Effects of electrical stimulation of the lower extremities on postprandial hyperglycemia and arterial stiffness
Article information
Abstract
[Purpose]
To compare the acute effects of electrical stimulation (ES) of the lower extremities on postprandial hyperglycemia and arterial stiffness during oral glucose tolerance testing (OGTT).
[Methods]
In a randomized crossover study, eight healthy young men completed three experimental trials in which they underwent ES for 30 min, starting 60 min before (Before) or 30 min after (After) ingesting 75 g of glucose; ES was not performed in the control trial (Control). The subjects’ blood glucose levels and brachial-ankle pulse wave velocity (baPWV) were measured as an index of arterial stiffness at baseline and 30, 60, and 120 min after glucose ingestion. Serum insulin levels were measured at baseline and 60 min after glucose ingestion.
[Results]
The subjects’ glucose intake led to an increase in their blood glucose concentration in all trials, however, in the After trial, ES resulted in significantly lower blood glucose concentrations at 60 min post glucose ingestion compared to the Control and Before trials. The area under the curve (AUC) of serum insulin concentrations during the OGTT in the After trial was significantly lower than that in the other two trials. Moreover, glucose ingestion did not increase the baPWV, however, 30 min of ES during the postprandial state acutely reduced the baPWV.
[Conclusion]
These results suggest that ES is most effective in reducing postprandial hyperglycemia when administered after a meal. Thus, lower extremity ES may be an alternative exercise method to activate postprandial glucose metabolism in healthy individuals.
INTRODUCTION
Postprandial hyperglycemia and greater postprandial glycemic variability may increase the risk of developing cardiometabolic disorders, not only in individuals with diabetes but also in healthy individuals [1]. Arterial stiffness increases after the consumption of meals, and to prevent cardiovascular diseases, it is desirable to control the postprandial increase in arterial stiffness. A close correlation between blood glucose concentration and systemic arterial stiffness was demonstrated after glucose ingestion [2], suggesting that postprandial hyperglycemia could potentially be linked to an increase in postprandial arterial stiffness.
It is well known that acute exercise has been shown to be effective in controlling postprandial hyperglycemia [3-5]. Previous studies have reported that acute exercise before or after glucose ingestion suppresses the increase in postprandial arterial stiffness. A series of studies by Kobayashi et al. [6-8] reported that 30 min of aerobic exercise reduced the increase in postprandial arterial stiffness. However, it is important to acknowledge that individuals with exercise limitations may face challenges and that some work environments may not allow immediate exercise during employees’ lunch breaks. Alternative exercise methods may be worth considering as a means of controlling postprandial hyperglycemia and arterial stiffness.
Electrical stimulation (ES) of the skeletal muscle has been used as an alternative exercise method, especially in medical athletic training and rehabilitation [9,10]. Since ES of the skeletal muscles can induce involuntary muscle contraction, exercise-like effects can be achieved with less effort than with actual exercise. Previous studies have demonstrated that ES exerts a hypoglycemic effect [11,12]. Studies in rodents and humans have shown that ES increases the translocation [13] and protein expression [14] of the glucose transporter GLUT4. Postprandial arterial stiffness is closely related to postprandial blood glucose concentration. However, it is uncertain whether ES reduces postprandial arterial stiffness by lowering the blood glucose concentration. Based on these reports, it has been hypothesized that ES may reduce postprandial arterial stiffness by lowering blood glucose concentration. In contrast to exercise, the effects of ES on postprandial hyperglycemia and arterial stiffness have not been examined. Furthermore, the optimal timing for ES, whether before or after a meal, remains unclear.
We conducted the present study to determine whether ES improves postprandial increase in arterial stiffness and reduces blood glucose concentrations. We also examined the optimal ES timing to suppress postprandial hyperglycemia and arterial stiffness.
METHODS
Subjects
Eight healthy young males participated in the study. All participants were nonsmokers, normotensive (<140/90 mmHg), asymptomatic, and had no history of overt chronic diseases (Table 1). All participants were fully informed of the experimental procedures and purpose of the study before providing their written informed consent. This study was approved by the Ethics Committee of Tokushima University (ref. #: 2023-289) and conducted in accordance with the latest version of the Declaration of Helsinki.
Participants characteristics.
Study design
Each subject completed three trials in random order: no ES (Control), ES for 30 min starting 60 min before (Before), and 30 min after (After) ingestion of 75 g glucose orally. After each trial, each participant underwent a ≥1 week washout period. For the oral glucose tolerance test (OGTT), each subject consumed a beverage, i.e., Trelan®-G75 (Ajinomoto Pharmaceutical Co., Tokyo), which provided 75 g of glucose. They abstained from caffeine and alcohol for 24 h before each trial and were reported to the laboratory after an overnight (10–12 h) fast. They rested for 20 min in the supine position, and their blood glucose, serum insulin levels, and arterial stiffness were measured at baseline and 30, 60, and 120 min after the 75 g oral glucose intake (Figure 1). All measurements were carried out at a constant room temperature between 22 °C– 24 °C in a quiet room.
The experimental protocol. Eight subjects completed three trials in random order: no electrical stimulation (Control), electrical stimulation for 30 min starting at 60 min before (Before) and at 30 min after (After) a 75-g oral glucose ingestion. All subjects ingested 75 g of glucose at 0 min. Baseline measurements for the Before trial were taken at −60 min to avoid the effect of the electrical stimulation (ES). baPWV: brachial to ankle pulse wave velocity.
Electrical stimulation (ES)
ES was applied to the calf and thigh muscles using a belt electrode skeletal muscle electrical stimulator (G-TES; Homer Ion, Tokyo, Japan). One silicon-rubber electrode band (5.3×93.3 cm) was wrapped around the lumbar region, two bands (5.3×69.6 cm) were wrapped around both distal parts of the thighs, and two bands (5.3×54.6 cm) were applied to both ankles. ES was performed at a frequency of 4 Hz, pulse width of 250 μs, and exponentially increasing waves with a stimulation intensity at the individual maximum tolerance [15]. A frequency of 4 Hz was used in the present study as high frequency ES can easily lead to tonic contraction and fatigue [16]. The 4 Hz frequency also promotes peripheral circulation, similar to aerobic exercise [17]. As the stimulation cycles of the bilateral thighs and lower legs were synchronized, the bilateral lower extremity muscles were simultaneously stimulated.
Body composition
The body composition of the subjects was measured using bioelectric impedance (RD-803L Body Composition Meter, Tanita Corp., Tokyo, Japan). Their body weight was measured once to the nearest 0.1 kg and their height was measured once to the nearest 0.1 cm with the use of a wall-mounted stadiometer. Body mass index (BMI) was calculated by dividing the weight (kg) by the square of the height (m).
Blood pressure and heart rate
Systolic and diastolic blood pressure (SBP and DBP, respectively) and heart rate (HR) were measured in the supine position using a noninvasive and automatic vascular profiling system (form PWV/ABI, Colin Medical Technology, Komaki, Japan).
Arterial stiffness
The measurement of brachial-ankle pulse wave velocity (baPWV) is a simple method for evaluating systemic arterial stiffness. The baPWV can be measured automatically with separate cuffs for each of the four limbs using an oscillometric pressure-sensor method (form PWV/ABI; Colin Medical Technology) as described in our previous study [18].
Electrocardiography, bilateral brachial and ankle blood pressures, and pulse waves were measured simultaneously. The bilateral brachial and post-tibial arterial pressure waveforms were stored for 10 s, with each cuff connected to an oscillometric pressure sensor wrapped around the subject’s upper arms and ankles. Pulse wave velocity was calculated from the arterial length (estimated from the subject’s height) divided by the measured transit time. The baPWV was calculated as the distance divided by the transit time and expressed in m/s. All subjects underwent two or three measurements and the mean values of the right and left baPWVs were used for analysis.
Blood glucose and serum insulin concentrations
For measuring each subject’s blood glucose concentration, capillary blood was sampled from a puncture (Medisafe® Finetouch Pro; Terumo Corp., Tokyo) on a warmed finger. Following the initial appearance of blood on the subject’s fingertip, the surface was cleaned with a sterile cotton swab, and the blood sample was then collected and analyzed for the presence of glucose (Medisafe® FIT; Terumo Corporation, Tokyo).
For serum insulin concentration measurements, an additional blood sample was collected in capillary blood tubes (MBS capillary; Micro Blood Science, Tokyo) containing lithium heparin at baseline and 60 min after the subject’s glucose ingestion. The tubes were then centrifuged for 10 min at 3,000 rpm. The serum was extracted from the capillary blood tubes and frozen at -80 °C for analysis. Serum insulin concentrations were determined using a commercial enzyme-linked immunosorbent assay (ELISA) kit for human insulin (Mercodia Insulin ELISA, Uppsala, Sweden).
Statistical analysis
Results are expressed as mean ± standard error (SE). The area under the curve (AUC) for blood glucose and serum insulin concentrations were calculated as the sum of the trapezoidal areas separated by each measurement time point. Time series data were analyzed using a two-way (time × trial) analysis of variance (ANOVA), followed by the Bonferroni post-hoc test. One-way ANOVA with the Bonferroni post-hoc test was used for AUC data analysis. Differences (two-tailed) were considered statistically significant at p < 0.05. All statistical analyses were conducted using the GraphPad Prism 8 software (GraphPad, La Jolla, CA, USA).
RESULTS
Subjects’ characteristics
The baseline characteristics of the eight subjects are summarized in Table 1. Blood glucose levels, serum insulin concentrations, and homeostatic model assessment of insulin resistance (HOMA-IR), an index of insulin resistance, were within normal ranges, confirming the absence of abnormal glucose metabolism.
Blood glucose concentrations
Changes in the subjects’ blood glucose concentrations and AUC are shown in Figure 2. There were no significant differences in blood glucose concentrations at baseline among the three trials. In all trials, the subjects blood glucose concentrations significantly increased 30 min after ingestion of glucose compared to baseline concentrations. Approximately, 60 min post-glucose ingestion, the participants’ blood glucose concentrations were significantly lower in the After trial than the Before trial. The AUC for blood glucose concentration in the After trial was significantly lower than that in the Before trial.
The blood glucose concentration response curve and its area under the curve (AUC) during the OGTT. Data are mean ± SE. cc, bb, and aa show the significant differences compared to the corresponding baseline values in the Control, Before, and After trials, respectively (p<0.01). *p<0.05 vs. both the Control and Before trials at 60 min in the After trial. #p<0.05 between the Before and After trials.
Serum insulin concentrations
Changes in the subjects’ serum insulin concentrations and AUC are shown in Figure 3. There were no significant differences in serum insulin concentrations at baseline among the Control, Before and After trials. The serum insulin concentrations at 60 min post glucose ingestion in the Before trial were significantly higher compared to those at baseline, and the serum insulin concentrations in the After trial at 60 min were significantly lower than those in the Before trial. The AUC of the subjects serum insulin concentrations in the After trial was significantly lower than that in the Control and Before trials.
Changes in the eight subjects’ serum insulin concentrations from baseline to 60 min and their AUC. Data are mean ± SE. bbA significant difference compared to the baseline values in the Before trial (p<0.01). †p<0.05 vs. the Before trial at 60 min in the After trial. #p<0.05 between trials.
The baPWV
Changes in the baPWV values of the subjects during the 75 g OGTT are shown in Figure 4. However, ingestion of glucose did not significantly increase the baPWV at 30 min, although there was a significant interaction (time × trial) between the changes in arterial stiffness. The baPWV values 60 min in the After trial were significantly lower than those at both baseline and at 30 min. In addition, the baPWV values at 60 min in the After trial were significantly lower than those at 60 min in the other two trials.
The baPWV response curve during the OGTT. Data are mean ± SE. aa, AA: A significant difference compared to both the baseline and 30-min values, respectively, in the After trial (p<0.01). *p<0.05 vs. both the Control and Before trials at 60 min in the After trial. #p<0.05 between trials.
Blood pressure and heart rate values
Changes in both brachial and ankle blood pressures and heart rates in the three trials are described in Table 2. All baseline data showed no significant differences among the trials, and these data were not altered by the OGTT, ES, or a combination of OGTT and ES.
Changes in both brachial and ankle blood pressures and heart rate.
DISCUSSION
In the present study, we focused on ES as an alternative to exercise and examined the effects of acute ES on postprandial blood glucose levels and arterial stiffness after glucose ingestion. We also examined the optimal timing of ES (before and after glucose ingestion), as the effects of exercise on postprandial hyperglycemia have focused on the timing of its stimulation [6,19-23]. Our results demonstrated that 30 min of ES, starting 30 min after the ingestion of glucose, rapidly improved postprandial hyperglycemia in healthy subjects induced during the OGTT. Thus, ES may be effective in suppressing postprandial hyperglycemia in individuals who are unable to exercise promptly after meals or face exercise restrictions. We speculate that since exercise has been shown to be effective when performed earlier (15 minutes after a meal) [22], it is possible that a greater effect may be obtained with ES if performed promptly after a meal.
In all three trials (Control, Before, and After), the subjects’ ingestion of glucose resulted in peak blood glucose concentrations at 30 min, which was followed by a gradual decrease (Figure 2). A rapid decrease in blood glucose concentration was observed in the After trial from 30 to 60 min after blood glucose concentrations peaked. However, in the Before trial, in which ES was administered for 30 min before glucose ingestion, the suppressive effect on postprandial hyperglycemia was not confirmed. Thus, the results of the present study demonstrated that the most effective timing for ES to suppress postprandial hyperglycemia is after a meal. ES stimulus duration is considered an important factor, as is the timing of the ES implementation. Previous research has shown that the hypoglycemic effect after 20 min of ES was maintained for 90 min after the cessation of ES [12]. The 30 min duration of the ES stimulus in the present study is sufficient to enhance the hypoglycemic effect during the OGTT. However, investigate whether a longer ES stimulus duration can further enhance the hypoglycemic effect.
These results are consistent with those of earlier investigations with respect to the effects of exercise on postprandial hyperglycemia [21,22]. Two studies revealed that engaging in walking exercise before a meal had no effect on postprandial hyperglycemia, however performing walking exercise after a meal did have an effect. It has also been reported that the earlier postprandial exercise is performed, the greater the effect of postprandial hyperglycemia suppression. In the present study, although the timing of ES before and after glucose ingestion was set according to previous studies [6,23], we suspect that it may be possible to effectively control postprandial hyperglycemia by performing ES earlier after a meal.
Our experiment revealed that ES applied after the subjects ingested glucose significantly reduced not only their blood glucose concentrations, but also their serum insulin concentrations (Figure 3). Insulin, an important hormone secreted by the pancreas, lowers blood glucose levels. It is likely that the postprandial ES used in the present study enhanced insulin sensitivity in the skeletal muscles since the subjects’ blood glucose concentrations reduced with lower serum insulin concentrations in the After trial. However, the subjects’ serum insulin levels were measured only at baseline and 60 min after glucose ingestion. Thus, it is not clear whether ES reduced or inhibited the elevated insulin concentration. Sacchetti et al. [24] reported, as we also did, that exercise started 40 min after the consumption of a meal reduced blood glucose and serum insulin concentrations. In their study, participants’ serum insulin concentrations increased progressively until 30 min after having their meal and decreased quickly after the initiation of exercise. Thus, we suspect that in the present study, the application of postprandial ES also rapidly decreased serum insulin concentrations, which had increased due to the ingestion of glucose.
Glucose transport in skeletal muscle is facilitated by GLUT4. This process can be stimulated by exercise (skeletal muscle contraction) or insulin, mainly by inducing the translocation of GLUT4 from the storage vesicles to the plasma membrane [25]. Roy et al. [13] demonstrated that 20 min of ES enhanced GLUT4 translocation in the rat skeletal muscle, which is consistent with previous research [25]. Furthermore, a study conducted by Chilibeck et al. [14] demonstrated that a combination of ES and cycle ergometer training, consisting of 30 min sessions, 3 days per week for 8 weeks, resulted in a 72% increase in GLUT4 protein expression in the human vastus lateralis muscle. However, it is important to consider that the present study only examined the acute effects of ES for 30 min, and it is possible that the observed improvement in insulin sensitivity was due to increased translocation of GLUT4 to the plasma membrane rather than increased GLUT4 protein expression.
We also observed that the baPWV of the participants did not increase by glucose ingestion in any trial (Figure 4). It has been reported that glucose ingestion increases leg (femoral-ankle) pulse wave velocity (PWV) and ankle blood pressure, however not aortic arterial stiffness or blood pres-sure [6]. Although baPWV reflects systemic arterial stiffness, it is influenced more by local arterial stiffness [26,27]. Thus, the slight local change in arterial stiffness in the present study may not have been detectable using baPWV. To validate the effects of ES on postprandial hyperglycemia-induced changes in arterial stiffness, it is necessary to differentiate and evaluate each locality rather than the baPWV, which reflects systemic arterial stiffness. This is one limitation of the present study.
In the After trial, the baPWV values at 60 min were significantly lower than the baseline values (Figure 4). In other words, 30 min of ES may rapidly decrease arterial stiffness. The baPWV values at 30 min after glucose ingestion in the After trial appeared to be higher than the baseline values, although not significantly. It can be inferred from our present findings that 30 min of ES may be an effective intervention tool for arterial stiffness when an individual’s blood glucose levels are elevated compared with resting levels. However, our subjects’ blood glucose concentrations in the Before trial at 30 min were not higher than those at baseline. This could be because ES was conducted beforehand, which may have prevented an increase in the PWV after glucose ingestion. As this is not discussed in the present study, further investigation is necessary.
The study only included young, healthy men, therefore, it is uncertain whether the same effects would be observed in older individuals or in those with chronic conditions such as diabetes. Although biochemical mechanisms, such as GLUT4 translocation, may contribute to how ES reduces postprandial hyperglycemia and serum insulin concentrations, the present study could not confirm this. Further research is necessary to verify the effects of ES training. One potential limitation of the present study is that it was not feasible to evaluate energy expenditure during ES and OGTT. However, previous studies reported no significant difference in energy expenditure between exercise and ES of the same duration [12].
Thus, we examined the potential of ES to reduce postprandial hyperglycemia and arterial stiffness and investigated the optimal timing of ES. The results demonstrated that ES of the lower extremities for 30 min after the ingestion of glucose was more effective in suppressing postprandial hyperglycemia than ES before ingestion. In addition, postprandial ES decreased serum insulin concentrations, suggesting that it may enhance insulin sensitivity in the skeletal muscle. For individuals with exercise restrictions and those who were unable to exercise immediately after a meal, 30 min of ES of the lower extremities may reduce the metabolic risk of the postprandial state. Our findings suggest that ES, as an alternative to exercise, may help reduce the risks associated with postprandial hyperglycemia, which is linked to future development of cardiovascular disease and diabetes. While the present study had a relatively small sample size, future studies exploring the effects of chronic ES training may contribute to reducing the risk of metabolic diseases in prediabetes and diabetes.