintervention. The overall intra-assay coefficient of variation was 3.3% in TNF estimation; the TNF-α value of 0-8 pg/ml was considered normal.
In the present study, the data were collected on continuous scale; descriptive statistics (mean, standard deviation) were used to present the data. Further, appropriate graphical representation was done. For the discrete as well as qualitative variables, univariate and bivariate tables were prepared. Appropriate statistical test (paired t-test) was applied to check whether there is significant effect of intervention in the study participants. Multiple correlation analysis was done. In multiple regression analysis, we used HbA1c values as the dependent variable and TNF-α as the independent variable. Tool for statistical analysis was Microsoft Excel version 2015.
| Results|| |
The study investigated the effect of 12 weeks physical activity on serum TNF-α concentration in 100 participants with Stage 2 essential hypertension. Out of these participants, 77% were males with a mean age of 49.65 ± 7.33 years and 23% were females with a mean age of 47.35 ± 4.76 years. Demographic and anthropometric variables of the study participants at baseline and postintervention are given in [Table 1]. The decrease in weight, BMI, and BP both (systolic and diastolic) were found to be significant (P < 0.0001) postintervention [Table 1]. No significant change was found in WHR in the study participants postintervention.
|Table 1: Demographic and anthropometric variables of study participants at baseline and postintervention|
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Study participant's distribution by TNF-α level before and after intervention is depicted in [Figure 1].
|Figure 1: Study participants distribution by tumor necrosis factor-a levels before and post intervention *(P = 0.000001) At X-axis - values of tumor necrosis factor-a (pg/ml); at Y axis - number of cases (%)|
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The multiple correlation of TNF-α on BP (systolic and diastolic) is statistically significant (R = 0.2326) with P = 0.0099. On the basis of multiple correlation, the multiple regression equation of TNF-α on BP is: TNF-α = 0.0601* DBP – 0.025* SBP – 0.727. In this multiple regression analysis, we used TNF-α values as the dependent variable and BP (systolic and diastolic) as the independent variable [Table 2].
|Table 2: Multiple correlation of tumor necrosis factor-alpha on blood pressure in study participants|
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It was found that postintervention HbA1c levels decreased in both diabetic and nondiabetic hypertensive patients. However, decrease was found to be significant (P < 0.0001) in nondiabetic hypertensives and significant (P < 0.05) in diabetic hypertensives postintervention [Table 3].
|Table 3: Intragroup comparison of hemoglobin A1c at baseline and postintervention|
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Postintervention TNF-α levels decreased from 1.366 to 0.89 pg/ml. The results were found to statistically significant (P = 0.00001) as compared to baseline values.
A significant reduction in TNF-α levels in nondiabetic participants as compared to diabetic participants was observed in this study postintervention [Table 4]. There was no significant difference (P > 0.05) found in the TNF-α levels when compared gender-wise. A strong negative correlation was found in the levels of TNF-α reduction on moderate physical activity for 12 weeks duration with baseline HbA1c values in diabetics [Figure 2] and [Figure 3].
|Figure 2: Association between glycated hemoglobin and tumor necrosis factor-α at baseline in study participants|
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|Figure 3: Association between glycated hemoglobin and difference of tumor necrosis factor-α in study participants|
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|Table 4: Comparison of tumor necrosis factor-alpha in Group 1 (diabetic) and Group 2 (nondiabetic) hypertensives at baseline and postintervention|
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On the basis of correlation, we predict the TNF-α value on dependent HbA1c value by regression analysis.
On the basis of multiple correlation analysis, we predict the TNF α value on the basis of HbA1c value by below equation: TNF α = 3.368 – 0.2195*HbA1c (at baseline) is significant with P value is 0.00001 [Figure 2]. TNF α Diff. = 1.619 0.1256*HbA1c (at baseline) is significant with P value is 0.00001 [Figure 3].
| Discussion|| |
Hypertension and T2DM are associated with chronic inflammation and metabolic dysregulation. Modification of lifestyle which includes physical activity may improve both. Hypertension is characterized by vascular dysfunction and injury and hence is a risk factor for diabetes associated vascular complication. The findings of the present study show significant decrease in both SBP and DBP in essential hypertensives after 12 weeks of physical activity intervention. Similar findings have been observed in prehypertension or Stage 1 in a study which reported that moderate-intensity aerobic exercise is able to reduce both SBP and DBP in both male and female patients with essential hypertension.
The results of the present study show a significant decrease in HbA1c levels in hypertensives with diabetes and a significant (P < 0.0001) decrease in nondiabetic hypertensive participants. Our results are in accordance with other studies.,
In the present study, after 12 weeks of physical activity intervention in the form of walking, TNF-α levels were decreased in essential hypertensive participants. Our study findings are similar to the study which reported 24 weeks of moderate physical exercise with a duration of 60 min and a frequency of 3 times a week, decreases IL 6 and TNF α, but no decrease was found in IL 10. Decrease in TNF-α level due to exercise training has also been reported in a study on obese type 2 diabetic patients. Harbaum et al. studied the acute effects of exercise on the inflammatory state in participants with idiopathic pulmonary arterial hypertension and demonstrated exercise as a safer medium which does not aggravate inflammatory state. However, no effect of exercise on TNF-α was reported by Beavers et al., and they observed that only IL-8 was affected by exercise after 12 months of physical activity. A study with 3 months of aerobic exercise reported no effect on the serum TNF-α as the proinflammatory cytokine in obese males with type 2 diabetes. The discrepancy of findings of the present study with other studies is due to differences in the types of protocols, duration, and regularity of physical activity of studied subjects.
Low-grade inflammation is a common feature in subjects with type 2 diabetes. Increased levels of circulating inflammatory markers were observed to be significantly more prominent in type 2 diabetes. Boeno et al. in their study suggested that regular aerobic training and resistance training are beneficial for BP control and CVD risk reduction given the established role of chronic low-level inflammation in the pathogenesis of CVD.
The results of the present study show that postintervention, nondiabetic hypertensives exhibited more improvement in the serum TNF-α levels as compared to diabetic hypertensives. Beneficial effects of exercise on inflammation have been reported. Anti-inflammatory cytokine is enhanced by exercise, whereas proinflammatory cytokine production is suppressed. It can be stated that regular exercise results in prevention of damage to insulin producing beta-cells by decreasing cytotoxicity produced by proinflammatory cytokines, IL-6 and TNF-α. Thus, cytokines might act as a mediator for health-related beneficial effects of the exercise.
In this present study, we also report a negative correlation in amount of TNF-α reduction on moderate physical activity for 12 weeks duration with baseline HbA1c values in diabetics [Figure 2] and [Figure 3].
The physical activity intervention tested in the present study resulted in anti-inflammatory effect as it resulted in improved levels of proinflammatory cytokine TNF-α. Therefore, it is recommended to develop and implement strategies such as regular physical activity program to prevent and control hypertension and also adverse outcomes of diabetes mellitus.
Limitations of the study include small sample size, wide age range, and pooled effect for other inflammatory markers was not assessed. Due to specificity of intervention, blinding participants was not possible which may lead to performance bias.
| Conclusion|| |
Regular moderate physical activity induces anti-inflammatory state in hypertensives by lowering levels of proinflammatory marker TNF-α. It also resulted in good glycemic control and improvement in BP. Moderate physical activity should be integrated in treatment of hypertension alongwith medication to achieve health beneficial effects.
The authors express their acknowledgment to all the patients who have participated in our study who have been an integral part in the completion of this research work.
Financial support and sponsorship
This research is funded by Rajasthan University of Health Sciences, Jaipur, Rajasthan via letter no. 12758 dated 9th Oct 2017.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]