- Email: [email protected]
Effect of a physical activity intervention on suPAR levels: A randomized controlled trial
Accepted Manuscript Title: Effect of a Physical Activity Intervention on suPAR Levels: A Randomized Controlled Trial Authors: Christopher Rohde, Christoffer Polcwiartek, Eivind Andersen, Torkel Vang, Jimmi Nielsen PII: DOI: Reference:
S1440-2440(17)30935-0 http://dx.doi.org/doi:10.1016/j.jsams.2017.06.018 JSAMS 1557
To appear in:
Journal of Science and Medicine in Sport
Received date: Revised date: Accepted date:
29-3-2017 19-6-2017 27-6-2017
Please cite this article as: Rohde Christopher, Polcwiartek Christoffer, Andersen Eivind, Vang Torkel, Nielsen Jimmi.Effect of a Physical Activity Intervention on suPAR Levels: A Randomized Controlled Trial.Journal of Science and Medicine in Sport http://dx.doi.org/10.1016/j.jsams.2017.06.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Words count: 2463 Abstract word count: 254 Tables: 2 Figures: 1
Effect of a Physical Activity Intervention on suPAR Levels: A Randomized Controlled Trial
Christopher Rohde1 Christoffer Polcwiartek2,3,4 Eivind Andersen, PhD5 Torkel Vang, MD, PhD2 Jimmi Nielsen, MD, DmSc1,2,3
1.
Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark
2.
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
3.
Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
4.
Department of Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark
5.
Faculty of Humanities, Sports and Educational Science, Department of Sports, Physical Education and Outdoor Studies, University College of Southeast Norway
Correspondence: Christopher Rohde, [email protected], (+45) 28 26 09 90, Copenhagen University Hospital, Mental Health Centre Glostrup, Kristineberg 3, KBH Ø, 2100, Denmark.
1
Abstract Objectives: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel inflammatory marker, associated with lifestyle diseases and mortality risk. No studies have investigated whether physical activity may reduce suPAR levels using a randomized controlled design. Design and Methods: suPAR and C-reactive protein (CRP) levels were determined in blood samples from a previous randomized controlled trial with Pakistani immigrants in Norway, 2008. The study included physically inactive men that were randomized to an intervention group (supervised group exercises) or a control group and followed for five months. A linear regression model was used and adjusted for age, inactivity level at baseline, and mean difference in CRP levels. Results: Overall, 80 and 53 participants were included in the intervention and control group, respectively. Obesity and smoking were associated with higher suPAR levels at baseline. The intervention group had a mean suPAR level of 2.65 (95% CI=2.48-2.78) ng/mL at baseline compared to 2.80 (95% CI=2.65-2.95) ng/mL at post-test, and thereby significantly increased suPAR levels after intervention (p=0.02). In the control group, mean suPAR level significantly increased from 2.93 (95% CI=2.68-3.16) ng/mL at baseline to 3.09 (95% CI=2.81-3.38) ng/mL at post-test (p=0.04). When comparing change from baseline to post-test in suPAR levels for the intervention group versus the control group, no significant change in the unadjusted model was found (β=-0.002, 95% CI=-0.219-0.215). Similar results were found for CRP levels. Conclusion: There was no change in suPAR levels after regular exercise compared to a control group implying that suPAR rather reflects underlying harmful inflammatory responses associated with disease development.
2
Key words: C-reactive protein; exercise; immunology; inflammatory; soluble urokinase-type plasminogen activator receptor.
Introduction Soluble urokinase-type plasminogen activator receptor (suPAR) is a physiologically stable inflammatory marker positively correlated with other inflammatory markers, such as leukocytosis, C-reactive protein (CRP), and tumor necrosis factor- (TNF-)1, but suPAR levels have been shown to predict mortality in acute medical patients2 and patients with a variety of diseases3 better than these other known inflammatory markers. Overall, suPAR levels reflect the inflammatory state of the body. suPAR is generated as a result of cleavage and release of urokinase-type plasminogen activator receptor (uPAR) from the cell membrane. uPAR is a protein found on the cell surface of various cells, such as endothelial cells, monocytes, neutrophils and activated T cells4, and is believed to be involved in processes such as cellular adhesion, migration, and focused proteolysis. Consequently, defective migration of inflammatory cells can increase the risk of infection implying that the mortality-predictive effect of suPAR levels may reflect underlying harmful inflammatory processes in the body5. Due to the possible mortality-predictive effect of suPAR levels, the measurement of suPAR levels has received great interest in a variety of diseases. For instance, it has been suggested that suPAR levels may predict cardiovascular diseases6, have prognostic value in patients with sepsis7, are correlated with high Charlson comorbidity score and long-term admission3, and reflect low-grade inflammation in schizophrenia8. suPAR levels between 6-10 ng/mL indicate an increased risk of cancer, diabetes, and all-cause mortality, whereas levels above 10 ng/mL are correlated with current critical illness9. Other studies have investigated whether suPAR levels can be modulated by lifestyle interventions, and consequently reduce risk of disease development. Here, it has been shown that smoking cessation decrease suPAR levels to levels equal to
3
non-smokers, indicating a meaningful reduction in risk of disease10. In addition, suPAR levels have been shown to be influenced by unhealthy diet and sedentary lifestyle11. Overall, this suggests that the risk of disease can be monitored by suPAR levels, and that suPAR levels may assist in identifying those, who may benefit the most from lifestyle interventions. However, as only few studies have investigated whether physical activity may reduce suPAR levels, and none have used a randomized controlled design, it remains unknown whether physical activity can alter suPAR levels. We therefore analyzed this by using data from a randomized control trial with Pakistani immigrants in Norway, which is a group of individuals with high risk of developing type 2 diabetes and metabolic syndrome, probably due to unhealthy lifestyle patterns12-14. If suPAR levels are reduced by physical activity, it supports its use as a marker of the somatic health condition and would suggest that individuals with high suPAR levels may benefit from regular exercise and potentially reduce their risk of disease development.
4
Methods The present work is based on data from the Physical Activity and Minority Health study15, a randomized controlled trial conducted in Norway in 2008. Detailed descriptions of this study can be found elsewhere15-17. Therefore, in the following, we will only briefly explain the recruitment of the study population and the physical activity program. The Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services approved data for this study. Men living in Oslo, Norway, with a Pakistani background (either born in Pakistan or parents born in Pakistan) aged 25 to 60 years and not physically active on a regular basis (exercising at most twice per week at a moderate or higher intensity level for 30 min or more at a time, or were active commuters (e.g., cycling or walking to work on most days of the week)) were eligible for inclusion in this study. Participants were excluded if they were diagnosed with type 2 diabetes before randomization, had physical limitations making it difficult to participate, or were not able to speak Norwegian. The participants were recruited in September and October 2008 from six mosques and Muslim festivals in Oslo. A total of 182 participants were screened for participation, of which 32 participants were excluded leaving 150 participants for randomization (Figure 1). Written consent was obtained from every participant, and participants were then randomized to either a control or an intervention group. Each participant had a 60% chance of being allocated to the intervention group, as a randomization ratio of 60:40 was chosen. This ratio was allocated due to an anticipation of a high dropout rate in the intervention group. The participants were followed for five months, with 17 participants being lost to follow-up, leaving 133 participants for the follow-up test (i.e., 80 participants in the intervention group and 53 5
participants in the control group)15. The study was double blinded at first meaning that neither the participants nor the test personnel knew which group they were randomized to until the baseline test was performed. The participants randomized to the intervention group received supervised group exercises of moderate intensity (twice a week) with an exercise psychologist, one individual counseling session, group lectures (two sessions of two hours), written material, and a motivational telephone call. The supervised group exercise had the following structure: a 15 min warm-up, 40 min of floor ball and/or football plus some strength exercises and 5 min of cool down afterwards. The group lectures included topics such as harm of physical inactivity, activity examples, setting goals and making a physical activity plan. The individual counseling session had the primary goal to find activities that could be implemented in a normal week, with the sum of these enabling them to reach the physical activity recommendations. Five months after the randomization, participants were tested at the Norwegian School of Sports Sciences. The various parameters included have been described elsewhere15-17. After 12 hours of fasting, venous blood samples were drawn from an antecubital vein. The blood samples were mechanically agitated for 30 min, then aliquoted, separated, and centrifuged for 10 min at 2500 g, and this was done right after the blood was drawn and was subsequently stored at -80 degrees Celsius with no freeze-thaw cycle. Blood sample variables were determined at the Dr. V. Furst Laboratory for Clinical Chemistry, Oslo, Norway, using a Modular P Machine (Roche, Japan). suPAR levels were determined at Virogates, Birkerød, Denmark in November 2015. The assays used for the determining of suPAR were ELISA plates. It was carried out in singlets on the same plate. As both the baseline- and post-intervention blood suPAR levels were determined on the same plate, the difference found could not be explained by analytical variation. suPAR levels in the follow-up-test were determined in 72 participants in the intervention group and 45 participants in the control group, meaning that we were not able to measure levels in eight participants in the 6
intervention group and eight participants in the control group due to lack of blood. In these participants, CRP levels were also not measured. In addition, one participant in the intervention group and one participant in the control group were not able to have their CRP levels determined, leaving 71 participants in the intervention group and 44 participants in the control group. The mean and standard deviation (SD) were used to describe continuous variables and proportions to describe binomial data at baseline. Continuous baseline characteristics were compared using independent t-test, whereas binomial data were compared using risk difference. If data were not normally distributed, a log-transformation was made before the test was performed, and the variables were presented with 5th and 95th percentiles. The difference between suPAR and CRP levels at baseline and levels at the post-test were compared using a paired t-test. Assumptions were checked with Bland-Altman- and QQ-plots. The mean change in suPAR levels between the baseline- and the post-test for the intervention group were compared to the mean change in suPAR levels between baseline- and the post-test for the control group using a linear regression. The regression was first adjusted for age and inactivity level at baseline, as these variables were not equally distributed between the intervention and the control group. Afterwards, the regression was adjusted for the mean change in CRP levels, as suPAR and CRP are correlated. A similar regression comparing the mean change in CRP for the intervention group to the mean change in CRP for the control group was also performed.
7
Results Out of the 150 participants, 9 participants from the intervention group and 8 participants from the control group did not participate in the post-test (Figure 1). However, there were no differences between the dropouts and the subjects participating in the post-test on any of the variables included except a lower baseline physical activity level for the dropouts. The baseline characteristics for the intervention and control group are presented in table 1. The groups were significantly different on age, glucose levels (after two hours), and inactivity time in minutes per day. The mean age of the intervention group was 35.8 (SD=6.1) years compared to 39.7 (SD=9.2) years in control group (p=0.0047), and the intervention group were less sedentary at baseline (503.53 min/day, SD=100.4) than the control group (537.21 min/day, SD=94.6) (p=0.0446). Obesity and smoking were associated with higher suPAR levels at baseline. Obese participants, defined by a body mass index (BMI) above 25, had 0.33 ng/mL (95% CI=0.06-0.59, p=0.018) higher suPAR levels compared to participants with a BMI below 25. Adjustment for age and smoking status did not attenuate this association (β=0.34 ng/mL, 95% CI=0.08-0.59). suPAR levels in smokers were 0.57 ng/mL (95% CI=0.26-0.87, p<0.001) higher compared to non- or ex-smokers. Adjustment for age and BMI did not attenuate this association (β=0.61 ng/mL, 95% CI=0.32-0.90). 8
The intervention group had a mean suPAR level of 2.65 (95% CI=2.48-2.78) ng/mL at baseline compared to 2.80 (95% CI=2.65-2.95) ng/mL at the post-test, and thereby significantly increased suPAR levels after intervention (p=0.02). A similar significant increase in CRP levels was found (mean difference=1.27, 95% CI=0.36-2.18). In the control group, mean suPAR level significantly increased from 2.93 (95% CI=2.68-3.16) ng/mL at baseline to 3.09 (95% CI=2.81-3.38) ng/mL at the post-test (p=0.04). However, CRP levels were not significantly changed (p=0.2066) (Table 1, second part). At the post-test, the intervention group were less sedentary (477 min/day, SD=104) than the control group (534 min/day, SD=95) and had a higher degree of moderate- and vigorous intensity physical activity (48.5 min/day, SD=24.7) than the control group (32.6 min/day, SD=21.9). The control group did not significantly change their moderate- and vigorous intensity physical activity between the baseline and post-test (difference: 3.47 min/day, p=0.09), whereas the intervention group had a significant increase (12.9 min/day, p<0.001). This indicated a meaningful intervention program. In addition, the intervention group had a significant weight loss (1.68 kg, p<0.001), whereas the control group did not change body weight (p=0.73). When comparing the change from baseline to the post-test in suPAR levels for the intervention group versus the control group there was no significant change in the unadjusted model (β=-0.002, 95% CI=-0.219-0.215). Adjustment for age, time spent sedentary, and mean difference in CRP levels did not substantially change the findings (Table 2). Similar observations were made for the mean change in CRP levels; there was no significant difference between the intervention and the control group (β=0.785, 95% CI=-0.507-2.076) (Table 2).
9
Discussion To our knowledge, this is the first randomized-control trial investigating the effect of physical activity on suPAR levels. We found significantly increased suPAR and CRP levels after 5 months of physical activity intervention but with a similar increase in suPAR levels for the control group. These findings are in discrepancy with earlier studies finding that exercise leads to a reduction in the levels of inflammatory markers such as CRP and IL-618, 19
. Our findings may reflect that suPAR levels are more related to underlying harmful inflammatory responses
related to diseases or disease development. Regarding the effect of lifestyle interventions on suPAR levels, only few studies have investigated the effect of exercise, and these studies have provided inconsistent results. Sanchis-Gomar et al.20 found that acute exercise such as a professional football match did not change suPAR levels. In contrast, Niemelä et al.21 found augmented suPAR levels in runners participating in a marathon or half-marathon. These inconsistent findings might reflect that professional sport athletes do not respond with an inflammatory response to acute exercise, whereas less active individuals respond with an inflammatory response to extreme exercise. Instead, Mikkelsen et al.22 focused on life-long exercise, finding that life-long exercise was associated with lower levels of inflammatory markers, such as CRP and IL-6, but with no change in suPAR levels. Overall, it may seem that increases in suPAR levels may be anticipated after extreme exercise, but that regular exercise do not change 10
suPAR levels. This view is in agreement with the findings from this study, where the change in suPAR levels in the intervention group was not different from the control group after a short-term physical activity intervention. Whether longer-term exercise intervention may alter suPAR levels is rather unknown, but the findings from Mikkelsen et al.22 may suggest that suPAR levels are not changed after long-term exercise either. These data are in discrepancy with the finding of decreased CRP levels after exercise interventions18. Therefore, we are tempted to speculate that suPAR levels are more related to underlying harmful inflammatory responses associated with disease or development of disease3, 9. In contrast, CRP levels may be more predictive of overall inflammatory responses in the body, regardless of the seriousness of the underlying cause. As with any study, various limitations need to be considered. As expected, a proportion of the participants in the intervention group withdrew early, and the high dropout rate can limit the generalizability of our findings. Despite the randomized study design, unmeasured and unknown potential confounders, such as family history of inflammatory and cardiovascular disease and unhealthy lifestyle habits, may also have biased the findings. Unfortunately, we did not have access to such information. This is an important limitation, as other lifestyle factors such as unhealthy diet and alcohol consumption have been associated with increased suPAR levels11. Similarly, smoking and morbid obesity have also been found to be associated with increased suPAR levels11, thus corroborating with our study. However, due to randomization, these factors were not expected to affect the findings, as participants in both groups were generally similar regarding smoking status and anthropometric measures, such as body mass index and blood sample results. Notably, most participants were overweight (i.e., BMI >25) potentially indicating increased amounts of adipose tissue. In obesity, adipose tissue is an important source of inflammatory cytokines such as TNF- and IL-623, which may reflect low-grade inflammation and consequently increased suPAR levels. In addition, another limitation was the physical intervention program was rather modest, making it difficult to elucidate whether more intense exercise may alter suPAR levels.
11
Although the effect of exercise on suPAR levels is rather unclear regarding factors such as duration and intensity, further knowledge about other lifestyle interventions is clearly warranted.
Conclusion As the first randomized controlled trial investigating the effect of physical activity on suPAR levels, our findings of no change in suPAR levels for the physical activity intervention group compared to a control group indicate that suPAR levels may not be modulated by exercise. Instead, this may suggest that suPAR levels are more related to underlying harmful inflammatory responses associated with disease or disease development. However, more research is needed to see how suPAR levels in other population groups respond to physical activity.
Practical Implication
An exercise intervention do not seem to change suPAR levels.
suPAR levels might be a marker that reflect more harmful inflammatory responses associated with disease or disease development.
suPAR levels cannot be used as a marker for a successful exercise intervention program in contrast to other inflammatory markers, such as CRP, that might be affected by exercise.
12
Conflict of interest
The authors declare that they have not conflicts of interest.
Acknowledgements We thank Eirik Grindaker for his contribution to the data collection. We also thank our participants without whom this project would not have been possible. The project was financially supported by the Norwegian Extra Foundation for Health and Rehabilitation through EXTRA funds and the Norwegian School of Sports Sciences.
References 1.
2. 3.
4.
5.
6. 7. 8.
Persson M, Engstrom G, Bjorkbacka H, Hedblad B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmo Diet and Cancer Study. Atherosclerosis. 2012; 220(2):502-505. Nayak RK, Allingstrup M, Phanareth K, Kofoed-Enevoldsen A. suPAR as a biomarker for risk of readmission and mortality in the acute medical setting. Dan Med J. 2015; 62(10):A5146. Haupt TH, Petersen J, Ellekilde G, et al. Plasma suPAR levels are associated with mortality, admission time, and Charlson Comorbidity Index in the acutely admitted medical patient: a prospective observational study. Crit Care. 2012; 16(4):R130. Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F, Dano K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991; 266(3):1926-1933. Rijneveld AW, Levi M, Florquin S, Speelman P, Carmeliet P, van Der Poll T. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J Immunol. 2002; 168(7):3507-3511. Botha S, Fourie CM, Schutte R, Kruger A, Schutte AE. Associations of suPAR with lifestyle and cardiometabolic risk factors. Eur J Clin Invest. 2014; 44(7):619-626. Backes Y, van der Sluijs KF, Mackie DP, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012; 38(9):1418-1428. Nielsen J, Roge R, Pristed SG, et al. Soluble urokinase-type plasminogen activator receptor levels in patients with schizophrenia. Schizophrenia bulletin. 2015; 41(3):764-771. 13
9.
10. 11.
12.
13.
14. 15.
16. 17.
18.
19. 20.
21.
22.
23.
Kofoed K, Eugen-Olsen J, Petersen J, Larsen K, Andersen O. Predicting mortality in patients with systemic inflammatory response syndrome: an evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor. Eur J Clin Microbiol Infect Dis. 2008; 27(5):375-383. Eugen-Olsen J, Ladelund S, Sorensen LT. Plasma suPAR is lowered by smoking cessation: a randomized controlled study. Eur J Clin Invest. 2016; 46(4):305-311. Haupt TH, Kallemose T, Ladelund S, et al. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population. Biomark Insights. 2014; 9:91-100. Riste L, Khan F, Cruickshank K. High prevalence of type 2 diabetes in all ethnic groups, including Europeans, in a British inner city: relative poverty, history, inactivity, or 21st century Europe? Diabetes care. 2001; 24(8):1377-1383. Bhatnagar D, Anand IS, Durrington PN, et al. Coronary risk factors in people from the Indian subcontinent living in west London and their siblings in India. Lancet (London, England). 1995; 345(8947):405-409. Jenum AK, Holme I, Graff-Iversen S, Birkeland KI. Ethnicity and sex are strong determinants of diabetes in an urban Western society: implications for prevention. Diabetologia. 2005; 48(3):435-439. Andersen E, Hostmark AT, Holme I, Anderssen SA. Intervention effects on physical activity and insulin levels in men of Pakistani origin living in Oslo: a randomised controlled trial. Journal of immigrant and minority health. 2013; 15(1):101-110. Andersen E, Ekelund U, Anderssen SA. Effects of reducing sedentary time on glucose metabolism in immigrant Pakistani men. Medicine and science in sports and exercise. 2015; 47(4):775-781. Andersen E, Hostmark AT, Anderssen SA. Effect of a physical activity intervention on the metabolic syndrome in Pakistani immigrant men: a randomized controlled trial. Journal of immigrant and minority health. 2012; 14(5):738-746. Fedewa MV, Hathaway ED, Ward-Ritacco CL. Effect of exercise training on C-reactive protein: a systematic review and meta-analysis of randomised and non-randomised controlled trials. British journal of sports medicine. 2016. Hopps E, Canino B, Caimi G. Effects of exercise on inflammation markers in type 2 diabetic subjects. Acta diabetologica. 2011; 48(3):183-189. Sanchis-Gomar F, Bonaguri C, Pareja-Galeano H, et al. Effects of acute exercise and allopurinol administration on soluble urokinase plasminogen activator receptor (suPAR). Clinical laboratory. 2013; 59(1-2):207-210. Niemela M, Kangastupa P, Niemela O, Bloigu R, Juvonen T. Acute Changes in Inflammatory Biomarker Levels in Recreational Runners Participating in a Marathon or Half-Marathon. Sports medicine - open. 2016; 2(1):21. Mikkelsen UR, Couppe C, Karlsen A, et al. Life-long endurance exercise in humans: circulating levels of inflammatory markers and leg muscle size. Mechanisms of ageing and development. 2013; 134(11-12):531-540. Hill AA, Reid Bolus W, Hasty AH. A decade of progress in adipose tissue macrophage biology. Immunological reviews. 2014; 262(1):134-152.
14
Figure 1. Flowchart of Participants through the Trial.
15
Figures and Tables Table 1. Characteristics of the Intervention and Control Group at Baseline and Change in suPAR and CRP Levels between Baseline and the Post-test. Characteristics
Intervention group (n=89)
Control group (n=61)
p-value
35.8(6.1) 83.7 (12.0) 174.5 (6.3) 27.1 (3.2) 97.7 (8.8) 5.6 (0.6) 5.3 (0.8) 1.8 (1.4-2.4) 101 (53.2) 750.9 (607.5) 993.2 (296.8)
39.7 (9.2) 84.1 (14.4) 173.8 (6.2) 27.4 (4.2) 98.9 (11.8) 5.7 (0.7) 5.5 (1.2) 1.9 (1.4-2.9) 107 (61.8) 865.8 (553.2) 1017.2 (346.1)
0.0047 0.8804 0.5087 0.6425 0.5053 0.3465 0.3273 0.0164 0.5275 0.2456 0.6511
3688.8 (1348.2) 34.0 (5.2) 119.2 (11.2) 85.9 (9.1) 503.5 (100.5) 35.1 (19.5)
4057.5 (1369) 34.7 (6.5) 119.9 (10.8) 85.6 (10.1) 537.2 (94.6) 28.6 (19.5)
0.1076 0.5573 0.7072 0.8850 0.0446 0.0636
27.6 12.6 59.8
15.5 19.0 65.5
0.089 0.2986 0.4847
Baseline (SD) Post-test (SD) Difference (95 % CI)
2.63 (0.65) 2.80 (0.63) 0.17 (0.03 ; 0.31)
2.92 (0.80) 3.09 (0.94) 0.17 (0.01 ; 0.34)
0.033 0.046
Baseline (SD) Post-test (SD) Difference (95 % CI)
1.49 (2.46) 2.76 (4.95) 1.27 (0.36 ; 2.18)
1.43 (1.85) 1.91 (1.65) 0.48 (-0.28 ; 1.24)
0.893 0.278
Continuous variables (mean): Age, years (SD) Weight, kg (SD) Height, cm (SD) BMI (SD) Waist, cm (SD) HbA1c, mmol/l (SD) Fasting glucose, mmol/l (SD) Postprandial glucose, mmol/l (5-95 percentiles)a Fasting insulin, pmol/l (SD) Postprandial insulin, pmol/l (SD) Fasting C-peptide, pmol/l (SD) Postprandial C-peptide, pmol/l (SD) VO2-max, ml/kg/min (SD) Blood Pressure systolic, mm hg (SD) Blood Pressure diastolic, mm hg (SD) Inactivity time, min/day (SD) MVPAb, min/day (SD) Binomial (proportion) Smoker (%) Ex-smoker (%) Non-smoker (%) SuPAR levels
CRP levels
a
The variable was log transformered mass index, MVPA=Moderate- and vigorous intensity physical activity
b BMI=body
16
Table 2: Mean Change in SuPAR and CRP levels for the Intervention Group Compared to the Change in SuPAR and CRP levels in the Control Group. Coefficient (95% CI)
P Value
Unadjusted Adjusted for age and inactivity level Adjusted for difference in CRP
-0.002 (-0.219 : 0.215) -0.006 (-0.230 ; 0.218) 0.042 (-0.174 ; 0.257)
0.988 0.957 0.703
Unadjusted Adjusted for age and inactivity level
0.785 (-0.507 ; 2.076) 0.691 (-0.653 ; 2.036)
0.231 0.310
SuPAR
CRP
17
S1440-2440(17)30935-0 http://dx.doi.org/doi:10.1016/j.jsams.2017.06.018 JSAMS 1557
To appear in:
Journal of Science and Medicine in Sport
Received date: Revised date: Accepted date:
29-3-2017 19-6-2017 27-6-2017
Please cite this article as: Rohde Christopher, Polcwiartek Christoffer, Andersen Eivind, Vang Torkel, Nielsen Jimmi.Effect of a Physical Activity Intervention on suPAR Levels: A Randomized Controlled Trial.Journal of Science and Medicine in Sport http://dx.doi.org/10.1016/j.jsams.2017.06.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Words count: 2463 Abstract word count: 254 Tables: 2 Figures: 1
Effect of a Physical Activity Intervention on suPAR Levels: A Randomized Controlled Trial
Christopher Rohde1 Christoffer Polcwiartek2,3,4 Eivind Andersen, PhD5 Torkel Vang, MD, PhD2 Jimmi Nielsen, MD, DmSc1,2,3
1.
Mental Health Centre Glostrup, Copenhagen University Hospital, Copenhagen, Denmark
2.
Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
3.
Department of Psychiatry, Aalborg University Hospital, Aalborg, Denmark
4.
Department of Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark
5.
Faculty of Humanities, Sports and Educational Science, Department of Sports, Physical Education and Outdoor Studies, University College of Southeast Norway
Correspondence: Christopher Rohde, [email protected], (+45) 28 26 09 90, Copenhagen University Hospital, Mental Health Centre Glostrup, Kristineberg 3, KBH Ø, 2100, Denmark.
1
Abstract Objectives: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel inflammatory marker, associated with lifestyle diseases and mortality risk. No studies have investigated whether physical activity may reduce suPAR levels using a randomized controlled design. Design and Methods: suPAR and C-reactive protein (CRP) levels were determined in blood samples from a previous randomized controlled trial with Pakistani immigrants in Norway, 2008. The study included physically inactive men that were randomized to an intervention group (supervised group exercises) or a control group and followed for five months. A linear regression model was used and adjusted for age, inactivity level at baseline, and mean difference in CRP levels. Results: Overall, 80 and 53 participants were included in the intervention and control group, respectively. Obesity and smoking were associated with higher suPAR levels at baseline. The intervention group had a mean suPAR level of 2.65 (95% CI=2.48-2.78) ng/mL at baseline compared to 2.80 (95% CI=2.65-2.95) ng/mL at post-test, and thereby significantly increased suPAR levels after intervention (p=0.02). In the control group, mean suPAR level significantly increased from 2.93 (95% CI=2.68-3.16) ng/mL at baseline to 3.09 (95% CI=2.81-3.38) ng/mL at post-test (p=0.04). When comparing change from baseline to post-test in suPAR levels for the intervention group versus the control group, no significant change in the unadjusted model was found (β=-0.002, 95% CI=-0.219-0.215). Similar results were found for CRP levels. Conclusion: There was no change in suPAR levels after regular exercise compared to a control group implying that suPAR rather reflects underlying harmful inflammatory responses associated with disease development.
2
Key words: C-reactive protein; exercise; immunology; inflammatory; soluble urokinase-type plasminogen activator receptor.
Introduction Soluble urokinase-type plasminogen activator receptor (suPAR) is a physiologically stable inflammatory marker positively correlated with other inflammatory markers, such as leukocytosis, C-reactive protein (CRP), and tumor necrosis factor- (TNF-)1, but suPAR levels have been shown to predict mortality in acute medical patients2 and patients with a variety of diseases3 better than these other known inflammatory markers. Overall, suPAR levels reflect the inflammatory state of the body. suPAR is generated as a result of cleavage and release of urokinase-type plasminogen activator receptor (uPAR) from the cell membrane. uPAR is a protein found on the cell surface of various cells, such as endothelial cells, monocytes, neutrophils and activated T cells4, and is believed to be involved in processes such as cellular adhesion, migration, and focused proteolysis. Consequently, defective migration of inflammatory cells can increase the risk of infection implying that the mortality-predictive effect of suPAR levels may reflect underlying harmful inflammatory processes in the body5. Due to the possible mortality-predictive effect of suPAR levels, the measurement of suPAR levels has received great interest in a variety of diseases. For instance, it has been suggested that suPAR levels may predict cardiovascular diseases6, have prognostic value in patients with sepsis7, are correlated with high Charlson comorbidity score and long-term admission3, and reflect low-grade inflammation in schizophrenia8. suPAR levels between 6-10 ng/mL indicate an increased risk of cancer, diabetes, and all-cause mortality, whereas levels above 10 ng/mL are correlated with current critical illness9. Other studies have investigated whether suPAR levels can be modulated by lifestyle interventions, and consequently reduce risk of disease development. Here, it has been shown that smoking cessation decrease suPAR levels to levels equal to
3
non-smokers, indicating a meaningful reduction in risk of disease10. In addition, suPAR levels have been shown to be influenced by unhealthy diet and sedentary lifestyle11. Overall, this suggests that the risk of disease can be monitored by suPAR levels, and that suPAR levels may assist in identifying those, who may benefit the most from lifestyle interventions. However, as only few studies have investigated whether physical activity may reduce suPAR levels, and none have used a randomized controlled design, it remains unknown whether physical activity can alter suPAR levels. We therefore analyzed this by using data from a randomized control trial with Pakistani immigrants in Norway, which is a group of individuals with high risk of developing type 2 diabetes and metabolic syndrome, probably due to unhealthy lifestyle patterns12-14. If suPAR levels are reduced by physical activity, it supports its use as a marker of the somatic health condition and would suggest that individuals with high suPAR levels may benefit from regular exercise and potentially reduce their risk of disease development.
4
Methods The present work is based on data from the Physical Activity and Minority Health study15, a randomized controlled trial conducted in Norway in 2008. Detailed descriptions of this study can be found elsewhere15-17. Therefore, in the following, we will only briefly explain the recruitment of the study population and the physical activity program. The Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services approved data for this study. Men living in Oslo, Norway, with a Pakistani background (either born in Pakistan or parents born in Pakistan) aged 25 to 60 years and not physically active on a regular basis (exercising at most twice per week at a moderate or higher intensity level for 30 min or more at a time, or were active commuters (e.g., cycling or walking to work on most days of the week)) were eligible for inclusion in this study. Participants were excluded if they were diagnosed with type 2 diabetes before randomization, had physical limitations making it difficult to participate, or were not able to speak Norwegian. The participants were recruited in September and October 2008 from six mosques and Muslim festivals in Oslo. A total of 182 participants were screened for participation, of which 32 participants were excluded leaving 150 participants for randomization (Figure 1). Written consent was obtained from every participant, and participants were then randomized to either a control or an intervention group. Each participant had a 60% chance of being allocated to the intervention group, as a randomization ratio of 60:40 was chosen. This ratio was allocated due to an anticipation of a high dropout rate in the intervention group. The participants were followed for five months, with 17 participants being lost to follow-up, leaving 133 participants for the follow-up test (i.e., 80 participants in the intervention group and 53 5
participants in the control group)15. The study was double blinded at first meaning that neither the participants nor the test personnel knew which group they were randomized to until the baseline test was performed. The participants randomized to the intervention group received supervised group exercises of moderate intensity (twice a week) with an exercise psychologist, one individual counseling session, group lectures (two sessions of two hours), written material, and a motivational telephone call. The supervised group exercise had the following structure: a 15 min warm-up, 40 min of floor ball and/or football plus some strength exercises and 5 min of cool down afterwards. The group lectures included topics such as harm of physical inactivity, activity examples, setting goals and making a physical activity plan. The individual counseling session had the primary goal to find activities that could be implemented in a normal week, with the sum of these enabling them to reach the physical activity recommendations. Five months after the randomization, participants were tested at the Norwegian School of Sports Sciences. The various parameters included have been described elsewhere15-17. After 12 hours of fasting, venous blood samples were drawn from an antecubital vein. The blood samples were mechanically agitated for 30 min, then aliquoted, separated, and centrifuged for 10 min at 2500 g, and this was done right after the blood was drawn and was subsequently stored at -80 degrees Celsius with no freeze-thaw cycle. Blood sample variables were determined at the Dr. V. Furst Laboratory for Clinical Chemistry, Oslo, Norway, using a Modular P Machine (Roche, Japan). suPAR levels were determined at Virogates, Birkerød, Denmark in November 2015. The assays used for the determining of suPAR were ELISA plates. It was carried out in singlets on the same plate. As both the baseline- and post-intervention blood suPAR levels were determined on the same plate, the difference found could not be explained by analytical variation. suPAR levels in the follow-up-test were determined in 72 participants in the intervention group and 45 participants in the control group, meaning that we were not able to measure levels in eight participants in the 6
intervention group and eight participants in the control group due to lack of blood. In these participants, CRP levels were also not measured. In addition, one participant in the intervention group and one participant in the control group were not able to have their CRP levels determined, leaving 71 participants in the intervention group and 44 participants in the control group. The mean and standard deviation (SD) were used to describe continuous variables and proportions to describe binomial data at baseline. Continuous baseline characteristics were compared using independent t-test, whereas binomial data were compared using risk difference. If data were not normally distributed, a log-transformation was made before the test was performed, and the variables were presented with 5th and 95th percentiles. The difference between suPAR and CRP levels at baseline and levels at the post-test were compared using a paired t-test. Assumptions were checked with Bland-Altman- and QQ-plots. The mean change in suPAR levels between the baseline- and the post-test for the intervention group were compared to the mean change in suPAR levels between baseline- and the post-test for the control group using a linear regression. The regression was first adjusted for age and inactivity level at baseline, as these variables were not equally distributed between the intervention and the control group. Afterwards, the regression was adjusted for the mean change in CRP levels, as suPAR and CRP are correlated. A similar regression comparing the mean change in CRP for the intervention group to the mean change in CRP for the control group was also performed.
7
Results Out of the 150 participants, 9 participants from the intervention group and 8 participants from the control group did not participate in the post-test (Figure 1). However, there were no differences between the dropouts and the subjects participating in the post-test on any of the variables included except a lower baseline physical activity level for the dropouts. The baseline characteristics for the intervention and control group are presented in table 1. The groups were significantly different on age, glucose levels (after two hours), and inactivity time in minutes per day. The mean age of the intervention group was 35.8 (SD=6.1) years compared to 39.7 (SD=9.2) years in control group (p=0.0047), and the intervention group were less sedentary at baseline (503.53 min/day, SD=100.4) than the control group (537.21 min/day, SD=94.6) (p=0.0446). Obesity and smoking were associated with higher suPAR levels at baseline. Obese participants, defined by a body mass index (BMI) above 25, had 0.33 ng/mL (95% CI=0.06-0.59, p=0.018) higher suPAR levels compared to participants with a BMI below 25. Adjustment for age and smoking status did not attenuate this association (β=0.34 ng/mL, 95% CI=0.08-0.59). suPAR levels in smokers were 0.57 ng/mL (95% CI=0.26-0.87, p<0.001) higher compared to non- or ex-smokers. Adjustment for age and BMI did not attenuate this association (β=0.61 ng/mL, 95% CI=0.32-0.90). 8
The intervention group had a mean suPAR level of 2.65 (95% CI=2.48-2.78) ng/mL at baseline compared to 2.80 (95% CI=2.65-2.95) ng/mL at the post-test, and thereby significantly increased suPAR levels after intervention (p=0.02). A similar significant increase in CRP levels was found (mean difference=1.27, 95% CI=0.36-2.18). In the control group, mean suPAR level significantly increased from 2.93 (95% CI=2.68-3.16) ng/mL at baseline to 3.09 (95% CI=2.81-3.38) ng/mL at the post-test (p=0.04). However, CRP levels were not significantly changed (p=0.2066) (Table 1, second part). At the post-test, the intervention group were less sedentary (477 min/day, SD=104) than the control group (534 min/day, SD=95) and had a higher degree of moderate- and vigorous intensity physical activity (48.5 min/day, SD=24.7) than the control group (32.6 min/day, SD=21.9). The control group did not significantly change their moderate- and vigorous intensity physical activity between the baseline and post-test (difference: 3.47 min/day, p=0.09), whereas the intervention group had a significant increase (12.9 min/day, p<0.001). This indicated a meaningful intervention program. In addition, the intervention group had a significant weight loss (1.68 kg, p<0.001), whereas the control group did not change body weight (p=0.73). When comparing the change from baseline to the post-test in suPAR levels for the intervention group versus the control group there was no significant change in the unadjusted model (β=-0.002, 95% CI=-0.219-0.215). Adjustment for age, time spent sedentary, and mean difference in CRP levels did not substantially change the findings (Table 2). Similar observations were made for the mean change in CRP levels; there was no significant difference between the intervention and the control group (β=0.785, 95% CI=-0.507-2.076) (Table 2).
9
Discussion To our knowledge, this is the first randomized-control trial investigating the effect of physical activity on suPAR levels. We found significantly increased suPAR and CRP levels after 5 months of physical activity intervention but with a similar increase in suPAR levels for the control group. These findings are in discrepancy with earlier studies finding that exercise leads to a reduction in the levels of inflammatory markers such as CRP and IL-618, 19
. Our findings may reflect that suPAR levels are more related to underlying harmful inflammatory responses
related to diseases or disease development. Regarding the effect of lifestyle interventions on suPAR levels, only few studies have investigated the effect of exercise, and these studies have provided inconsistent results. Sanchis-Gomar et al.20 found that acute exercise such as a professional football match did not change suPAR levels. In contrast, Niemelä et al.21 found augmented suPAR levels in runners participating in a marathon or half-marathon. These inconsistent findings might reflect that professional sport athletes do not respond with an inflammatory response to acute exercise, whereas less active individuals respond with an inflammatory response to extreme exercise. Instead, Mikkelsen et al.22 focused on life-long exercise, finding that life-long exercise was associated with lower levels of inflammatory markers, such as CRP and IL-6, but with no change in suPAR levels. Overall, it may seem that increases in suPAR levels may be anticipated after extreme exercise, but that regular exercise do not change 10
suPAR levels. This view is in agreement with the findings from this study, where the change in suPAR levels in the intervention group was not different from the control group after a short-term physical activity intervention. Whether longer-term exercise intervention may alter suPAR levels is rather unknown, but the findings from Mikkelsen et al.22 may suggest that suPAR levels are not changed after long-term exercise either. These data are in discrepancy with the finding of decreased CRP levels after exercise interventions18. Therefore, we are tempted to speculate that suPAR levels are more related to underlying harmful inflammatory responses associated with disease or development of disease3, 9. In contrast, CRP levels may be more predictive of overall inflammatory responses in the body, regardless of the seriousness of the underlying cause. As with any study, various limitations need to be considered. As expected, a proportion of the participants in the intervention group withdrew early, and the high dropout rate can limit the generalizability of our findings. Despite the randomized study design, unmeasured and unknown potential confounders, such as family history of inflammatory and cardiovascular disease and unhealthy lifestyle habits, may also have biased the findings. Unfortunately, we did not have access to such information. This is an important limitation, as other lifestyle factors such as unhealthy diet and alcohol consumption have been associated with increased suPAR levels11. Similarly, smoking and morbid obesity have also been found to be associated with increased suPAR levels11, thus corroborating with our study. However, due to randomization, these factors were not expected to affect the findings, as participants in both groups were generally similar regarding smoking status and anthropometric measures, such as body mass index and blood sample results. Notably, most participants were overweight (i.e., BMI >25) potentially indicating increased amounts of adipose tissue. In obesity, adipose tissue is an important source of inflammatory cytokines such as TNF- and IL-623, which may reflect low-grade inflammation and consequently increased suPAR levels. In addition, another limitation was the physical intervention program was rather modest, making it difficult to elucidate whether more intense exercise may alter suPAR levels.
11
Although the effect of exercise on suPAR levels is rather unclear regarding factors such as duration and intensity, further knowledge about other lifestyle interventions is clearly warranted.
Conclusion As the first randomized controlled trial investigating the effect of physical activity on suPAR levels, our findings of no change in suPAR levels for the physical activity intervention group compared to a control group indicate that suPAR levels may not be modulated by exercise. Instead, this may suggest that suPAR levels are more related to underlying harmful inflammatory responses associated with disease or disease development. However, more research is needed to see how suPAR levels in other population groups respond to physical activity.
Practical Implication
An exercise intervention do not seem to change suPAR levels.
suPAR levels might be a marker that reflect more harmful inflammatory responses associated with disease or disease development.
suPAR levels cannot be used as a marker for a successful exercise intervention program in contrast to other inflammatory markers, such as CRP, that might be affected by exercise.
12
Conflict of interest
The authors declare that they have not conflicts of interest.
Acknowledgements We thank Eirik Grindaker for his contribution to the data collection. We also thank our participants without whom this project would not have been possible. The project was financially supported by the Norwegian Extra Foundation for Health and Rehabilitation through EXTRA funds and the Norwegian School of Sports Sciences.
References 1.
2. 3.
4.
5.
6. 7. 8.
Persson M, Engstrom G, Bjorkbacka H, Hedblad B. Soluble urokinase plasminogen activator receptor in plasma is associated with incidence of CVD. Results from the Malmo Diet and Cancer Study. Atherosclerosis. 2012; 220(2):502-505. Nayak RK, Allingstrup M, Phanareth K, Kofoed-Enevoldsen A. suPAR as a biomarker for risk of readmission and mortality in the acute medical setting. Dan Med J. 2015; 62(10):A5146. Haupt TH, Petersen J, Ellekilde G, et al. Plasma suPAR levels are associated with mortality, admission time, and Charlson Comorbidity Index in the acutely admitted medical patient: a prospective observational study. Crit Care. 2012; 16(4):R130. Ploug M, Ronne E, Behrendt N, Jensen AL, Blasi F, Dano K. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol. J Biol Chem. 1991; 266(3):1926-1933. Rijneveld AW, Levi M, Florquin S, Speelman P, Carmeliet P, van Der Poll T. Urokinase receptor is necessary for adequate host defense against pneumococcal pneumonia. J Immunol. 2002; 168(7):3507-3511. Botha S, Fourie CM, Schutte R, Kruger A, Schutte AE. Associations of suPAR with lifestyle and cardiometabolic risk factors. Eur J Clin Invest. 2014; 44(7):619-626. Backes Y, van der Sluijs KF, Mackie DP, et al. Usefulness of suPAR as a biological marker in patients with systemic inflammation or infection: a systematic review. Intensive Care Med. 2012; 38(9):1418-1428. Nielsen J, Roge R, Pristed SG, et al. Soluble urokinase-type plasminogen activator receptor levels in patients with schizophrenia. Schizophrenia bulletin. 2015; 41(3):764-771. 13
9.
10. 11.
12.
13.
14. 15.
16. 17.
18.
19. 20.
21.
22.
23.
Kofoed K, Eugen-Olsen J, Petersen J, Larsen K, Andersen O. Predicting mortality in patients with systemic inflammatory response syndrome: an evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor. Eur J Clin Microbiol Infect Dis. 2008; 27(5):375-383. Eugen-Olsen J, Ladelund S, Sorensen LT. Plasma suPAR is lowered by smoking cessation: a randomized controlled study. Eur J Clin Invest. 2016; 46(4):305-311. Haupt TH, Kallemose T, Ladelund S, et al. Risk factors associated with serum levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor in a general population. Biomark Insights. 2014; 9:91-100. Riste L, Khan F, Cruickshank K. High prevalence of type 2 diabetes in all ethnic groups, including Europeans, in a British inner city: relative poverty, history, inactivity, or 21st century Europe? Diabetes care. 2001; 24(8):1377-1383. Bhatnagar D, Anand IS, Durrington PN, et al. Coronary risk factors in people from the Indian subcontinent living in west London and their siblings in India. Lancet (London, England). 1995; 345(8947):405-409. Jenum AK, Holme I, Graff-Iversen S, Birkeland KI. Ethnicity and sex are strong determinants of diabetes in an urban Western society: implications for prevention. Diabetologia. 2005; 48(3):435-439. Andersen E, Hostmark AT, Holme I, Anderssen SA. Intervention effects on physical activity and insulin levels in men of Pakistani origin living in Oslo: a randomised controlled trial. Journal of immigrant and minority health. 2013; 15(1):101-110. Andersen E, Ekelund U, Anderssen SA. Effects of reducing sedentary time on glucose metabolism in immigrant Pakistani men. Medicine and science in sports and exercise. 2015; 47(4):775-781. Andersen E, Hostmark AT, Anderssen SA. Effect of a physical activity intervention on the metabolic syndrome in Pakistani immigrant men: a randomized controlled trial. Journal of immigrant and minority health. 2012; 14(5):738-746. Fedewa MV, Hathaway ED, Ward-Ritacco CL. Effect of exercise training on C-reactive protein: a systematic review and meta-analysis of randomised and non-randomised controlled trials. British journal of sports medicine. 2016. Hopps E, Canino B, Caimi G. Effects of exercise on inflammation markers in type 2 diabetic subjects. Acta diabetologica. 2011; 48(3):183-189. Sanchis-Gomar F, Bonaguri C, Pareja-Galeano H, et al. Effects of acute exercise and allopurinol administration on soluble urokinase plasminogen activator receptor (suPAR). Clinical laboratory. 2013; 59(1-2):207-210. Niemela M, Kangastupa P, Niemela O, Bloigu R, Juvonen T. Acute Changes in Inflammatory Biomarker Levels in Recreational Runners Participating in a Marathon or Half-Marathon. Sports medicine - open. 2016; 2(1):21. Mikkelsen UR, Couppe C, Karlsen A, et al. Life-long endurance exercise in humans: circulating levels of inflammatory markers and leg muscle size. Mechanisms of ageing and development. 2013; 134(11-12):531-540. Hill AA, Reid Bolus W, Hasty AH. A decade of progress in adipose tissue macrophage biology. Immunological reviews. 2014; 262(1):134-152.
14
Figure 1. Flowchart of Participants through the Trial.
15
Figures and Tables Table 1. Characteristics of the Intervention and Control Group at Baseline and Change in suPAR and CRP Levels between Baseline and the Post-test. Characteristics
Intervention group (n=89)
Control group (n=61)
p-value
35.8(6.1) 83.7 (12.0) 174.5 (6.3) 27.1 (3.2) 97.7 (8.8) 5.6 (0.6) 5.3 (0.8) 1.8 (1.4-2.4) 101 (53.2) 750.9 (607.5) 993.2 (296.8)
39.7 (9.2) 84.1 (14.4) 173.8 (6.2) 27.4 (4.2) 98.9 (11.8) 5.7 (0.7) 5.5 (1.2) 1.9 (1.4-2.9) 107 (61.8) 865.8 (553.2) 1017.2 (346.1)
0.0047 0.8804 0.5087 0.6425 0.5053 0.3465 0.3273 0.0164 0.5275 0.2456 0.6511
3688.8 (1348.2) 34.0 (5.2) 119.2 (11.2) 85.9 (9.1) 503.5 (100.5) 35.1 (19.5)
4057.5 (1369) 34.7 (6.5) 119.9 (10.8) 85.6 (10.1) 537.2 (94.6) 28.6 (19.5)
0.1076 0.5573 0.7072 0.8850 0.0446 0.0636
27.6 12.6 59.8
15.5 19.0 65.5
0.089 0.2986 0.4847
Baseline (SD) Post-test (SD) Difference (95 % CI)
2.63 (0.65) 2.80 (0.63) 0.17 (0.03 ; 0.31)
2.92 (0.80) 3.09 (0.94) 0.17 (0.01 ; 0.34)
0.033 0.046
Baseline (SD) Post-test (SD) Difference (95 % CI)
1.49 (2.46) 2.76 (4.95) 1.27 (0.36 ; 2.18)
1.43 (1.85) 1.91 (1.65) 0.48 (-0.28 ; 1.24)
0.893 0.278
Continuous variables (mean): Age, years (SD) Weight, kg (SD) Height, cm (SD) BMI (SD) Waist, cm (SD) HbA1c, mmol/l (SD) Fasting glucose, mmol/l (SD) Postprandial glucose, mmol/l (5-95 percentiles)a Fasting insulin, pmol/l (SD) Postprandial insulin, pmol/l (SD) Fasting C-peptide, pmol/l (SD) Postprandial C-peptide, pmol/l (SD) VO2-max, ml/kg/min (SD) Blood Pressure systolic, mm hg (SD) Blood Pressure diastolic, mm hg (SD) Inactivity time, min/day (SD) MVPAb, min/day (SD) Binomial (proportion) Smoker (%) Ex-smoker (%) Non-smoker (%) SuPAR levels
CRP levels
a
The variable was log transformered mass index, MVPA=Moderate- and vigorous intensity physical activity
b BMI=body
16
Table 2: Mean Change in SuPAR and CRP levels for the Intervention Group Compared to the Change in SuPAR and CRP levels in the Control Group. Coefficient (95% CI)
P Value
Unadjusted Adjusted for age and inactivity level Adjusted for difference in CRP
-0.002 (-0.219 : 0.215) -0.006 (-0.230 ; 0.218) 0.042 (-0.174 ; 0.257)
0.988 0.957 0.703
Unadjusted Adjusted for age and inactivity level
0.785 (-0.507 ; 2.076) 0.691 (-0.653 ; 2.036)
0.231 0.310
SuPAR
CRP
17