A randomized trial of exercise for blood pressure reduction in type 2 diabetes: Effect on flow-mediated dilation and circulating biomarkers of endothelial function
Introduction
Type 2 diabetes (T2DM) increases the risk of cardiovascular disease (CVD) 2–4-fold [1], [2]. In contrast, physical activity reduces CVD risk and has been recommended by the American Diabetes Association (ADA) as a treatment strategy for T2DM with the highest level of evidence [3]. Physical activity is believed to confer cardioprotection through improvements in traditional CVD risk factors, such as obesity, glycemic control, hypertension, and dyslipidemia [4]. Yet, risk factor improvements do not fully account for the reduction in mortality risk seen in observation studies, leading some researchers to suggest that this unexplained benefit may be attributable, in part, to a direct effect of exercise on vascular health [5], [6]. One theory is that the repetitive changes in shear stress associated with regular exercise provide the stimulus for beneficial vascular adaptations, most notably improved endothelial function [7]. Specifically, increased shear stress during exercise improves the bioavailability of nitric oxide, which is thought to increase the liberation of endothelial progenitor cells from the bone marrow which could help repair a damaged endothelium [8] and decrease oxidative stress and expression of atherogenic molecules (e.g. adhesion molecules) [9]. The endothelium is a key regulator of vascular homeostasis [10], and endothelial dysfunction is an independent predictor of cardiovascular events [11], is considered an early marker of atherosclerosis [12], and is common in T2DM [13].
Several methodologies are available to assess endothelial function [14]. Among them, endothelium-dependent flow-mediated dilation (FMD) describes the vasodilatory response of conduit and resistance vessels to hyperemic blood flow [15]. FMD predicts cardiovascular events [11] and generally improves with exercise training in populations with CVD risk factors or established CVD [16]. Biomarkers of endothelial origin circulating in the blood also reflect endothelial function. Adhesion molecules, including E-selectin, P-selectin, intracellular adhesion molecule 1 (ICAM), and vascular cell adhesion molecule 1 (VCAM), are expressed on the endothelium and leukocytes, and play a role in the recruitment of circulating inflammatory molecules during the initial phases of atherosclerosis. Higher serum levels of these markers are thought to reflect endothelial activation or damage [14], [17] and associate with CVD risk factors and events [17]. Tissue plasminogen activator (tPA), a molecule involved in fibrinolysis, is a later consequence of endothelial activation and higher serum levels are also linked to CVD outcomes [18].
Though exercise usually improves FMD in adults with pre-existing vascular dysfunction [19], fewer studies have investigated the effect of exercise on FMD or endothelial biomarkers in persons with T2DM [20], [21], [22], [23], [24], [25]. Further, since lower FMD and higher levels of endothelial biomarkers are associated with CVD risk factors that improve with exercise training (i.e. obesity, hypertension, glycemia, and hyperlipidemia), it is uncertain whether exercise-induced changes in FMD and endothelial biomarkers are due to concomitant changes in these CVD risk factors or as a direct effect of exercise.
We report ancillary outcomes from the clinical trial, Sugar, Hypertension, and Physical Exercise (SHAPE2) [26], which randomized participants with T2DM and milder forms of hypertension to either a 6-month exercise intervention or a control group with resting blood pressure (BP) as the primary outcome. The primary aim of the current investigation was to measure the effect of exercise training in this population on FMD and biomarkers of endothelial function. Our secondary aim was to describe associations of exercise-induced changes in FMD and endothelial biomarkers with changes in CVD risk factors.
Section snippets
Participants
Subjects were recruited primarily through newspaper advertisements from the greater Baltimore area. Sedentary participants, aged 40–65, with T2DM and with untreated pre or Stage I hypertension, or treated hypertension, were randomized to a supervised exercise program or a usual care control group. Pre or Stage I hypertension, as defined by the JNC VII Guidelines [27], was a systolic BP 120–159 mmHg or a diastolic BP 80–99 mmHg. Participants who were being treated for hypertension were also
Results
A total of 140 participants were randomized to either the exercise (n = 70) or the control (n = 70) condition. Of these, 80% (49 exercisers and 63 controls) completed the study, with 46 subjects having complete data for FMD (see Fig. 1). Participants who completed or did not complete the study were similar with respect to baseline variables, except that those who completed the study were more likely to be Caucasian (64% vs. 36%, p = 0.03) and male (62% vs. 38%, p = 0.03), have less body fat
Discussion
We found that 6-months of exercise training produced the expected training effect as evidenced by decreased BMI and body fat percentage, improved HbA1c, and improved VO2peak compared to controls in participants with T2DM and mild forms of hypertension. Nevertheless, we did not find a change in FMD or endothelial biomarkers. In further analysis, we found that improvements in CVD risk factors were associated with improvements in endothelial biomarkers among exercisers, suggesting that individual
Acknowledgments
This work was supported by grants from the National Heart Lung and Blood Institute (R21-HL095157, 12/01/2008 – 12/01/2010), the National Institute for Diabetes, Digestive, and Kidney Disorders (R01 DK062368-04, 02/02/04 – 12/31/10), and Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research.
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