Background
Type 2 diabetes (T2D) is one of the major risk factors for cardiovascular disease (CVD) [
1]. According to American Heart Association, CVD in older adults with T2D accounts for 84% of the deaths [
2]. Vascular endothelial dysfunction is related to elevated blood glucose level and insulin resistance and is a major cause in the pathological progression towards CVD [
3,
4]. Endothelial dysfunction is considered a precursor of atherosclerosis and CVD [
5] because the vascular endothelium plays an important physiological role in vascular homeostasis [
6]. In most clinical and physiological settings, the direct physiological or biochemical effects signaling within the endothelium are more associated with endothelial dysfunction than smooth muscle dysfunction per se [
7]. Vascular endothelial and smooth muscle cells release and respond to the internally generated substances including nitric oxide (NO) to regulate the vascular relaxation and tone [
8].
Regular physical activity has been recommended as an effective treatment together with medications and dietary control to improve vascular endothelial function (EF) in T2D. Skeletal muscle contraction during physical activity increases local blood flow and cardiac output, which results in increased shear stress on vascular endothelium and increased NO production [
9]. From a review of six previous studies, Way et al. [
10] concluded that exercise training did not result in a significant effect on EF in T2D , whereas Montero et al. [
11] observed that exercise training in four studies improved EF in T2D. There were mixed results, potentially in part, because of the small number of participants in which EF was evaluated by brachial artery FMD, the gold standard measure of EF [
12].
Therefore, the primary purpose of this study was to evaluate the effects of exercise training on EF measured by brachial artery FMD in adults with T2D by conducting a systematic review and meta-analysis. In doing this, we carefully examined the specifics of the exercise training regimens (such as intensity, modality, duration, and frequency of exercise) and the reported body mass index (BMI) in order to provide more evidence for designing exercise programs for T2D patients at risk of CVD.
Discussion
The primary results of this meta-analysis study are that exercise training significantly increased brachial artery FMD by 1.7% in T2D patients with an average age of 59, but there was no change in shear rate AUC, baseline diameter, and BMI.
Regular exercise-induced improvement in vascular EF measured by FMD can be attributed in large part to the increase in endothelium-derived NO production and bioavailability [
49]. NO is a major vasodilator, and plays an additional role in inhibiting atherosclerotic inflammatory process, oxidative stress [
49], and smooth muscle cell proliferation [
50]. In the current study, however, shear rate AUC remains unchanged after training, suggesting that medium- to long-term exercise training does not necessarily require altering only this physical stimulation for triggering FMD. Exercise also enhances antioxidant capacity by increased expression of the antioxidant enzymes and reduced nicotinamide adenine dinucleotide oxidase activity [
51], resulting in the increase in NO bioavailability [
52]. In addition to enhanced endothelial function, the improvement in vascular smooth muscle sensitivity to NO might play a partial role in increasing FMD through promoting vasodilation. T2D patients compared to healthy population may have lowered sensitivity to NO in vascular smooth muscle, and so pathways for vasodilation were degraded [
53] because elevated blood glucose can decrease a response of smooth muscle cells by increasing oxidative stress [
54]. However, previous human studies generally reported that exercise training does not result in effects on vascular smooth muscle sensitivity to NO [
55‐
57], and these results may be due to that almost all human studies used a single dose of vasodilator nitroglycerine for assessing vascular smooth muscle function without considering the effects of dose–response changes [
58] and that smooth muscle adaptation to exercise training might not be observed in vivo research [
59]. Further studies using the elaborate assessment of smooth muscle function in humans is required.
Subgroups with low to moderate intensity training increased FMD more than moderate to high intensity subgroups in our study. Since shear stress is a potent factor for NO release, one might expect that moderate to high intensity training would have caused greater change in FMD than low to moderate intensity due to a greater rise in cardiac output and peripheral blood flow. This unexpected result may also suggest that increased NO production and availability in T2D patients do not solely depend on an increase in flow and/or shear stress. On the other hand, shear rate is determined by diameter because shear rate is calculated as blood flow velocity divided by diameter according to Pyke and Tschakovsky [
60]. In our study, baseline brachial artery diameter remained unchanged after intervention, which may explain the reason why the amount of shear rate AUC change was insignificant even though blood flow velocity increased by exercise training. Therefore, there might have been a negligible difference in shear stress between low to moderate and moderate to high intensity training because variations of shear rate might be abated by unchanged diameter although high intensity training increased more blood flow velocity than low intensity training.
However, there is certainly a growing appreciation that the optimal exercise training program for many outcomes does not necessarily follow a dose–response relationship around the relative effort, and sometimes “more is not better” as once thought. There are also other factors to consider in the present set of studies measuring FMD in patients with diabetes. Firstly, the results we found may be due to that most subgroups with low to moderate intensity performed AE whereas most subgroups with moderate to high intensity did combination of AE and RE. Although there are few studies investigating effects of RE on EF comparing with AE in T2D patients, AE is more likely to improve EF than RE or combination AE and RE. Kwon et al. reported that AE significantly increased FMD in T2D patients but RE group also showed a tendency increasing FMD [
44]. In the meta-analysis study by Ashor et al., FMD in adults was increased more by AE than RE or combination of AE and RE, but the two latter groups also increased FMD significantly [
61]. RE has been considered increasing vascular stiffness because RE can induce endothelin-1 [
62], a potent vasoconstrictor. Also, frequently elevated blood pressure during RE may alter the arterial structure or arterial load-bearing properties [
63], which can attenuate the improvement in FMD by AE. However, Miyachi [
63] reported, in his meta-analysis study, that high-intensity RE results in a significant increase in arterial stiffness, but combined AE and RE can prevent arteries from stiffening by high-intensity RE. Secondly, another possible description for more favorable effects of low to moderate intensity training subgroups on EF than moderate to high intensity training subgroups is that most subgroups with moderate to high intensity conducted both AE and traditional RE using a few specific skeletal muscles at once, resulting in an increase in local blood flow, in contrast to AE promoting blood circulation in whole body. However, in the current study,
P value of the difference in effects between training with low to moderate intensity and moderate to high (
P = 0.007) is greater than the one between AE and combination of AE and RE (
P = 0.028), suggesting that training intensity may be more influential factor for improving vascular EF than training modality. Moreover, combination of AE and RE in our study mostly devotes more time on AE than RE. In particular, the combined exercise training subgroups have no high intensity RE (low: 40–50% of 1-RM [
44,
47] to moderate: 12-RM [
42,
46]) and moderate to high intensity AE (60% of HRmax [
45], 60–90% of HRmax [
47], 70–75% of HRR [
41,
42,
46]). Thus, we can speculate that the reason why moderate to high intensity subgroups mostly conducting combination of AE and RE showed less increase in FMD is not just due to inclusion of RE to AE. Our results could provide opposing views against the previous studies placing more weight on the high intensity of AE in order to improve EF, and ultimately can suggest the possibility of low to moderate training as a new alternative therapeutic strategy for T2D patients.
However, in order to determine whether low to moderate intensity training can be an alternative treatment for T2D patients, further studies are required. Because original studies had a small sample size and this current study evaluated some even smaller subgroups of the original studies. Of 7870 potential studies, only eight studies were included for our meta-analysis by narrowing inclusion criteria, which could increase a risk of both bias and extrapolation of the results. On the other hand, heterogeneity between studies decreased due to the small number of well conducted studies in this field. Thus, one of the main positive aspects of this study was to uncover poor evidence on this field and assume a critical position.
Meanwhile, our results show that there was no significant difference in the effect of training duration on FMD between eight and twelve or more weeks, which indicates that vascular EF in T2D patients could be improved by exercise training for a relatively short period of time. Also, we can speculate that overweight or obese (≥ 30 kg/m
2) T2D patients need to have different exercise prescription from normal weight patients (< 30 kg/m
2) because improvement of FMD in subgroups with low BMI levels (< 30 kg/m
2) was higher compared to in subgroups with high BMI levels (≥ 30 kg/m
2). Though each 10 kg decrease in body weight was correlated with 1.1% increase in fasting FMD [
64], our results suggest that FMD can be increased by exercise training without weight loss. In regard to training frequency, almost all trials performed 3 days per week so that we cannot further analysis.
Although AE may be currently the most effective exercise modality for improving EF, focusing largely on AE cannot be a recommended treatment for most T2D patients who have the risk of CVD. Recent studies reported that low skeletal muscle mass is associated with increase in arterial stiffness [
65,
66]. Ohara et al. [
67] also reported that thigh muscle cross-sectional area in 1470 older adults significantly and independently correlated with arterial stiffness measured by brachial pulse wave velocity. In particular, T2D patients should take into account that glucose uptake and glycogen storage predominantly occurred in skeletal muscle [
68]. Furthermore, considering two facts, (1) those aged 65 and older account for the largest proportion of total T2D patients [
69]; (2) muscle weakness starts at age 50 [
70] and more aggravates by age 65 [
71], it is certainly necessary for T2D patients, especially elderly to improve vascular function and increase muscular strength and mass together in order to not only reduce the risk of CVD but also improve glycemic control, their fundamental problems. Therefore, we believe that combination of AE and RE should be considered as more optimized strategy for most T2D patients rather than unitary exercise modality. Further studies need to be warranted to devise new modality of combined exercise, such as circuit training being consist of AE and RE or low intensity-high repetition RE with short rest times or active recovery to enhance oxygen utilization and muscle protein synthesis at the same time.
There are some limitations in our study. First, in the EX, those who have other intervention, such as ET receptor blockade, meditation, and hypoxic environment were included. Although these supplementary interventions did not make significant effects on FMD, it could cause bias. Second, the methods measuring FMD are somewhat different between research groups, which might influence on the results. Third, only one study [
42] was blinded for outcomes, diminishing the quality of studies. Fourth, there is the possibility of the Hawthorne effect influencing the results. However, there is not any control group in included studies which reported significant change in all outcomes although the control groups participated in a study but did not perform exercise training. Moreover, one of the inclusion criteria for eligible studies was training for at least 8 weeks, averagely 12 weeks which may be sufficient to induce certain physiological responses to exercise. Thus, we speculate that the Hawthorne effect might be trivial. Lastly, the number of studies included in our study may not be adequate, which could augment a risk of bias, however significant publication bias was not found in all variables.
We first investigated effects of exercise training on both vascular EF as well as shear rate AUC, baseline diameter, and BMI in T2D patients. The study design is valuable because on the basis of the finding, we can suggest low to moderate intensity training can be an alternative strategy for improving EF. Second, we performed meta-analysis based on studies targeting only T2D patients where EF is assessed by only brachial artery FMD, the major predictor for CVD and atherosclerosis, which importantly provides the validity of the results. Thus, we believe that this study extends our knowledge to provide an optimized therapeutic strategy to reduce the risk of CVD in T2D patients.